Synthesizing Partial Component-Level Behavior Models From System: Fill & Download for Free

I already gave the spiritual definition of life. It is too hard to express the life as a single sentence or a bunch of sentence it has its uniqueness on its own way.. so today I write what is life in biological way..Life is a characteristic that distinguishes physical entities that have biological processes, such as signaling and self-sustaining processes, from those that do not, either because such functions have ceased (they have died), or because they never had such functions and are classified as inanimate. Various forms of life exist, such as plants, animals, fungi, protists, archaea, and bacteria. The criteria can at times be ambiguous and may or may not define viruses, viroids, or potential synthetic life as "living". Biology is the science concerned with the study of life.LifePlants in the Rwenzori Mountains, UgandaScientific classificationDomains and SupergroupsLife on Earth:Non-cellular life[note 1] [note 2]Viruses[note 3]ViroidsCellular lifeDomain BacteriaDomain ArchaeaDomain EukaryaArchaeplastidaSARExcavataAmoebozoaOpisthokontaThere is currently no consensus regarding the definition of life. One popular definition is that organisms are open systems that maintain homeostasis, are composed of cells, have a life cycle, undergo metabolism, can grow, adapt to their environment, respond to stimuli, reproduce and evolve. However, several other definitions have been proposed, and there are some borderline cases of life, such as viruses or viroids.Abiogenesis attempts to describe the natural process of life arising from non-living matter, such as simple organic compounds. The prevailing scientific hypothesis is that the transition from non-living to living entities was not a single event, but a gradual process of increasing complexity. Life on Earth first appeared as early as 4.28 billion years ago, soon after ocean formation 4.41 billion years ago, and not long after the formation of the Earth 4.54 billion years ago.[1][2][3][4]The earliest known life forms are microfossils of bacteria.[5][6]Earth's current life may have descended from an RNA world, although RNA-based life may not have been the first. The mechanism by which life began on Earth is unknown, though many hypotheses have been formulated and are often based on the Miller–Urey experiment.Since its primordial beginnings, life on Earth has changed its environment on a geologic time scale, but it has also adapted to survive in most ecosystems and conditions. Some microorganisms, called extremophiles, thrive in physically or geochemically extreme environments that are detrimental to most other life on Earth. The cell is considered the structural and functional unit of life.[7]There are two kinds of cells, prokaryotic and eukaryotic, both of which consist of cytoplasm enclosed within a membrane and contain many biomolecules such as proteinsand nucleic acids. Cells reproduce through a process of cell division, in which the parent cell divides into two or more daughter cells.In the past, there have been many attempts to define what is meant by "life" through obsolete concepts such as odic force, hylomorphism, spontaneous generation and vitalism, that have now been disproved by biological discoveries. Aristotle was the first person to classify organisms. Later, Carl Linnaeus introduced his system of binomial nomenclature for the classification of species. Eventually new groups and categories of life were discovered, such as cells and microorganisms, forcing dramatic revisions of the structure of relationships between living organisms. Though currently only known on Earth, life need not be restricted to it, and many scientists speculate in the existence of extraterrestrial life. Artificial life is a computer simulation or man-made reconstruction of any aspect of life, which is often used to examine systems related to natural life.Death is the permanent termination of all biological functions which sustain an organism, and as such, is the end of its life. Extinction is the term describing the dying out of a group or taxon, usually a species. Fossilsare the preserved remains or traces of organisms.DefinitionsThe definition of life has long been a challenge for scientists and philosophers, with many varied definitions put forward.[8][9][10]This is partially because life is a process, not a substance.[11][12][13]This is complicated by a lack of knowledge of the characteristics of living entities, if any, that may have developed outside of Earth.[14][15]Philosophical definitions of life have also been put forward, with similar difficulties on how to distinguish living things from the non-living.[16]Legal definitions of life have also been described and debated, though these generally focus on the decision to declare a human dead, and the legal ramifications of this decision.[17]BiologySee also: OrganismThe characteristics of lifeSince there is no unequivocal definition of life, most current definitions in biology are descriptive. Life is considered a characteristic of something that preserves, furthers or reinforces its existence in the given environment. This characteristic exhibits all or most of the following traits:[10][18][19][20][21][22][23]Homeostasis: regulation of the internal environment to maintain a constant state; for example, sweating to reduce temperatureOrganization: being structurally composed of one or more cells – the basic units of lifeMetabolism: transformation of energy by converting chemicals and energy into cellular components (anabolism) and decomposing organic matter (catabolism). Living things require energy to maintain internal organization (homeostasis) and to produce the other phenomena associated with life.Growth: maintenance of a higher rate of anabolism than catabolism. A growing organism increases in size in all of its parts, rather than simply accumulating matter.Adaptation: the ability to change over time in response to the environment. This ability is fundamental to the process of evolution and is determined by the organism's heredity, diet, and external factors.Response to stimuli: a response can take many forms, from the contraction of a unicellular organism to external chemicals, to complex reactions involving all the senses of multicellular organisms. A response is often expressed by motion; for example, the leaves of a plant turning toward the sun (phototropism), and chemotaxis.Reproduction: the ability to produce new individual organisms, either asexually from a single parent organism or sexually from two parent organisms.These complex processes, called physiological functions, have underlying physical and chemical bases, as well as signaling and control mechanisms that are essential to maintaining life.Alternative definitionsSee also: Entropy and lifeFrom a physics perspective, living beings are thermodynamic systems with an organized molecular structure that can reproduce itself and evolve as survival dictates.[24][25]Thermodynamically, life has been described as an open system which makes use of gradients in its surroundings to create imperfect copies of itself.[26]Hence, life is a self-sustained chemical system capable of undergoing Darwinian evolution.[27][28]A major strength of this definition is that it distinguishes life by the evolutionary process rather than its chemical composition.[29]Others take a systemic viewpoint that does not necessarily depend on molecular chemistry. One systemic definition of life is that living things are self-organizing and autopoietic (self-producing). Variations of this definition include Stuart Kauffman's definition as an autonomous agent or a multi-agent system capable of reproducing itself or themselves, and of completing at least one thermodynamic work cycle.[30]This definition is extended by the apparition of novel functions over time.[31]VirusesMain article: VirusAdenovirus as seen under an electron microscopeWhether or not viruses should be considered as alive is controversial. They are most often considered as just replicators rather than forms of life.[32]They have been described as "organisms at the edge of life"[33]because they possess genes, evolve by natural selection,[34][35]and replicate by creating multiple copies of themselves through self-assembly. However, viruses do not metabolize and they require a host cell to make new products. Virus self-assembly within host cells has implications for the study of the origin of life, as it may support the hypothesis that life could have started as self-assembling organic molecules.[36][37][38]BiophysicsTo reflect the minimum phenomena required, other biological definitions of life have been proposed,[39]with many of these being based upon chemical systems. Biophysicists have commented that living things function on negative entropy.[40][41]In other words, living processes can be viewed as a delay of the spontaneous diffusion or dispersion of the internal energy of biological moleculestowards more potential microstates.[8]In more detail, according to physicists such as John Bernal, Erwin Schrödinger, Eugene Wigner, and John Avery, life is a member of the class of phenomena that are open or continuous systems able to decrease their internal entropy at the expense of substances or free energy taken in from the environment and subsequently rejected in a degraded form.[42][43]Living systems theoriesLiving systems are open self-organizing living things that interact with their environment. These systems are maintained by flows of information, energy, and matter.Some scientists have proposed in the last few decades that a general living systems theory is required to explain the nature of life.[44]Such a general theory would arise out of the ecological and biological sciences and attempt to map general principles for how all living systems work. Instead of examining phenomena by attempting to break things down into components, a general living systems theory explores phenomena in terms of dynamic patterns of the relationships of organisms with their environment.[45]Gaia hypothesisMain article: Gaia hypothesisThe idea that the Earth is alive is found in philosophy and religion, but the first scientific discussion of it was by the Scottish scientist James Hutton. In 1785, he stated that the Earth was a superorganism and that its proper study should be physiology. Hutton is considered the father of geology, but his idea of a living Earth was forgotten in the intense reductionism of the 19th century.[46]:10The Gaia hypothesis, proposed in the 1960s by scientist James Lovelock,[47][48]suggests that life on Earth functions as a single organism that defines and maintains environmentalconditions necessary for its survival.[46]This hypothesis served as one of the foundations of the modern Earth system science.NonfractionabilityThe first attempt at a general living systemstheory for explaining the nature of life was in 1978, by American biologist James Grier Miller.[49]Robert Rosen (1991) built on this by defining a system component as "a unit of organization; a part with a function, i.e., a definite relation between part and whole." From this and other starting concepts, he developed a "relational theory of systems" that attempts to explain the special properties of life. Specifically, he identified the "nonfractionability of components in an organism" as the fundamental difference between living systems and "biological machines."[50]Life as a property of ecosystemsA systems view of life treats environmental fluxes and biological fluxes together as a "reciprocity of influence,"[51]and a reciprocal relation with environment is arguably as important for understanding life as it is for understanding ecosystems. As Harold J. Morowitz (1992) explains it, life is a property of an ecological system rather than a single organism or species.[52]He argues that an ecosystemic definition of life is preferable to a strictly biochemical or physical one. Robert Ulanowicz (2009) highlights mutualism as the key to understand the systemic, order-generating behavior of life and ecosystems.[53]Complex systems biologyMain article: Complex systems biologySee also: Mathematical biologyComplex systems biology (CSB) is a field of science that studies the emergence of complexity in functional organisms from the viewpoint of dynamic systems theory.[54]The latter is also often called systems biology and aims to understand the most fundamental aspects of life. A closely related approach to CSB and systems biology called relational biology is concerned mainly with understanding life processes in terms of the most important relations, and categories of such relations among the essential functional components of organisms; for multicellular organisms, this has been defined as "categorical biology", or a model representation of organisms as a category theory of biological relations, as well as an algebraic topology of the functional organization of living organisms in terms of their dynamic, complex networks of metabolic, genetic, and epigenetic processes and signaling pathways.[55][56]Alternative but closely related approaches focus on the interdependance of constraints, where constraints can be either molecular, such as enzymes, or macroscopic, such as the geometry of a bone or of the vascular system.[57]Darwinian dynamicIt has also been argued that the evolution of order in living systems and certain physical systems obeys a common fundamental principle termed the Darwinian dynamic.[58][59]The Darwinian dynamic was formulated by first considering how macroscopic order is generated in a simple non-biological system far from thermodynamic equilibrium, and then extending consideration to short, replicating RNA molecules. The underlying order-generating process was concluded to be basically similar for both types of systems.[58]Operator theoryAnother systemic definition called the operator theory proposes that "life is a general term for the presence of the typical closures found in organisms; the typical closures are a membrane and an autocatalytic set in the cell"[60]and that an organism is any system with an organisation that complies with an operator type that is at least as complex as the cell.[61][62][63][64]Life can also be modeled as a network of inferior negative feedbacks of regulatory mechanisms subordinated to a superior positive feedback formed by the potential of expansion and reproduction.[65]History of studyMaterialismMain article: MaterialismPlant growth in the Hoh RainforestHerds of zebra and impala gathering on the Maasai MaraplainAn aerial photo of microbial mats around the Grand Prismatic Spring of Yellowstone National ParkSome of the earliest theories of life were materialist, holding that all that exists is matter, and that life is merely a complex form or arrangement of matter. Empedocles (430 BC) argued that everything in the universe is made up of a combination of four eternal "elements" or "roots of all": earth, water, air, and fire. All change is explained by the arrangement and rearrangement of these four elements. The various forms of life are caused by an appropriate mixture of elements.[66]Democritus (460 BC) thought that the essential characteristic of life is having a soul(psyche). Like other ancient writers, he was attempting to explain what makes something a living thing. His explanation was that fiery atoms make a soul in exactly the same way atoms and void account for any other thing. He elaborates on fire because of the apparent connection between life and heat, and because fire moves.[67]Plato's world of eternal and unchanging Forms, imperfectly represented in matter by a divine Artisan, contrasts sharply with the various mechanistic Weltanschauungen, of which atomism was, by the fourth century at least, the most prominent ... This debate persisted throughout the ancient world. Atomistic mechanism got a shot in the arm from Epicurus ... while the Stoics adopted a divine teleology ... The choice seems simple: either show how a structured, regular world could arise out of undirected processes, or inject intelligence into the system.[68]—R.J. Hankinson, Cause and Explanation in Ancient Greek ThoughtThe mechanistic materialism that originated in ancient Greece was revived and revised by the French philosopher René Descartes, who held that animals and humans were assemblages of parts that together functioned as a machine. In the 19th century, the advances in cell theory in biological science encouraged this view. The evolutionary theory of Charles Darwin (1859) is a mechanistic explanation for the origin of species by means of natural selection.[69]HylomorphismMain article: HylomorphismThe structure of the souls of plants, animals, and humans, according to AristotleHylomorphism is a theory first expressed by the Greek philosopher Aristotle (322 BC). The application of hylomorphism to biology was important to Aristotle, and biology is extensively covered in his extant writings. In this view, everything in the material universe has both matter and form, and the form of a living thing is its soul (Greek psyche, Latin anima). There are three kinds of souls: the vegetative soul of plants, which causes them to grow and decay and nourish themselves, but does not cause motion and sensation; the animal soul, which causes animals to move and feel; and the rational soul, which is the source of consciousness and reasoning, which (Aristotle believed) is found only in man.[70]Each higher soul has all of the attributes of the lower ones. Aristotle believed that while matter can exist without form, form cannot exist without matter, and that therefore the soul cannot exist without the body.[71]This account is consistent with teleologicalexplanations of life, which account for phenomena in terms of purpose or goal-directedness. Thus, the whiteness of the polar bear's coat is explained by its purpose of camouflage. The direction of causality (from the future to the past) is in contradiction with the scientific evidence for natural selection, which explains the consequence in terms of a prior cause. Biological features are explained not by looking at future optimal results, but by looking at the past evolutionary history of a species, which led to the natural selection of the features in question.[72]Spontaneous generationMain article: Spontaneous generationSpontaneous generation was the belief that living organisms can form without descent from similar organisms. Typically, the idea was that certain forms such as fleas could arise from inanimate matter such as dust or the supposed seasonal generation of mice and insects from mud or garbage.[73]The theory of spontaneous generation was proposed by Aristotle,[74]who compiled and expanded the work of prior natural philosophers and the various ancient explanations of the appearance of organisms; it held sway for two millennia. It was decisively dispelled by the experiments of Louis Pasteur in 1859, who expanded upon the investigations of predecessors such as Francesco Redi.[75][76]Disproof of the traditional ideas of spontaneous generation is no longer controversial among biologists.[77][78][79]VitalismMain article: VitalismVitalism is the belief that the life-principle is non-material. This originated with Georg Ernst Stahl (17th century), and remained popular until the middle of the 19th century. It appealed to philosophers such as Henri Bergson, Friedrich Nietzsche, and Wilhelm Dilthey,[80]anatomists like Marie François Xavier Bichat, and chemists like Justus von Liebig.[81]Vitalism included the idea that there was a fundamental difference between organic and inorganic material, and the belief that organic material can only be derived from living things. This was disproved in 1828, when Friedrich Wöhler prepared urea from inorganic materials.[82]This Wöhler synthesisis considered the starting point of modern organic chemistry. It is of historical significance because for the first time an organic compound was produced in inorganicreactions.[81]During the 1850s, Hermann von Helmholtz, anticipated by Julius Robert von Mayer, demonstrated that no energy is lost in muscle movement, suggesting that there were no "vital forces" necessary to move a muscle.[83]These results led to the abandonment of scientific interest in vitalistic theories, although the belief lingered on in pseudoscientific theories such as homeopathy, which interprets diseases and sickness as caused by disturbances in a hypothetical vital force or life force.[84]OriginThe age of the Earth is about 4.54 billion years.[85][86][87] Evidence suggests that life on Earth has existed for at least 3.5 billion years,[88][89][90][91][92][93][94][95][96] with the oldest physical traces of life dating back 3.7 billion years;[97][98][99] however, some theories, such as the Late Heavy Bombardment theory, suggest that life on Earth may have started even earlier, as early as 4.1–4.4 billion years ago,[88][89][90][91][92] and the chemistry leading to life may have begun shortly after the Big Bang, 13.8 billion years ago, during an epoch when the universe was only 10–17 million years old.[100][101][102]More than 99% of all species of life forms, amounting to over five billion species,[103] that ever lived on Earth are estimated to be extinct.[104][105]Although the number of Earth's catalogued species of lifeforms is between 1.2 million and 2 million,[106][107] the total number of species in the planet is uncertain. Estimates range from 8 million to 100 million,[106][107] with a more narrow range between 10 and 14 million,[106] but it may be as high as 1 trillion (with only one-thousandth of one percent of the species described) according to studies realized in May 2016.[108][109] The total number of related DNA base pairs on Earth is estimated at 5.0 x 1037 and weighs 50 billion tonnes.[110] In comparison, the total mass of the biosphere has been estimated to be as much as 4 TtC (trillion tons of carbon).[111] In July 2016, scientists reported identifying a set of 355 genes from the Last Universal Common Ancestor (LUCA) of all organisms living on Earth.[112]All known life forms share fundamental molecular mechanisms, reflecting their common descent; based on these observations, hypotheses on the origin of life attempt to find a mechanism explaining the formation of a universal common ancestor, from simple organic molecules via pre-cellular life to protocells and metabolism. Models have been divided into "genes-first" and "metabolism-first" categories, but a recent trend is the emergence of hybrid models that combine both categories.[113]There is no current scientific consensus as to how life originated. However, most accepted scientific models build on the Miller–Urey experiment and the work of Sidney Fox, which show that conditions on the primitive Earth favored chemical reactions that synthesize amino acids and other organic compounds from inorganic precursors,[114] and phospholipids spontaneously form lipid bilayers, the basic structure of a cell membrane.Living organisms synthesize proteins, which are polymers of amino acids using instructions encoded by deoxyribonucleic acid (DNA). Protein synthesis entails intermediary ribonucleic acid (RNA) polymers. One possibility for how life began is that genes originated first, followed by proteins;[115] the alternative being that proteins came first and then genes.[116]However, because genes and proteins are both required to produce the other, the problem of considering which came first is like that of the chicken or the egg. Most scientists have adopted the hypothesis that because of this, it is unlikely that genes and proteins arose independently.[117]Therefore, a possibility, first suggested by Francis Crick,[118] is that the first life was based on RNA,[117] which has the DNA-like properties of information storage and the catalytic properties of some proteins. This is called the RNA world hypothesis, and it is supported by the observation that many of the most critical components of cells (those that evolve the slowest) are composed mostly or entirely of RNA. Also, many critical cofactors (ATP, Acetyl-CoA, NADH, etc.) are either nucleotides or substances clearly related to them. The catalytic properties of RNA had not yet been demonstrated when the hypothesis was first proposed,[119] but they were confirmed by Thomas Cech in 1986.[120]One issue with the RNA world hypothesis is that synthesis of RNA from simple inorganic precursors is more difficult than for other organic molecules. One reason for this is that RNA precursors are very stable and react with each other very slowly under ambient conditions, and it has also been proposed that living organisms consisted of other molecules before RNA.[121] However, the successful synthesis of certain RNA molecules under the conditions that existed prior to life on Earth has been achieved by adding alternative precursors in a specified order with the precursor phosphate present throughout the reaction.[122] This study makes the RNA world hypothesis more plausible.[123]Geological findings in 2013 showed that reactive phosphorus species (like phosphite) were in abundance in the ocean before 3.5 Ga, and that Schreibersite easily reacts with aqueous glycerol to generate phosphite and glycerol 3-phosphate.[124] It is hypothesized that Schreibersite-containing meteorites from the Late Heavy Bombardment could have provided early reduced phosphorus, which could react with prebiotic organic molecules to form phosphorylated biomolecules, like RNA.[124]In 2009, experiments demonstrated Darwinian evolution of a two-component system of RNA enzymes (ribozymes) in vitro.[125] The work was performed in the laboratory of Gerald Joyce, who stated "This is the first example, outside of biology, of evolutionary adaptation in a molecular genetic system."[126]Prebiotic compounds may have originated extraterrestrially. NASA findings in 2011, based on studies with meteorites found on Earth, suggest DNA and RNA components (adenine, guanine and related organic molecules) may be formed in outer space.[127][128][129][130]In March 2015, NASA scientists reported that, for the first time, complex DNA and RNA organic compounds of life, including uracil, cytosine and thymine, have been formed in the laboratory under outer space conditions, using starting chemicals, such as pyrimidine, found in meteorites. Pyrimidine, like polycyclic aromatic hydrocarbons (PAHs), the most carbon-rich chemical found in the universe, may have been formed in red giants or in interstellar dust and gas clouds, according to the scientists.[131]According to the panspermia hypothesis, microscopic life—distributed by meteoroids, asteroids and other small Solar System bodies—may exist throughout the universe.[132]Environmental conditionsCyanobacteria dramatically changed the composition of life forms on Earth by leading to the near-extinction of oxygen-intolerant organisms.The diversity of life on Earth is a result of the dynamic interplay between genetic opportunity, metabolic capability, environmental challenges,[133] and symbiosis.[134][135][136] For most of its existence, Earth's habitable environment has been dominated by microorganisms and subjected to their metabolism and evolution. As a consequence of these microbial activities, the physical-chemical environment on Earth has been changing on a geologic time scale, thereby affecting the path of evolution of subsequent life.[133] For example, the release of molecular oxygen by cyanobacteria as a by-product of photosynthesis induced global changes in the Earth's environment. Because oxygen was toxic to most life on Earth at the time, this posed novel evolutionary challenges, and ultimately resulted in the formation of Earth's major animal and plant species. This interplay between organisms and their environment is an inherent feature of living systems.[133]BiosphereMain article: BiosphereThe biosphere is the global sum of all ecosystems. It can also be termed as the zone of life on Earth, a closed system (apart from solar and cosmic radiation and heat from the interior of the Earth), and largely self-regulating.[137] By the most general biophysiological definition, the biosphere is the global ecological system integrating all living beings and their relationships, including their interaction with the elements of the lithosphere, geosphere, hydrosphere, and atmosphere.Life forms live in every part of the Earth's biosphere, including soil, hot springs, inside rocks at least 19 km (12 mi) deep underground, the deepest parts of the ocean, and at least 64 km (40 mi) high in the atmosphere.[138][139][140] Under certain test conditions, life forms have been observed to thrive in the near-weightlessness of space[141][142] and to survive in the vacuum of outer space.[143][144] Life forms appear to thrive in the Mariana Trench, the deepest spot in the Earth's oceans.[145][146] Other researchers reported related studies that life forms thrive inside rocks up to 580 m (1,900 ft; 0.36 mi) below the sea floor under 2,590 m (8,500 ft; 1.61 mi) of ocean off the coast of the northwestern United States,[145][147] as well as 2,400 m (7,900 ft; 1.5 mi) beneath the seabed off Japan.[148] In August 2014, scientists confirmed the existence of life forms living 800 m (2,600 ft; 0.50 mi) below the ice of Antarctica.[149][150] According to one researcher, "You can find microbes everywhere—they're extremely adaptable to conditions, and survive wherever they are."[145]The biosphere is postulated to have evolved, beginning with a process of biopoesis (life created naturally from non-living matter, such as simple organic compounds) or biogenesis (life created from living matter), at least some 3.5 billion years ago.[151][152] The earliest evidence for life on Earth includes biogenic graphite found in 3.7 billion-year-old metasedimentary rocks from Western Greenland[97] and microbial mat fossils found in 3.48 billion-year-old sandstone from Western Australia.[98][99] More recently, in 2015, "remains of biotic life" were found in 4.1 billion-year-old rocks in Western Australia.[89][90] In 2017, putative fossilized microorganisms (or microfossils) were announced to have been discovered in hydrothermal vent precipitates in the Nuvvuagittuq Belt of Quebec, Canada that were as old as 4.28 billion years, the oldest record of life on earth, suggesting "an almost instantaneous emergence of life" after ocean formation 4.4 billion years ago, and not long after the formation of the Earth 4.54 billion years ago.[1][2][3][4] According to biologist Stephen Blair Hedges, "If life arose relatively quickly on Earth ... then it could be common in the universe."[89]In a general sense, biospheres are any closed, self-regulating systems containing ecosystems. This includes artificial biospheres such as Biosphere 2 and BIOS-3, and potentially ones on other planets or moons.[153]Range of toleranceDeinococcus radiodurans is an extremophile that can resist extremes of cold, dehydration, vacuum, acid, and radiation exposure.The inert components of an ecosystem are the physical and chemical factors necessary for life—energy (sunlight or chemical energy), water, heat, atmosphere, gravity, nutrients, and ultraviolet solar radiation protection.[154] In most ecosystems, the conditions vary during the day and from one season to the next. To live in most ecosystems, then, organisms must be able to survive a range of conditions, called the "range of tolerance."[155] Outside that are the "zones of physiological stress," where the survival and reproduction are possible but not optimal. Beyond these zones are the "zones of intolerance," where survival and reproduction of that organism is unlikely or impossible. Organisms that have a wide range of tolerance are more widely distributed than organisms with a narrow range of tolerance.[155]ExtremophilesFurther information: ExtremophileTo survive, selected microorganisms can assume forms that enable them to withstand freezing, complete desiccation, starvation, high levels of radiation exposure, and other physical or chemical challenges. These microorganisms may survive exposure to such conditions for weeks, months, years, or even centuries.[133] Extremophiles are microbial life forms that thrive outside the ranges where life is commonly found.[156] They excel at exploiting uncommon sources of energy. While all organisms are composed of nearly identical molecules, evolution has enabled such microbes to cope with this wide range of physical and chemical conditions. Characterization of the structure and metabolic diversity of microbial communities in such extreme environments is ongoing.[157]Microbial life forms thrive even in the Mariana Trench, the deepest spot in the Earth's oceans.[145][146] Microbes also thrive inside rocks up to 1,900 feet (580 m) below the sea floor under 8,500 feet (2,600 m) of ocean.[145][147]Investigation of the tenacity and versatility of life on Earth,[156] as well as an understanding of the molecular systems that some organisms utilize to survive such extremes, is important for the search for life beyond Earth.[133] For example, lichen could survive for a month in a simulated Martian environment.[158][159]Chemical elementsAll life forms require certain core chemical elements needed for biochemical functioning. These include carbon, hydrogen, nitrogen, oxygen, phosphorus, and sulfur—the elemental macronutrients for all organisms[160]—often represented by the acronym CHNOPS. Together these make up nucleic acids, proteins and lipids, the bulk of living matter. Five of these six elements comprise the chemical components of DNA, the exception being sulfur. The latter is a component of the amino acids cysteine and methionine. The most biologically abundant of these elements is carbon, which has the desirable attribute of forming multiple, stable covalent bonds. This allows carbon-based (organic) molecules to form an immense variety of chemical arrangements.[161] Alternative hypothetical types of biochemistry have been proposed that eliminate one or more of these elements, swap out an element for one not on the list, or change required chiralities or other chemical properties.[162][163]DNAMain article: DNADeoxyribonucleic acid is a molecule that carries most of the genetic instructions used in the growth, development, functioning and reproduction of all known living organisms and many viruses. DNA and RNA are nucleic acids; alongside proteins and complex carbohydrates, they are one of the three major types of macromolecule that are essential for all known forms of life. Most DNA molecules consist of two biopolymer strands coiled around each other to form a double helix. The two DNA strands are known as polynucleotides since they are composed of simpler units called nucleotides.[164] Each nucleotide is composed of a nitrogen-containing nucleobase—either cytosine (C), guanine (G), adenine (A), or thymine (T)—as well as a sugar called deoxyribose and a phosphate group. The nucleotides are joined to one another in a chain by covalent bonds between the sugar of one nucleotide and the phosphate of the next, resulting in an alternating sugar-phosphate backbone. According to base pairing rules (A with T, and C with G), hydrogen bonds bind the nitrogenous bases of the two separate polynucleotide strands to make double-stranded DNA. The total amount of related DNA base pairs on Earth is estimated at 5.0 x 1037, and weighs 50 billion tonnes.[110] In comparison, the total mass of the biosphere has been estimated to be as much as 4 TtC (trillion tons of carbon).[111]DNA stores biological information. The DNA backbone is resistant to cleavage, and both strands of the double-stranded structure store the same biological information. Biological information is replicated as the two strands are separated. A significant portion of DNA (more than 98% for humans) is non-coding, meaning that these sections do not serve as patterns for protein sequences.The two strands of DNA run in opposite directions to each other and are therefore anti-parallel. Attached to each sugar is one of four types of nucleobases (informally, bases). It is the sequence of these four nucleobases along the backbone that encodes biological information. Under the genetic code, RNA strands are translated to specify the sequence of amino acids within proteins. These RNA strands are initially created using DNA strands as a template in a process called transcription.Within cells, DNA is organized into long structures called chromosomes. During cell division these chromosomes are duplicated in the process of DNA replication, providing each cell its own complete set of chromosomes. Eukaryotic organisms (animals, plants, fungi, and protists) store most of their DNA inside the cell nucleus and some of their DNA in organelles, such as mitochondria or chloroplasts.[165] In contrast, prokaryotes (bacteria and archaea) store their DNA only in the cytoplasm. Within the chromosomes, chromatin proteins such as histones compact and organize DNA. These compact structures guide the interactions between DNA and other proteins, helping control which parts of the DNA are transcribed.DNA was first isolated by Friedrich Miescher in 1869.[166] Its molecular structure was identified by James Watson and Francis Crick in 1953, whose model-building efforts were guided by X-ray diffraction data acquired by Rosalind Franklin.[167]ClassificationMain article: Biological classificationThe hierarchy of biological classification's eight major taxonomic ranks. Life is divided into domains, which are subdivided into further groups. Intermediate minor rankings are not shown.AntiquityThe first known attempt to classify organisms was conducted by the Greek philosopher Aristotle (384–322 BC), who classified all living organisms known at that time as either a plant or an animal, based mainly on their ability to move. He also distinguished animals with blood from animals without blood (or at least without red blood), which can be compared with the concepts of vertebrates and invertebrates respectively, and divided the blooded animals into five groups: viviparous quadrupeds (mammals), oviparous quadrupeds (reptiles and amphibians), birds, fishes and whales. The bloodless animals were also divided into five groups: cephalopods, crustaceans, insects (which included the spiders, scorpions, and centipedes, in addition to what we define as insects today), shelled animals (such as most molluscs and echinoderms), and "zoophytes" (animals that resemble plants). Though Aristotle's work in zoology was not without errors, it was the grandest biological synthesis of the time and remained the ultimate authority for many centuries after his death.[168]LinnaeanThe exploration of the Americas revealed large numbers of new plants and animals that needed descriptions and classification. In the latter part of the 16th century and the beginning of the 17th, careful study of animals commenced and was gradually extended until it formed a sufficient body of knowledge to serve as an anatomical basis for classification.In the late 1740s, Carl Linnaeus introduced his system of binomial nomenclature for the classification of species. Linnaeus attempted to improve the composition and reduce the length of the previously used many-worded names by abolishing unnecessary rhetoric, introducing new descriptive terms and precisely defining their meaning.[169] The Linnaean classification has eight levels: domains, kingdoms, phyla, class, order, family, genus, and species.The fungi were originally treated as plants. For a short period Linnaeus had classified them in the taxon Vermes in Animalia, but later placed them back in Plantae. Copeland classified the Fungi in his Protoctista, thus partially avoiding the problem but acknowledging their special status.[170] The problem was eventually solved by Whittaker, when he gave them their own kingdom in his five-kingdom system. Evolutionary history shows that the fungi are more closely related to animals than to plants.[171]As new discoveries enabled detailed study of cells and microorganisms, new groups of life were revealed, and the fields of cell biology and microbiology were created. These new organisms were originally described separately in protozoa as animals and protophyta/thallophyta as plants, but were united by Haeckel in the kingdom Protista; later, the prokaryotes were split off in the kingdom Monera, which would eventually be divided into two separate groups, the Bacteria and the Archaea. This led to the six-kingdom system and eventually to the current three-domain system, which is based on evolutionary relationships.[172] However, the classification of eukaryotes, especially of protists, is still controversial.[173]As microbiology, molecular biology and virology developed, non-cellular reproducing agents were discovered, such as viruses and viroids. Whether these are considered alive has been a matter of debate; viruses lack characteristics of life such as cell membranes, metabolism and the ability to grow or respond to their environments. Viruses can still be classed into "species" based on their biology and genetics, but many aspects of such a classification remain controversial.[174]In May 2016, scientists reported that 1 trillion species are estimated to be on Earth currently with only one-thousandth of one percent described.[108]The original Linnaean system has been modified over time as follows:Linnaeus1735[175] Haeckel1866[176] Chatton1925[177] Copeland1938[178] Whittaker1969[179] Woese et al.1990[172] Cavalier-Smith1998[180] Cavalier-Smith2015[181]2 kingdoms 3 kingdoms 2 empires 4 kingdoms 5 kingdoms 3 domains 2 empires, 6 kingdoms 2 empires, 7 kingdoms(not treated) Protista Prokaryota Monera Monera Bacteria Bacteria BacteriaArchaea ArchaeaEukaryota Protoctista Protista Eucarya Protozoa ProtozoaChromista ChromistaVegetabilia Plantae Plantae Plantae Plantae PlantaeFungi Fungi FungiAnimalia Animalia Animalia Animalia Animalia AnimaliaMain article: Kingdom (biology) § SummaryCladisticIn the 1960s cladistics emerged: a system arranging taxa based on clades in an evolutionary or phylogenetic tree.[182]CellsMain article: Cell (biology)Cells are the basic unit of structure in every living thing, and all cells arise from pre-existing cells by division. Cell theory was formulated by Henri Dutrochet, Theodor Schwann, Rudolf Virchow and others during the early nineteenth century, and subsequently became widely accepted.[183] The activity of an organism depends on the total activity of its cells, with energy flow occurring within and between them.[184] Cells contain hereditary information that is carried forward as a genetic code during cell division.[185]There are two primary types of cells. Prokaryotes lack a nucleus and other membrane-bound organelles, although they have circular DNA and ribosomes. Bacteria and Archaea are two domains of prokaryotes. The other primary type of cells are the eukaryotes, which have distinct nuclei bound by a nuclear membrane and membrane-bound organelles, including mitochondria, chloroplasts, lysosomes, rough and smooth endoplasmic reticulum, and vacuoles. In addition, they possess organized chromosomes that store genetic material. All species of large complex organisms are eukaryotes, including animals, plants and fungi, though most species of eukaryote are protist microorganisms.[186] The conventional model is that eukaryotes evolved from prokaryotes, with the main organelles of the eukaryotes forming through endosymbiosis between bacteria and the progenitor eukaryotic cell.[187]The molecular mechanisms of cell biology are based on proteins. Most of these are synthesized by the ribosomes through an enzyme-catalyzed process called protein biosynthesis. A sequence of amino acids is assembled and joined together based upon gene expression of the cell's nucleic acid.[188] In eukaryotic cells, these proteins may then be transported and processed through the Golgi apparatus in preparation for dispatch to their destination.[189]Cells reproduce through a process of cell division in which the parent cell divides into two or more daughter cells. For prokaryotes, cell division occurs through a process of fission in which the DNA is replicated, then the two copies are attached to parts of the cell membrane. In eukaryotes, a more complex process of mitosis is followed. However, the end result is the same; the resulting cell copies are identical to each other and to the original cell (except for mutations), and both are capable of further division following an interphase period.[190]Multicellular organisms may have first evolved through the formation of colonies of identical cells. These cells can form group organisms through cell adhesion. The individual members of a colony are capable of surviving on their own, whereas the members of a true multi-cellular organism have developed specializations, making them dependent on the remainder of the organism for survival. Such organisms are formed clonally or from a single germ cell that is capable of forming the various specialized cells that form the adult organism. This specialization allows multicellular organisms to exploit resources more efficiently than single cells.[191] In January 2016, scientists reported that, about 800 million years ago, a minor genetic change in a single molecule, called GK-PID, may have allowed organisms to go from a single cell organism to one of many cells.[192]Cells have evolved methods to perceive and respond to their microenvironment, thereby enhancing their adaptability. Cell signaling coordinates cellular activities, and hence governs the basic functions of multicellular organisms. Signaling between cells can occur through direct cell contact using juxtacrine signalling, or indirectly through the exchange of agents as in the endocrine system. In more complex organisms, coordination of activities can occur through a dedicated nervous system.[193]ExtraterrestrialMain articles: Extraterrestrial life, Astrobiology, and AstroecologyThough life is confirmed only on Earth, many think that extraterrestrial life is not only plausible, but probable or inevitable.[194][195] Other planets and moons in the Solar System and other planetary systems are being examined for evidence of having once supported simple life, and projects such as SETI are trying to detect radio transmissions from possible alien civilizations. Other locations within the Solar System that may host microbial life include the subsurface of Mars, the upper atmosphere of Venus,[196] and subsurface oceans on some of the moons of the giant planets.[197][198] Beyond the Solar System, the region around another main-sequence star that could support Earth-like life on an Earth-like planet is known as the habitable zone. The inner and outer radii of this zone vary with the luminosity of the star, as does the time interval during which the zone survives. Stars more massive than the Sun have a larger habitable zone, but remain on the Sun-like "main sequence" of stellar evolution for a shorter time interval. Small red dwarfs have the opposite problem, with a smaller habitable zone that is subject to higher levels of magnetic activity and the effects of tidal locking from close orbits. Hence, stars in the intermediate mass range such as the Sun may have a greater likelihood for Earth-like life to develop.[199] The location of the star within a galaxy may also affect the likelihood of life forming. Stars in regions with a greater abundance of heavier elements that can form planets, in combination with a low rate of potentially habitat-damaging supernova events, are predicted to have a higher probability of hosting planets with complex life.[200] The variables of the Drake equation are used to discuss the conditions in planetary systems where civilization is most likely to exist.[201] Use of the equation to predict the amount of extraterrestrial life, however, is difficult; because many of the variables are unknown, the equation functions as more of a mirror to what its user already thinks. As a result, the number of civilizations in the galaxy can be estimated as low as 9.1 x 10−11 or as high as 156 million; for the calculations, see Drake equation.ArtificialMain articles: Artificial life and Synthetic biologyArtificial life is the simulation of any aspect of life, as through computers, robotics, or biochemistry.[202] The study of artificial life imitates traditional biology by recreating some aspects of biological phenomena. Scientists study the logic of living systems by creating artificial environments—seeking to understand the complex information processing that defines such systems.[184] While life is, by definition, alive, artificial life is generally referred to as data confined to a digital environment and existence.Synthetic biology is a new area of biotechnology that combines science and biological engineering. The common goal is the design and construction of new biological functions and systems not found in nature. Synthetic biology includes the broad redefinition and expansion of biotechnology, with the ultimate goals of being able to design and build engineered biological systems that process information, manipulate chemicals, fabricate materials and structures, produce energy, provide food, and maintain and enhance human health and the environment.[203]DeathMain article: DeathAnimal corpses, like this African buffalo, are recycled by the ecosystem, providing energy and nutrients for living creaturesDeath is the permanent termination of all vital functions or life processes in an organism or cell.[204][205] It can occur as a result of an accident, medical conditions, biological interaction, malnutrition, poisoning, senescence, or suicide. After death, the remains of an organism re-enter the biogeochemical cycle. Organisms may be consumed by a predator or a scavenger and leftover organic material may then be further decomposed by detritivores, organisms that recycle detritus, returning it to the environment for reuse in the food chain.One of the challenges in defining death is in distinguishing it from life. Death would seem to refer to either the moment life ends, or when the state that follows life begins.[205] However, determining when death has occurred is difficult, as cessation of life functions is often not simultaneous across organ systems.[206] Such determination therefore requires drawing conceptual lines between life and death. This is problematic, however, because there is little consensus over how to define life. The nature of death has for millennia been a central concern of the world's religious traditions and of philosophical inquiry. Many religions maintain faith in either a kind of afterlife or reincarnation for the soul, or resurrection of the body at a later date.ExtinctionMain article: ExtinctionExtinction is the process by which a group of taxa or species dies out, reducing biodiversity.[207] The moment of extinction is generally considered the death of the last individual of that species. Because a species' potential range may be very large, determining this moment is difficult, and is usually done retrospectively after a period of apparent absence. Species become extinct when they are no longer able to survive in changing habitat or against superior competition. In Earth's history, over 99% of all the species that have ever lived are extinct;[208][103][104][105] however, mass extinctions may have accelerated evolution by providing opportunities for new groups of organisms to diversify.[209]FossilsMain article: FossilsFossils are the preserved remains or traces of animals, plants, and other organisms from the remote past. The totality of fossils, both discovered and undiscovered, and their placement in fossil-containing rock formations and sedimentary layers (strata) is known as the fossil record. A preserved specimen is called a fossil if it is older than the arbitrary date of 10,000 years ago.[210] Hence, fossils range in age from the youngest at the start of the Holocene Epoch to the oldest from the Archaean Eon, up to 3.4 billion years old.[211][212]

Brain insulin and IGF deficiency and resistance could account for the cytoskeletal collapse, neurite retraction, synaptic disconnection, loss of neuronal plasticity, and deficiencies in acetylcholine production, all of which correlate with cognitive decline and dementia in AD. Altogether, the studies utilizing postmortem human brain tissue provide solid evidence that AD is associated with fundamental abnormalities in insulin/IGF signaling mechanisms that are highly correlated with development and progression of structural, molecular, and biochemical lesions that correlate with dementia. Although the abnormalities noted in AD share features in common with T1MD and T2MD, they are nonetheless distinguished by the dual presence of trophic factor deficiencies and trophic factor receptor resistance, ergo the term “type 3 diabetes.”Eating meat linked to higher risk of diabetes. ... Higher intake of red meat and poultry is associated with significantly increased risk of developing diabetes, which is partially attributed to their higher content of heme iron in these meats, new research shows.You probably know that eating too much sugar and fat increases your risk of getting type 2 diabetes. But research increasingly shows that a food you might not expect — meat — can dramatically raise your chances as well. Your body needs protein.This “type 3 diabetes” is a term that has been proposed to describe the hypothesis that Alzheimer's disease, which is a major cause of dementia, is triggered by a type of insulin resistance and insulin-like growth factor dysfunction that occurs specifically in the brain.Choline increases acetylcholine release and protects against the stimulation-induced decrease in phosphatide levels within membranes of rat corpus striatum.Ulus IH, et al. Brain Res. 1989.Show full citationAbstractThis study examined the possibility that membrane phospholipids might be a source of choline used for acetylcholine (ACh) synthesis. Slices of rat striatum or cerebellum were superfused with a choline-free or choline-containing (10, 20 or 40 microM) physiological solution with eserine, for alternating 20 min periods of rest or electrical stimulation. Superfusion media were assayed for choline and ACh, and slice samples taken before and after stimulation were assayed for choline, ACh, various phospholipids, protein and DNA. The striatal slices were able to sustain the stimulation-induced release of ACh, releasing a total of about 3 times their initial ACh contents during the 8 periods of stimulation and rest. During these 8 cycles, 885 pmol/micrograms DNA free choline was released from the slices into the medium, an amount about 45-fold higher than the initial or final free choline levels in the slices. Although repeated stimulation of the striatal slices failed to affect tissue levels of free choline or of ACh, this treatment did cause significant, dose-related (i.e., number of stimulation periods) stoichiometric decreases in tissue levels of phosphatidylcholine (PC) and of the other major phospholipids; tissue protein levels also declined significantly. Addition of exogenous choline to the superfusion medium produced dose-related increases in resting and evoked ACh release. The choline also fully protected the striatal slices from phospholipid depletion for as many as 6 stimulation periods. Cerebellar slices liberated large amounts of free choline into the medium but did not release measurable quantities of ACh; their phospholipid and protein levels did not decline with electrical stimulation. These data show that membrane phospholipids constitute a reservoir of free choline that can be used for ACh synthesis. When free choline is in short supply, ACh synthesis and release are sustained at the expense of this reservoir. The consequent reduction in membrane PC apparently is associated with a depletion of cellular membrane. The use of free choline by cholinergic neurons for two purposes, the syntheses of both ACh and membrane phospholipids, may thus impart vulnerability to them in situations where the supply of free choline is less than that needed for acetylation.Journal of diabetes science and technology (Online)Diabetes Technology SocietyAlzheimer's Disease Is Type 3 Diabetes–Evidence ReviewedSuzanne M. de la Monte, M.D., M.P.H. and Jack R. Wands, M.D.Additional article informationAbstractAlzheimer's disease (AD) has characteristic histopathological, molecular, and biochemical abnormalities, including cell loss; abundant neurofibrillary tangles; dystrophic neurites; amyloid precursor protein, amyloid-β (APP-Aβ) deposits; increased activation of prodeath genes and signaling pathways; impaired energy metabolism; mitochondrial dysfunction; chronic oxidative stress; and DNA damage. Gaining a better understanding of AD pathogenesis will require a framework that mechanistically interlinks all these phenomena. Currently, there is a rapid growth in the literature pointing toward insulin deficiency and insulin resistance as mediators of AD-type neurodegeneration, but this surge of new information is riddled with conflicting and unresolved concepts regarding the potential contributions of type 2 diabetes mellitus (T2DM), metabolic syndrome, and obesity to AD pathogenesis. Herein, we review the evidence that (1) T2DM causes brain insulin resistance, oxidative stress, and cognitive impairment, but its aggregate effects fall far short of mimicking AD; (2) extensive disturbances in brain insulin and insulin-like growth factor (IGF) signaling mechanisms represent early and progressive abnormalities and could account for the majority of molecular, biochemical, and histopathological lesions in AD; (3) experimental brain diabetes produced by intracerebral administration of streptozotocin shares many features with AD, including cognitive impairment and disturbances in acetylcholine homeostasis; and (4) experimental brain diabetes is treatable with insulin sensitizer agents, i.e., drugs currently used to treat T2DM. We conclude that the term “type 3 diabetes” accurately reflects the fact that AD represents a form of diabetes that selectively involves the brain and has molecular and biochemical features that overlap with both type 1 diabetes mellitus and T2DM.Keywords: Alzheimer's disease, central nervous system, diabetes, insulin gene expression, insulin signalingIntroductionAlzheimer's disease (AD) can only be diagnosed with certainty by postmortem demonstration of abundant neurofibrillary tangles and neuritic plaques with accompanying accumulation of amyloid precursor protein, amyloid-β (APP-Aβ) deposits in plaques and vessel walls in selected regions of the brain. Dementia-associated structural lesions are caused by neuronal cytoskeletal collapse and accumulation of hyperphosphorylated and polyubiquitinated microtubule-associated proteins, such as tau, resulting in the formation of neurofibrillary tangles, dystrophic neuritis, and neuropil threads.1–3Progressive loss of fibers and cells and disconnection of synaptic circuitry mediate the cerebral atrophy that worsens over time. The biochemical, molecular, and cellular abnormalities that precede or accompany AD neurodegeneration, including increased activation of prodeath genes and signaling pathways, impaired energy metabolism, mitochondrial dysfunction, chronic oxidative stress, and DNA damage, are virtually stereotypical,4–11yet they lack a clear etiology. For nearly three decades of relatively intense research on AD, the inability to interlink this constellation of abnormalities under a single primary pathogenic mechanism resulted in the emergence and propagation of various heavily debated theories, each of which focused on how one particular component of AD could trigger a cascade that contributes to the development of all other known abnormalities. However, reevaluation of the older literature revealed that impairments in cerebral glucose utilization and energy metabolism represent very early abnormalities that precede or accompany the initial stages of cognitive impairment12–14and led us to the concept that impaired insulin signaling has an important role in the pathogenesis of AD and the proposal that AD represents “type 3 diabetes.”5Characteristic features of diabetes mellitus syndromes include impairments in insulin actions and signaling that result in chronic hyperglycemia, irrespective of subtype, etiology, pathogenesis, or insulin availability. Type 1 diabetes mellitus (T1DM) is caused by destruction (usually autoimmune) of pancreatic islet beta cells and attendant insulin deficiency. Type 2 diabetes mellitus (T2DM), the most common form, is caused by insulin resistance in peripheral tissues and is most frequently associated with aging, a family history of diabetes, obesity, and failure to exercise. Individuals with T2DM have hyperglycemia and hyperinsulinemia. Insulin resistance in T2DM is partly mediated by reduced insulin receptor expression, insulin receptor tyrosine kinase activity, insulin receptor substrate (IRS) type 1 expression, and/or phosphatidyl-inositol-3 (PI3) kinase activation in skeletal muscle and adipocytes.15Gestational diabetes is pregnancy associated and caused by insulin deficiency and hyperglycemia. Nonalcoholic steatohepatitis (NASH), or metabolic syndrome, is associated with hepatic insulin resistance but overlaps with T2DM.16–18Type 3 diabetes mellitus (T3DM, discussed later) corresponds to a chronic insulin resistance plus insulin deficiency state that is largely confined to the brain but, like NASH, can overlap with T2DM. We have proposed that T3DM represents a major pathogenic mechanism of AD neurodegeneration.5,10Interest in clarifying the roles of T2DM, insulin resistance, and hyperinsulinemia in relation to cognitive impairment, AD-associated neuronal cytoskeletal lesions, or APP-Aβ deposits in the brain began around 2000,4,8,14,19–24but since around 2005, this field literally exploded with new information and a new concept, i.e., that primary brain insulin resistance and insulin deficiency mediate cognitive impairment and AD.5,10,25–29This idea was fueled by evidence that tau gene expression and phosphorylation are regulated through insulin and insulin-like growth factor (IGF) signaling cascades.23,24In addition, research performed in our laboratory demonstrated that many key aspects of the central nervous system (CNS) degeneration that occur in AD can be effectuated by impaired insulin signaling.30–33By way of review, insulin and IGF-1 mediate their effects by activating complex intracellular signaling pathways starting with ligand binding to cell surface receptors, followed by autophosphorylation and activation of the intrinsic receptor tyrosine kinases.34–36Insulin/IGF-1 receptor tyrosine kinases phosphorylate IRS molecules,34,37–39which transmit signals downstream by activating the extracellular signal-related kinase/mitogen-activated protein kinase (ERK/MAPK) and PI3 kinase/Akt pathways, and inhibit glycogen synthase kinase 3β (GSK-3β). Major biological responses to signaling through IRS molecules include increased cell growth; survival, energy metabolism, and cholinergic gene expression; and inhibition of oxidative stress and apoptosis.39–46These very same signaling pathways are activated in various cell types, tissues, and target organs that express insulin and IGF receptors and therefore are practically universal. Moreover, these pathways are phylogenetically conserved and have critical roles in regulating development, growth, survival, senescence, carcinogenesis, and neurodegeneration.Potential Roles of Obesity and Type 2 Diabetes Mellitus in Alzheimer's Disease PathogenesisThere is an ongoing debate about the degree to which T2DM and, more recently, T1DM contribute to AD pathogenesis. This concept has been fueled by the rising prevalence rates of obesity, T2DM, and AD over the past several decades. Moreover, an interrelationship among these entities is suggested by (1) increased risk of developing mild cognitive impairment (MCI), dementia, or AD in individuals with T2DM47,48or obesity/dyslipidemic disorders;49(2) progressive brain insulin resistance and insulin deficiency in AD;5,10,26,27(3) cognitive impairment in experimental animal models of T2DM and/or obesity;50,51(4) AD-type neurodegeneration and cognitive impairment in experimentally induced brain insulin resistance and insulin deficiency;29,52–55(5) improved cognitive performance in experimental models and humans with AD or MCI after treatment with insulin sensitizer agents or intranasal insulin;28,56–62and (6) shared molecular, biochemical, and mechanistic abnormalities in T2DM and AD.47,63–67The urgency of this problem is spotlighted by the estimated 24 million people in the world with dementia and the expectation that, if current trends continue,68prevalence rates of AD are likely to double every 20 years in the future. While aging is clearly the strongest risk factor for AD, emerging data suggest that T2DM and dyslipidemic states can contribute substantially to the pathogenesis of AD either directly or as cofactors.68Epidemiologic studies provide convincing evidence for a significant association between T2DM and MCI or dementia and furthermore suggest that T2DM is a significant risk factor for developing AD.47,69–73However, those findings are not without controversy,74and in a longitudinal survey, investigators found that although borderline diabetics had a significantly increased risk for future development of diabetes, dementia, or AD, the risk effects were independent rather than linked.75What this means is that insulin resistance, i.e., impaired ability to respond to insulin stimulation, can vary among target organs and be present in just one or two organs and not in others, a phenomenon that could explain the lack of complete overlap between T2DM and AD. Correspondingly, the finding that obesity (body mass index [BMI] > 30) without T2DM produces a three-fold increase in risk for subsequently developing AD whereas overweight, but nonobese, subjects (BMI 25–30) experience a two-fold increase in risk for AD76calls into question the specific effects of obesity and T2DM versus a yet unknown associated factor in relation to AD pathogenesis.Mechanistically, the increased risk of dementia in T2DM and obesity could be linked to chronic hyperglycemia, peripheral insulin resistance, oxidative stress, accumulation of advanced glycation end products, increased production of pro-inflammatory cytokines, and/orcerebral microvascular disease.73The potential role of cerebral microvascular disease as a complicating, initiating, or accelerating component of AD has been recognized for years.77However, a magnetic resonance imaging study demonstrated that older adults with T2DM have a moderately increased risk for developing lacunes and hippocampal atrophy and that the severity of those lesions increases with the duration and progression of T2DM.78Another study showed that T2DM and impaired fasting glucose occur significantly more frequently in AD than in non-AD controls.79However, since diffuse and neuritic plaques were similarly abundant in T2DM and control brains, and since neurofibrillary tangles, one of the hallmarks and correlates of dementia in AD, were not increased in T2DM,79the results suggest that T2DM can enhance progression but may not be sufficient to cause AD. Therefore, what remains unclear is the net contribution of T2DM or obesity to the pathogenesis of AD-type neurodegeneration. To address this question, we utilized an established experimental model of chronic high-fat diet (HFD) feeding of C57BL/6 mice to examine the degree to which obesity/T2DM was sufficient to produce histopathological, molecular, and/or biochemical brain abnormalities of AD-type neurodegeneration, i.e., T3DM.High-fat diet feeding for 16 weeks doubled mean body weight, caused T2DM, and marginally reduced mean brain weight.80Those effects were associated with significantly increased levels of tau, IGF-1 receptor, IRS-1, IRS-4, ubiquitin, glial fibrillary acidic protein (GFAP), and 4-hydroxynonenal and decreased expression of β actin. Importantly, HFD feeding also caused brain insulin resistance manifested by reduced top-level (Bmax) insulin receptor binding and modestly increased brain insulin gene expression. However, HFD fed mouse brains did not exhibit AD histopathology or increases in APP-Aβ or phospho-tau, nor were there impairments in IGF signaling, which typically occurs in AD.10In essence, although the chronic obesity with T2DM model exhibited mild brain atrophy with insulin resistance, oxidative stress, and cytoskeleton degradation, the effects were modest compared with AD5,10and other more robust experimental models of T3DM,28,29and most of the molecular, biochemical, and histopathological features that typify AD were not present. Therefore, T2DM and obesity may contribute to, i.e., serve as cofactors of AD but by themselves are probably not sufficient to cause AD. Moreover, the findings in the T2DM/obesity model indicate the unlikelihood that brain insulin resistance is sufficient to cause AD and that additional significant abnormalities, such as ongoing DNA damage and mitochondrial dysfunction, are required.Alzheimer's Disease is Type 3 Diabetes: Evidence from Human StudiesThis hypothesis was directly investigated by first examining postmortem cases of advanced AD and determining if the neurodegeneration was associated with significant abnormalities in the expression of genes encoding insulin, IGF-1, and IGF-2 peptides, their receptors, and downstream signaling mechanisms.5In that study, we demonstrated advanced AD to be associated with strikingly reduced levels of insulin and IGF-1 polypeptide and receptor genes in the brain (Figure 1). In addition, all the signaling pathways that mediate insulin and IGF-1-stimulated neuronal survival, tau expression, energy metabolism, and mitochondrial function were perturbed in AD. This study carries additional significance because it established that, like all other pancreatic and intestinal polypeptide genes, the insulin gene was also expressed in the adult human brain. Moreover, the results taught us that endogenous brain deficiencies in insulin, IGF-1, IGF-2, and their corresponding receptors, in the absence of T2DM or obesity, could be linked to the most common form of dementia-associated neurodegeneration in the Western hemisphere. Since the abnormalities identified in the brain were quite similar to the effects of T1DM or T2DM (though none of the patients had either of these diseases), including abnormalities in IGFs,81–83which are important for islet cell function,84,85we proposed the concept that AD may represent a brain-specific form of diabetes mellitus and coined the term “type 3 diabetes.”Figure 1.Impaired insulin and IGF (A, C) receptor and (B, D) polypeptide gene expression in late/end-stage AD (A, B) temporal cortex and (C, D) hippocampus.5 Gene expression was measured by qRT-PCR using RNA isolated from the temporal cortex or hippocampus from ...Even before the initial study had been published, it was realized that if brain insulin/IGF resistance and insulin/IGF deficiency were causal in the pathogenesis of AD, the related abnormalities should be detectable in the early stages of disease and possibly worsen as disease progresses. The investigations were extended to examine the brains of patients with different degrees, i.e., Braak stages,86,87of AD.10In that study, we measured the expression of genes encoding insulin, IGF-1, IGF-2 polypeptides, and their corresponding receptors as well as tau and amyloid precursor protein (APP). In addition, we used competitive equilibrium and saturation binding assays to further characterize the degree to which growth factor-transmitted signaling was impaired in the brains with different severities of AD. Finally, the study included the measurement of steady-state levels of adenosine triphosphate and genes regulating acetylcholine homeostasis and energy metabolism.Using the previously mentioned approaches, we demonstrated progressive AD Braak stage-dependent reductions in insulin, IGF-1, and IGF-2 receptor expression, with more pronounced deterioration in insulin and IGF-1 compared with IGF-2 receptors, and the lowest levels of gene expression in brains with AD Braak Stage 6 (Figure 2). Therefore, loss of insulin and IGF-1 receptor-bearing neurons begins early and progresses with disease such that, in the advanced stages, the deficits are severe and global. These results provided further evidence that the abnormalities in AD are not restricted to insulin signaling pathways, as they also involve IGF-1 and IGF-2 stimulated mechanisms. Analysis of growth-factor polypeptide genes also revealed AD Braak stage-dependent impairments in insulin, IGF-1, and IGF-2 polypeptide expression, corresponding with progressive trophic factor withdrawal (Figure 2). Again, the results support the hypothesis that abnormalities in insulin and IGF signaling mechanisms begin early in the course of AD and are therefore likely have an important role in its pathogenesis.Figure 2.Brain insulin and IGF deficiency and resistance increase with progression of AD.10 Postmortem histopathological studies categorized the brains as having normal aging (Braak 0–1), or mild (Braak 2–3), moderate to severe (Braak 4–5), ...The eventual paucity of local growth-factor gene expression could substantially impair growth-factor signaling and produce a state of growth-factor withdrawal, which is a well-established mechanism of neuronal death. Therefore, to complement the molecular data, we performed competitive equilibrium and saturation binding assays to determine if reduced levels of growth factor receptor expression were associated with and perhaps mediated by impaired ligand-receptor binding as occurs with insulin/IGF resistance. Those investigations demonstrated progressive declines in equilibrium (Figure 2) and top-level binding (Bmax) to the insulin, IGF-1, and IGF-2 receptors but either unchanged or increased binding affinity, suggesting that impaired insulin/IGF actions in AD brains were mediated by decreased polypeptide and receptor gene expression due to cell loss.Through a series of in vitro and in vivo experiments performed by several groups, including our own, we have been able to draw the conclusion that neuronal and oligodendroglial cell survival and function are integrally related to the integrity of insulin and IGF signaling mechanisms in the brain.10,28,29,31,33,88,89Similarly, impairments in insulin/IGF signaling lead to deficits in energy metabolism with attendant increased oxidative stress, mitochondrial dysfunction, proinflammatory cytokine activation, and APP expression.4,10,28,89Correspondingly, the reduced expression of neuronal and oligodendroglial specific genes and the increased expression of astrocytic and microglial inflammatory genes in AD were attributed to progressive brain insulin/IGF deficiency and resistance. Although this point requires the generation of experimental models to demonstrate proof of principle, the finding that microglial, astrocytic, and APP mRNA levels are all increased in the early stages of neurodegeneration supports the inflammatory hypothesis of AD.6Previous studies demonstrated that microglial activation promotes APP-Aβ accumulation90–92and that APP gene expression and cleavage increase with oxidative stress.93Therefore, the mechanism we propose is that impaired insulin/ IGF signaling leads to increased oxidative stress and mitochondrial dysfunction,32,94,95which induces APP gene expression and cleavage.93The attendant APP-Aβ accumulations cause local neurotoxicity96–98and further increase in oxidative stress-induced APP expression and APP-Aβ deposition.A critical goal in these investigations was to draw connections between brain insulin/IGF deficiency and resistance and the major dementia-associated structural and biochemical abnormalities in AD. In this regard, the postmortem studies demonstrated that the Braak stage-associated declines in tau mRNA paralleled the progressive reductions in insulin and IGF-1 receptor expression in AD. In addition, the studies demonstrated AD Braak stage-associated declines in choline acetyltransferase (ChAT) expression with reduced colocalization of ChAT with insulin or IGF-1 receptor immunoreactivity in cortical neurons. These results correspond with experimental data demonstrating that neuronal tau and ChAT gene expression are regulated by IGF-1 and insulin stimulation.88Therefore, brain insulin and IGF deficiency and resistance could account for the cytoskeletal collapse, neurite retraction, synaptic disconnection, loss of neuronal plasticity, and deficiencies in acetylcholine production, all of which correlate with cognitive decline and dementia in AD. Altogether, the studies utilizing postmortem human brain tissue provide solid evidence that AD is associated with fundamental abnormalities in insulin/IGF signaling mechanisms that are highly correlated with development and progression of structural, molecular, and biochemical lesions that correlate with dementia. Although the abnormalities noted in AD share features in common with T1MD and T2MD, they are nonetheless distinguished by the dual presence of trophic factor deficiencies and trophic factor receptor resistance, ergo the term “type 3 diabetes.”Alzheimer's Disease Is Type 3 Diabetes: Experimental Animal Model ResultsThe human postmortem brain studies linked many of the characteristic molecular and pathological features of AD to the reduced expression of the insulin and IGF genes and their corresponding receptors. However, without direct experimentation that generates cause–effect data, conclusions drawn from human studies would remain correlative rather than mechanistic. Consequently, we utilized experimental models to demonstrate that diabetes mellitus-type molecular and biochemical abnormalities could be produced in CNS neurons and brain by exposure to streptozotocin (STZ). Streptozotocin is 2-Deoxy-2{[methyl-nitrosoamino)carbonyl]amino}D-glucopyranose, i.e., a nitrosamide methylnitrosourea linked to the C2 position of D glucose. Once metabolized, the N nitrosoureido is liberated and causes DNA damage through generation of reactive oxygen species such as superoxide, hydrogen peroxide, and nitric oxide.99,100Streptozotocin causes diabetes because it is taken up by insulin-producing cells, such as beta cells, in pancreatic islets.We treated rats with a single intracerebral injection of STZ (ic-STZ) and allowed the rats to grow older for 2 to 8 weeks. The rats were subjected to Morris water maze tests of spatial learning and memory, and their brains were examined for histopathological, biochemical, and molecular indices of AD-type neurodegeneration.Although a similar model had been generated much earlier by other investigators,101–104and it was noted that the ic-STZ treatments reduced cerebral glucose utilization104and oxidative metabolism,101it inhibited insulin receptor function,95and it caused progressive deficits in learning, memory, cognitive behavior, and cerebral energy balance,94,103efforts were not made to connect these effects of ic-STZ to AD by characterizing the neuropathology, molecular pathology, abnormalities in genes expression pertinent to insulin and IGF-1 signaling in brain or by evaluating the integrity of the pancreas. Our goal in generating the model was to demonstrate that AD-type neurodegeneration with features of T3DM could be produced in the absence of either T1DM or T2DM.The ic-STZ-injected rats did not have elevated blood glucose or insulin levels, and pancreatic architecture and insulin immunoreactivity were similar to control, yet their brains were atrophied and had striking evidence of neurodegeneration with cell loss, gliosis, and increased immunoreactivity for p53, activated GSK-3β, phospho-tau, ubiquitin, and APP-Aβ.28,29Moreover, quantitative reverse transcriptase polymerase chain reaction (qRT-PCR) studies demonstrated that the ic-STZ-treated brains had significantly reduced expression of genes corresponding to neurons (Hu), oligodendroglia [myelin-associated glycoprotein-1 (MAG-1)], and ChAT and to increased expression of genes encoding GFAP, microglia-specific proteins [allograft inflammatory factor-1 (AiF-1)]), acetylcholinesterase (AChE), tau, and APP.28,29Increased p53 and decreased Hu and MAG-1 expression in ic-STZ-treated brains suggest that neuronal and oligodendroglial cell loss and cerebral atrophy were mediated by apoptosis. These findings correspond well with previous studies demonstrating increased expression of various proapoptosis molecules, including p53,105,106colocalization of increased p53 immunoreactivity in neurons and white matter glia, and reduced levels of Hu and MAG-1 mRNA in human brains with AD. Loss of oligodendroglia could contribute to the early white matter degeneration107and synaptic disconnection108–111in AD.The previously mentioned adverse effects of ic-STZ were associated with reduced expression of genes encoding insulin, IGF-2, insulin receptor, IGF-1 receptor, and IRS-1 and reduced ligand binding to the insulin and IGF-2 receptors (Figure 3). Note that most of these effects were also detected in brains with sporadic AD5and were found to increase with disease progression.10The reduced levels of IRS-1 mRNA observed in both AD and rats treated with ic-STZ were reminiscent of the murine IRS-1 and insulin receptor knock-out models, which exhibit reduced brain and body weights due to impaired insulin stimulated growth and survival signaling.23,112,113The combined effects of reduced insulin/IGF polypeptide gene expression, receptor expression, receptor binding, and IRS expression all point toward failure of insulin/IGF signaling mechanisms in the brain as a major consequence of ic-STZ treatment. Importantly, many molecular abnormalities that characteristically occur in AD and were produced by ic-STZ, including increased GSK-3β activation, increased tau phosphorylation, and decreased neuronal survival, could be mediated by downstream effects of impaired insulin and IGF signaling in the CNS. Again, similar results have been reported by other investigators using this experimental model of neurodegeneration.114–117Therefore, the ic-STZ experimental animal model recapitulates many of the characteristic features of AD-type neurodegeneration/T3DM.Figure 3.Effects of intracerebral ic-STZ treatment on CNS expression of insulin and IGF (A) genes and (B) receptors and (C) ligand binding to the insulin, IGF-1, or IGF-2 receptors in temporal lobe tissue. Rat pups were given 50 mg/kg ic-STZ or vehicle and sacrificed ...Corresponding with the findings in AD,5the ic-STZ-treated brains had increased levels of activated GSK-3β, phospho-tau, ubiquitin, APP and APP-Aβ and decreased levels of tau protein. These results are consistent with previous studies demonstrating that tau is regulated by insulin/IGF-1 stimulation88,118and that tau phosphorylation and ubiquitination increase with oxidative stress and activation of GSK-3β.93Similarly, APP mRNA increases with oxidative stress and is a feature of sporadic AD.5,10Increased APP gene expression could account for APP-Aβ accumulation in AD and ic-STZ-treated brains. Potential sources of oxidative stress in AD and the ic-STZ model include (1) mitochondrial dysfunction;6,53,95(2) microglial cell activation with increased cytokine release; and (3) impaired insulin/IGF signaling through PI3 kinaseAkt, leading to increased levels of GSK-3β activity.A crucial step was to determine whether ic-STZ could cause disturbances in acetylcholine homeostasis and cognitive impairment as they occur in AD. QRT-PCR and immunohistochemistry detected reduced levels of ChAT and increased levels of AChE mRNA and protein in icSTZ-treated brains relative to control brains. Note that energy metabolism leads to production of Acetyl-CoA, which is needed to make acetylcholine. Since the ChAT gene is responsive to insulin and IGF-1 stimulation, deficits in insulin/IGF signaling and energy metabolism push in the direction of cholinergic deficiency mediated by impaired energy metabolism and decreased expression of ChAT, which are key features in AD. In addition, increased levels of AChE expression in the ic-STZ brains could result in increased degradation of acetylcholine, thereby exacerbating the acetylcholine deficits caused by reduced ChAT expression. The significance of these results is highlighted by the prominent learning and memory deficits detected in ic-STZ-treated rats.28,29Type 3 Diabetes May Be Treatable, Preventable, or Curable with Antidiabetes DrugsThe findings that (1) pronounced insulin/IGF deficiency and resistance develop early in the course of AD; (2) insulin/IGF signaling abnormalities progress with severity of neurodegeneration;5,10and (3) an experimental animal model with features closely mimicking the molecular, biochemical, and neuroanatomical pathologies of AD could be generated by intracerebral delivery of a drug that causes T1DM or T2DM led us to test the hypothesis that AD-type neurodegeneration and cognitive could be reduced or prevented by early treatment with insulin-sensitizer antidiabetes agents such as peroxisome proliferator-activated receptor (PPAR) agonists. Peroxisome proliferator-activated receptor agonists function at the level of the nucleus to activate insulin-responsive genes and signaling mechanisms. PPAR-α, PPAR-δ, and PPAR-γ are all expressed in adult human brains, including AD, but PPAR-δ is the most abundant of the three isoforms.6The experimental design involved treating rats with ic-STZ, followed by a single intraperitoneal injection of saline, a PPAR-α (GW7647; 25 µg/kg), PPAR-δ (L-160,043; 2 µg/kg), or PPAR-γ (F-L-Leu; 20 µg/kg) activator (CalBiochem, Carlsbad, CA).28The doses used were considerably lower than those routinely given to treat T2DM. The major effects of the PPAR agonist treatments were to prevent brain atrophy, preserve insulin and IGF-2 receptor bearing CNS neurons, and particularly with regard to the PPAR-δ agonist, prevent ic-STZ-induced deficits in learning and memory.28Since the ic-STZ-mediated losses of insulin and IGF-expressing cells were not prevented by the PPAR agonist treatments, the PPAR agonists probably functioned by preserving insulin and IGF responsive (receptor-bearing) cells, including neurons and oligodendroglia. In support of this concept was finding that insulin receptor expression and binding were increased by the PPAR agonist treatments (Figure 4). Peroxisome proliferator-activated receptor agonist mediated preservation of insulin/IGF responsive neurons was associated with increased expression of ChAT, which has an important role in cognition, as cholinergic neuron deficits are a fundamental feature of AD.119–122Importantly, the PPAR-δ agonist mediated increases in insulin binding, and ChAT were associated with significant improvements in learning and spatial memory tasks as demonstrated using Morris water maze tests28(Figure 5). These effects of the PPAR agonist treatments are consistent with the facts that ChAT expression is regulated by insulin/IGF88,118and insulin/IGF resistance mediates cognitive impairment in AD. The PPAR-mediated increases in MAG-1 expression, corresponding to oligodendroglia, were of particular interest because previous research demonstrated that one of the earliest AD lesions was white matter atrophy and degeneration with loss of oligodendroglial cells.107Within the context of the present discussion, white matter atrophy in AD can now be interpreted as a manifestation of CNS insulin/IGF resistance since oligodendroglia require intact insulin/IGF signaling mechanisms for survival and function, including myelin synthesis.123,124Besides preserving insulin and IGF receptor-bearing CNS cells and signaling mechanisms germane to survival, energy metabolism, and neurotransmitter functions, the PPAR agonists rescued the ic-STZ model by lowering critical AD-associated indices of oxidative stress, including microglial and astrocyte activation, p53, nitric oxide synthase and nicotinamide adenine dinucleotide phosphate (NADPH) oxidase gene expression, lipid peroxidation, DNA damage, APP expression, and tau phosphorylation.6,28,29,91,92,125,126Figure 4.Treatment with PPAR agonists restores brain insulin receptor binding in ic-STZ-treated rats.28 Long Evans rat pups were treated with 50 mg/kg ic-STZ or vehicle and sacrificed 30 days later to examine brains for insulin and IGF polypeptide and receptor ...Figure 5.Peroxisome proliferator-activated receptor-δ agonist treatment preserves visual-spatial learning and memory in ic-STZ-treated rats.28 Long Evans rat pups were treated with 50 mg/kg ic-STZ or vehicle, followed by a single intraperitoneal injection ...ConclusionsAltogether, the results from these studies provide strong evidence in support of the hypothesis that AD represents a form of diabetes mellitus that selectively afflicts the brain. Positive data stemmed from (1) direct analysis of postmortem human brains with documented AD; (2) an experimental animal model in which brain diabetes with cognitive impairment and molecular and pathological features that mimic AD was produced by intracerebral administration of a drug that is commonly used to produce T1DM or T2DM; and (3) a study showing that PPAR agonists, which are used to treat T2DM, prevent many of the AD-associated neurodegenerative effects of ic-STZ. The data are supported by abundant in vitro experiments that demonstrated essentially the same or similar effects of STZ or oxidative stress treatments of neuronal cells. The human and experimental animal model studies also showed that CNS impairments in insulin/IGF signaling mechanisms can occur in the absence of T1DM or T2DM. Finally, we demonstrated that although obesity with T2DM causes brain insulin resistance with some features of AD-type neurodegeneration, the effects are relatively modest, not associated with significant histopathological lesions, and lack most of the critical abnormalities that typify AD. Therefore, T2DM was deemed not sufficient to cause AD, although it could possibly serve as a cofactor in its pathogenesis or progression. Altogether, the data provide strong evidence that AD is intrinsically a neuroendocrine disease caused by selective impairments in insulin and IGF signaling mechanisms, including deficiencies in local insulin and IGF production. At the same time, it is essential to recognize that T2DM and T3DM are not solely the end results of insulin/IGF resistance and/or deficiency, because these syndromes are unequivocally accompanied by significant activation of inflammatory mediators, oxidative stress, DNA damage, and mitochondrial dysfunction, which contribute to the degenerative cascade by exacerbating insulin/ IGF resistance. Referring to AD as T3DM is justified, because the fundamental molecular and biochemical abnormalities overlap with T1DM and T2DM rather than mimic the effects of either one. Some of the most relevant data supporting this concept have emerged from clinical studies demonstrating cognitive improvement and/or stabilization of cognitive impairment in subjects with early AD following treatment with intranasal insulin or a PPAR agonist.58,60,127–130AbbreviationsAChEacetylcholinesteraseADAlzheimer's diseaseANOVAanalysis of varianceAAPamyloid precursor proteinAPP-Aβamyloid precursor protein, amyloid-βAUCarea under the curveBMIbody mass indexChATcholine acetyltransferaseCNScentral nervous systemGFAPglial fibrillary acidic proteinGSK-3βglycogen synthase kinase 3βHFDhigh-fat dietic-STZintracerebral injection of streptozotocinIGFinsulin-like growth factorIRSinsulin receptor substrateMAG-1myelin-associated glycoproteinMCImild cognitive impairmentNASHnonalcoholic steatohepatitisPI3phosphatidyl-inositol-3PPARperoxisome proliferator-activated receptorqRT-PCRquantitative reverse transcriptase polymerase chain reactionSTZstreptozotocinT1DMtype 1 diabetes mellitusT2DMtype 2 diabetes mellitusT3DMtype 3 diabetes mellitusArticle informationJ Diabetes Sci Technol. 2008 Nov; 2(6): 1101–1113.Published online 2008 Nov. doi: 10.1177/193229680800200619PMCID: PMC2769828PMID: 19885299Suzanne M. de la Monte, M.D., M.P.H.1,2,3and Jack R. Wands, M.D.31Department of Pathology, Rhode Island Hospital and the Warren Alpert Medical School at Brown University, Providence, Rhode Island2Department of Clinical Neuroscience, Rhode Island Hospital and the Warren Alpert Medical School at Brown University, Providence, Rhode Island3Department of Medicine, Rhode Island Hospital and the Warren Alpert Medical School at Brown University, Providence, Rhode IslandCorrespondence to: Suzanne M. de la Monte, M.D., M.P.H., Rhode Island Hospital, 55 Claverick Street, Room 419, Providence, RI 02903; e-mail address: ude.nworb@dm_etnomaled_ennazusFunding: This research is supported by AA02666, AA02169, AA11431, AA12908, and AA16126 from the National Institutes of Health.Copyright © 2008 Diabetes Technology SocietyThis article has been cited by other articles in PMC.Articles from Journal of Diabetes Science and Technology are provided here courtesy of Diabetes Technology SocietyReferences1. Jalbert JJ, Daiello LA, Lapane KL. 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No. But you could make yourself sick. Here's a thought. Don't poison yourself with all the garbage in meth and damage your brain.Your question makes me feel like maybe it's too late, though. Don't damage it further.Methamphetamine toxicity and messengers of deathMethamphetamine (METH) is an illicit psychostimulant that is widely abused in the world. Several lines of evidence suggest that chronic METH abuse lea…https://dx.doi.org/10.1016/j.brainresrev.2009.03.002Author ManuscriptHHS Public AccessMETHAMPHETAMINE TOXICITY AND MESSENGERS OF DEATHIrina N. Krasnova and Jean Lud CadetMETHAMPHETAMINE TOXICITY AND MESSENGERS OF DEATHMethamphetamine (METH) is an illicit psychostimulant that is widely abused in the world. Several lines of evidence suggest that chronic METH abuse leads to neurodegenerative changes in the human brain. These include damage to dopamine and serotonin axons, ...https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2731235/#__ffn_sectitleAbstractMethamphetamine (METH) is an illicit psychostimulant that is widely abused in the world. Several lines of evidence suggest that chronic METH abuse leads to neurodegenerative changes in the human brain. These include damage to dopamine and serotonin axons, loss of gray matter accompanied by hypertrophy of the white matter and microgliosis in different brain areas. In the present review, we summarize data on the animal models of METH neurotoxicity which include degeneration of monoaminergic terminals and neuronal apoptosis. In addition, we discuss molecular and cellular bases of METH-induced neuropathologies. The accumulated evidence indicates that multiple events, including oxidative stress, excitotoxicity, hyperthermia, neuroinflammatory responses, mitochondrial dysfunction, endoplasmic reticulum stress converge to mediate METH-induced terminal degeneration and neuronal apoptosis. When taken together, these findings suggest that pharmacological strategies geared towards the prevention and treatment of the deleterious effects of this drug will need to attack the various pathways that form the substrates of METH toxicity.Keywords: methamphetamine, neurotoxicity, dopamine, oxidative stress, serotonin, cell deathEpidemiology of Methamphetamine AbuseAbuse of the illegal psychostimulant, methamphetamine (METH), has become an international public health problem with an estimated 15–16 million users worldwide, a total which exceeds the number of people who abuse heroin and cocaine and makes METH the second most widely abused drug after cannabis (United Nations Office on Drugs and Crime, 2007). The inexpensive production of METH, its low cost, and long duration of action have made it a very desirable commodity. Indeed, METH is a popular drug of abuse in Australia (Australian Institure for Health and Welfare, 2005), Canada (Canadian Centre on Substance Abuse, 2005), Czech Republic and Slovakia (European Monitoring Center for Drugs and Drug Addiction, 2007). During the last decade, Southeast Asia and East Asia have become global hubs for METH production and trafficking, with a coincident epidemic of psychostimulant abuse in these regions (United Nations Office on Drugs and Crime, 2007). It is estimated that over half of the world’s METH consumers reside in Southeast Asia and East Asia (United Nations Office on Drugs and Crime, 2007). Japan, in particular, has experienced several epidemics of crystal METH abuse, including a peak in 1999–2000. Since the late 1990s, METH use rose to epidemic proportions in Thailand, Taiwan, the Philippines and Brunei (United Nations Office on Drugs and Crime, 2007). METH abuse is also a major problem in China, Cambodia, Indonesia, Malaysia, Singapore and Vietnam where smoking of the crystal form of the drug occurs concurrently with pill use (United Nations Office on Drugs and Crime, 2007). Mexico is another country with a growing prevalence of METH use. The proportion of people admitted to treatment for primary psychostimulant problem in this country increased from 3% in 1996 to 20% in 2006 (Mexican National Comorbidity Survey, 2007). In addition, Mexico is a major manufacturer of METH in the world (Dye, 2006). More than a half of METH abused in the USA comes from Mexican cartels primarily in the crystal from known as “ice”, with a purity ranging from 75 to 90% (Dye, 2006). METH is the most commonly synthesized illegal drug in the USA with the highest prelevance of abuse in Western, Southern and Midwestern states; there is an increasing pattern of use in some states in the Eastern corridor of the country (Substance Abuse and Mental Health Services Administration, 2007). A 2006 survey showed that 5.8% of Americans aged 12 years or older used METH at least once (Substance Abuse and Mental Health Services Administration, 2007). METH-related emergency room admissions have increased from 10 to 68 per 100,000 people between 1992 and 2005 (Substance Abuse and Mental Health Services Administration, 2007). Although METH abuse has been associated, traditionally, with white males, blue-collar construction workers, truck drivers, and motorcycle gangs in the USA, the profile of the typical METH abusing individual has shifted due to the increased popularity among minorities, high school students, women, and young professionals (Gettig et al., 2006; Gonzales et al., 2008; Maxwell and Rutkowski, 2008). In addition, METH use is high in men who have sex with men, with a greater frequency of METH abuse being observed in homosexual and bisexual men in comparison to the general population (Reback et al., 2008; Shoptaw and Reback, 2007).Clinical Toxicology of METH AbuseImmediately after taking the drug, users experience a sense of euphoria, increased productivity, hypersexuality, decreased anxiety and increased energy (Homer et al., 2008; Meredith et al., 2005). These effects can last for several hours because the elimination half-life of METH ranges from 10 to 12 hours (Schepers et al., 2003). METH abuse is also associated with a number of negative consequences in humans. These include acute toxicity, altered behavioral and cognitive functions, and neurological damage (Albertson et al., 1999; Barr et al., 2006; Murray, 1998; Scott et al., 2007). METH users might experience agitation, aggression, tachycardia, hypertension, and hyperthermia (Albertson et al., 1999; Lynch and House, 1992; Murray, 1998). Impaired judgment, euphoric disinhibition and psychomotor agitation are also associated with METH abuse (Meredith et al., 2005). Ingestions of large doses of the drug can cause more serious consequences that include life-threatening hyperthermia above 41°C, renal and liver failure, cardiac arrhythmias, heart attacks, cerebrovascular hemorrhages, strokes and seizures (Albertson et al., 1999; Darke et al., 2008; Perez et al., 1999). Chronic abuse of METH contributes to anxiety, depression, aggressiveness, social isolation, psychosis, mood disturbances, and psychomotor dysfunction (Darke et al., 2008; Homer et al., 2008; Scott et al., 2007). Neuropsychological studies have detected deficits in attention, working memory, and decision-making in chronic METH addicts (Gonzalez et al., 2004; Paulus et al., 2002; Rippeth et al., 2004; Salo et al., 2002; Semple et al., 2005; Sim et al., 2002; Simon et al., 2002, 2004; Verdejo-Garcia et al., 2006; Woods et al., 2005). Withdrawal from METH can produce anhedonia, irritability, fatigue, impaired social functioning, and intense craving for the drug (Brecht et al., 2004; Darke et al., 2008; Homer et al., 2008; Sekine et al., 2006; Zweben et al., 2004). There is compelling evidence that the negative neuropsychiatric consequences of METH abuse are due, at least in part, to drug-induced neuropathological changes in the brains of these METH-exposed individuals (Scott et al., 2007).Neuroimaging studies have revealed that METH can indeed cause neurodegenerative changes in the brains of human addicts (Aron and Paulus, 2007; Chang et al., 2007). These abnormalities include persistent decreases in the levels of dopamine transporters (DAT) in the orbitofrontal cortex, dorsolateral prefrontal cortex, and the caudate-putamen (McCann et al., 1998, 2008; Sekine et al., 2003; Volkow et al., 2001a, 2001c). The density of serotonin transporters (5-HTT) is also decreased in the midbrain, caudate, putamen, hypothalamus, thalamus, the orbitofrontal, temporal, and cingulate cortices of METH-dependent individuals (Sekine et al., 2006). Psychostimulant addicts also show abnormal glucose metabolism in cortical and subcortical brain areas (Volkow et al., 2001b; Wang et al., 2004). In addition, a recent positron emission tomography (PET) study has demonstrated prominent microglial activation in the midbrain, striatum, thalamus, orbitofrontal and insular cortices of METH abusers (Sekine et al., 2008). The levels of microglial activation correlated inversely with duration of METH abstinence (Sekine et al., 2008). Structural magnetic resonance imaging (MRI) studies in METH addicts have revealed substantial morphological changes in their brains. These include loss of gray matter in the cingulate, limbic and paralimbic cortices, significant shrinkage of hippocampi, and hypertrophy of white matter (Thompson et al., 2004). In addition, the brains of METH abusers show evidence of hyperintensities in white matter (Bae et al., 2006; Ernst et al., 2000), decreases in the neuronal marker, N-acetylaspartate (Ernst et al., 2000; Sung et al., 2007), reductions in a marker of metabolic integrity, creatine (Sekine et al., 2002) and increases in a marker of glial activation, myoinositol (Chang et al., 2002; Ernst et al., 2000; Sung et al., 2007; Yen et al., 1994). Elevated choline levels, which are indicative of increased cellular membrane synthesis and turnover are also evident in the frontal gray matter of METH abusers (Ernst et al., 2000; Salo et al., 2007; Taylor et al., 2007).Post-mortem analyses have also provided evidence of decreases in dopamine (DA), tyrosine hydroxylase (TH), and DAT levels in the caudate-putamen and in the nucleus accumbens (Kitamura et al., 2007; Moszczynska et al., 2004; Wilson et al., 1996) and reductions in 5-HTT levels in the orbitofrontal and occipital cortices (Kish et al., 2008) of chronic METH users. In addition, increased levels of the lipid peroxidation products, 4-hydroxynonenal and malonedialdehyde, are found in the caudate and frontal cortex of chronic METH users (Fitzmaurice et al., 2006). Finally, the levels of antioxidant compounds, CuZn superoxide dismutase (CuZnSOD), glutathione, and uric acid are increased in the caudate of METH abusers (Mirecki et al., 2004).Animal Models of METH ToxicityIn agreement with the clinical literature, a number of animal studies have shown that METH can cause long-term destruction of presynaptic dopaminergic and serotoninergic terminals. It has also been shown that the drug can elicit neuronal death in the brain by causing apoptosis. In what follows, we review some of the animal models of METH toxicity and further discuss mechanisms that might underlie these drug-induced neurodegenerative effects.MonkeysIn order to better reproduce human drug-taking behavior and tolerance related to chronic METH abuse, Seiden et al. (1976) studied the effects of long-term intravenous escalating-dose METH administration to rhesus monkeys. Animals treated for 2 weeks or 3–6 months with increasing doses of the psychostimulant showed acute reductions in norepinephrine (NE) levels in the frontal cortex, midbrain, hypothalamus and pons-medulla and 70–80% decreases in DA levels in the caudate nucleus that lasted up to 6 months after cessation of drug injections (Seiden et al., 1976). Later studies from the same group have demonstrated that treatment with increasing doses of METH causes persistent depletion of DA levels in the caudate (Ando et al., 1985; Finnegan et al., 1982; Preston et al., 1985a, 1985b) that is accompanied by a reduction in the number of DA uptake sites (Preston et al., 1985b). In addition, there are significant drug-related decreases in 5-HT concentrations in the striatum, cortex and hippocampus of nonhuman primates (Ando et al., 1985; Preston et al., 1985a). A study which used long-term escalating doses of METH in vervet monkeys in order to approximate human psychostimulant use has also shown that such a treatment regimen causes 20% reduction in DA levels and 35% decreases in DAT binding in the striatum (Melega et al., 2008).In agreement with these findings, PET studies in vervet monkeys and baboons have described METH-induced reduction in DA synthesis (Melega et al., 1997), DA levels (Melega et al., 2000; Villemagne et al., 1998), and decreases in DAT binding sites (Melega et al., 2000; Villemagne et al., 1998) in the striatum. In contrast, DA neuronal cell bodies in the substantia nigra were not affected by METH treatment (Melega et al., 1997). The absence of damage to DA neuronal cell bodies in the substantia nigra is thought to account for the time-dependent partial recovery of DA synthesis and DA concentrations observed in the striatum after injections of toxic doses of METH in nonhuman primates (Melega et al., 1997). Nevertheless, METH-induced decreases in brain DA and 5-HT levels in primates can be persistent, evident even at 4 years after administration of high doses of the drug (Woolverton et al., 1989). Because monkeys, like humans, metabolize METH mainly by side-chain deamination, whereas rats metabolize the drug by ring hydroxylation (Caldwell, 1976), the findings in non-human primates are thought to be more parallel to the effects of the drug in humans. Because post-mortem data have shown that the drug can cause respective ~60% and ~40% decreases in DA levels and DAT binding in the striatum of chronic abusers (Moszczynska et al., 2004; Wilson et al., 1996), it remains to be determined what patterns of METH injections in nonhuman primates will actually better mimic human conditions since humans also differ in their patterns of use. The results of the studies showing evidence of METH toxicity in nonhuman primates are summarized in Table 1.METHAMPHETAMINE TOXICITY AND MESSENGERS OF DEATHMethamphetamine (METH) is an illicit psychostimulant that is widely abused in the world. Several lines of evidence suggest that chronic METH abuse leads to neurodegenerative changes in the human brain. These include damage to dopamine and serotonin axons, ...https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2731235/table/T1/?report=objectonlySummary of studies showing evidences of METH neurotoxicity in monkeysRatsRats treated acutely with various doses of injected METH show long-lasting decreases in DA levels (Bittner et al., 1981; Cappon et al., 2000; Chapman et al., 2001; Eisch et al., 1992; Fukumura et al., 1998; Green et al., 1992; Kogan et al., 1976; Morgan and Gibb, 1980; Ricaurte et al., 1980; Richards et al., 1993; Truong et al., 2005; Wagner et al., 1979, 1980; Walsh and Wagner, 1992), long-term reductions in the activity of TH (Hotchkiss and Gibb, 1980; Hotchkiss et al., 1979; Morgan and Gibb, 1980), and marked decreases in the number of DAT (Eisch et al., 1992; Guilarte et al., 2003; Wagner et al., 1980) in the striatum. In addition, METH causes depletions of 5-HT levels in the rat striatum (Bakhit et al., 1981; Cappon et al., 2000; Friedman et al., 1998; Fukumura et al., 1998; Ricaurte et al., 1980; Richards et al., 1993; Walsh and Wagner, 1992) accompanied by decreases in tryptophan hydroxylase (TPH) activity (Bakhit et al., 1981; Hotchkiss and Gibb, 1980; Hotchkiss et al., 1979; Morgan and Gibb, 1980) and loss of 5-HTT (Armstrong and Noguchi, 2004; Guilarte et al., 2003). Similar METH injections have also been reported to cause decreases in vesicular monoamine transporter 2 (VMAT-2) binding (Guilarte et al., 2003; Segal et al., 2005) and immunoreactivity (Eyerman and Yamamoto, 2007) in the rat striatum. Morphological studies suggest that the reductions in the markers of DA and 5-HT system integrity are related to degeneration of DA and 5-HT axonal terminals (Axt and Molliver, 1991; Fukui et al., 1989; Lorez, 1981; Ricaurte et al., 1982, 1984). The neurotoxic damage to striatal axonal terminals is accompanied by reactive astrocytosis (Bowyer et al., 1994; Cappon et al., 2000; Fukumura et al., 1998) and microglial activation (Pubill et al., 2002).In addition to the striatum, METH has been shown to cause decreases in 5-HT levels in medial prefrontal and somatosensory cortices, nucleus accumbens, hippocampus, hypothalamus and amygdala (Bakhit et al., 1981; Baldwin et al., 1993; Commins and Seiden, 1986; Friedman et al., 1998; Green et al., 1992; Ohmori et al., 1993; Ricaurte et al., 1980; Richards et al., 1993). There was also a significant decrease in 5-HTT binding in the anterior cingulate, nucleus accumbens, amygdala, hippocampus, somatosensory cortex, hypothalamus, thalamus and septum (Armstrong and Noguchi, 2004; Guilarte et al., 2003). TPH activity in the cortex, hippocampus and nucleus accumbens is also affected by METH (Bakhit et al., 1981; Hotchkiss and Gibb, 1980; Morgan and Gibb, 1980). Moreover, binge doses of METH cause significant depletion of NE in the striatum, cortex and hippocampus (Graham et al., 2008). Similar to the observations in monkeys, rats showed some recovery in the levels of monoamines measured several months after the psychostimulant injections (Friedman et al., 1998). In addition to damage to monoaminergic terminals, METH treatment can cause death of neuronal cell bodies in the striatum (Jayanthi et al., 2005), the medial prefrontal (Kadota and Kadota, 2004) and in somatosensoty cortices (Commins and Seiden, 1986; Eisch and Marshall, 1998; O'Dell and Marshall, 2000) of the rat.Because single day binge METH injections are not thought to mimic the pattern of human METH use, which involves a gradual escalation of doses and frequency of intake, several groups of investigators focused their attention on using escalating METH dosing to evaluate its impact on monoaminergic systems (Danaceau et al., 2007; Graham et al., 2008; Johnson-Davis et al., 2003, 2004; Kuczenski et al., 2007; Schmidt et al., 1985b; Segal and Kuczenski, 1997; Segal et al., 2003, 2005; Stephans and Yamamoto, 1996). These studies have shown that the pretreatment with multiple low-dose injections of METH or with gradually escalating doses of the drug followed by a high-dose challenge METH administration may afford partial protection against its deleterious effects on DA and 5-HT systems when compared to the patterns of single-day multiple drug injections (Danaceau et al., 2007; Graham et al., 2008; Johnson-Davis et al., 2003, 2004; Schmidt et al., 1985b; Segal et al., 2003; Stephans and Yamamoto, 1996). Specifically, METH pretreatment attenuates acute decreases in TH and TPH activity in the striatum and hippocampus (Gygi et al., 1996; Schmidt et al., 1985b) as well as reductions in DA and 5-HT levels in the striatum and cortex of rats (Danaceau et al., 2007; Graham et al., 2008; Schmidt et al., 1985b) 18 and 24 hours after the last dose of the drug. In addition, pretreatment with METH prior to high-dose METH challenge attenuates long-term depletion of DA levels in the striatum (Johnson-Davis et al., 2003, 2004; Segal et al., 2003; Stephans and Yamamoto, 1996), reductions in 5-HT levels in the striatum, cortex and hippocampus (Johnson-Davis et al., 2003; Stephans and Yamamoto, 1996) and decline in DAT binding (Segal et al., 2003) in the striatum as shown 4 – 7 days after injections. Interestingly, a recent study demonstrated that the protection afforded by escalating dose regimen is diminished and eventually disappears if the duration between the initial METH insult and the challenge treatment was increased to 14 – 31 days (Danaceau et al., 2007). Together, these results suggest that DA and 5-HT axons become resistant to toxic effects of high doses of METH in animals previously exposed to the drug.Pretreatment with gradually escalating doses of METH followed by high-dose METH binge also causes cell death manifested by loss of pyramidal neurons in the rat cortex and in the CA3 region of the hippocampus 30 days after last injection (Kuczenski et al., 2007). In addition, some pyramidal neurons show loss of their dendrite complexity, tortuous processes and dystrophic neurites consistent with neurodegeneration in the frontal cortex and in both CA1 and CA3 regions of the hippocampus (Kuczenski et al., 2007). Moreover, escalating dose-multiple binge METH injections induce loss of calbinding interneurons in the cortex and dentate gyrus (Kuczenski et al., 2007). This regimen also causes microglial activation at 3 days and at 30 days after METH treatment (Kuczenski et al., 2007), in a manner similar to the observations of microgliosis in the brains of METH-addicted individuals (Sekine et al., 2008). The data on METH toxicity in rats are presented in Table 2.METHAMPHETAMINE TOXICITY AND MESSENGERS OF DEATHMethamphetamine (METH) is an illicit psychostimulant that is widely abused in the world. Several lines of evidence suggest that chronic METH abuse leads to neurodegenerative changes in the human brain. These include damage to dopamine and serotonin axons, ...https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2731235/table/T2/?report=objectonlySummary of studies showing evidences of METH toxicity in ratsMiceMice given repeated doses of METH experience significant loss of DA in the striatum (Achat-Mendes et al., 2005; Cadet et al., 1994b; Fantegrossi et al., 2008; Green et al., 1992; Ladenheim et al., 2000; O'Callaghan and Miller, 1994) and cortex (Achat-Mendes et al., 2005; Fantegrossi et al., 2008; Ladenheim et al., 2000); decreases in DAT binding (Achat-Mendes et al., 2005; Hirata et al., 1996; Ladenheim et al., 2000; Xu et al., 2005; Zhu et al., 2005) and DAT protein levels in the striatum (Deng et al., 1999; Fumagalli et al., 1999) and in the olfactory bulb (Deng et al., 2007), as well as decreased striatal TH immunoreactivity (Bowyer et al., 2008; Deng et al., 1999) and TH protein levels (O'Callaghan and Miller, 1994; Xu et al., 2005; Zhu et al., 2005). The majority of the mice strains studied have shown resistance to METH toxicity against 5-HT systems in contrast to the effects of the drug in rats and monkeys (Achat-Mendes et al., 2005; Anderson and Itzhak, 2006; Kita et al., 1998). Nevertheless, C57BL/6J and C57BL/129sVj mice do show METH-induced depletion of 5-HT levels in the striatum and hippocampus (Fumagalli et al., 1998; Ladenheim et al., 2000).METH can also cause neuronal death in the striatum, frontal and parietal cortices, hippocampus and olfactory bulb of mice (Deng et al., 1999, 2001, 2007; Ladenheim et al., 2000; Schmued and Bowyer, 1997; Zhu et al., 2005, 2006a, 2006b). This occurs through processes akin to neuronal apoptosis (Cadet et al., 2005, 2007; Cunha-Oliveira et al., 2008). In the striatum, METH-induced cell death involves medium spiny projection neurons that express enkephalin, cholinergic, and parvalbumin-positive interneurons, but not somatostatin/neuronal nitric oxide synthase (nNOS)-positive interneurons (Thiriet et al., 2005; Zhu et al., 2006a). METH injections also cause reactive astrocytosis (Achat-Mendes et al., 2007; Deng et al., 1999; Zhu et al., 2005) and microgliosis (Bowyer et al., 2008; Fantegrossi et al., 2008; Thomas and Kuhn, 2005a; Thomas et al., 2004c) in the mouse striatum. Table 3 summarizes data on METH toxicity in mice.METHAMPHETAMINE TOXICITY AND MESSENGERS OF DEATHMethamphetamine (METH) is an illicit psychostimulant that is widely abused in the world. Several lines of evidence suggest that chronic METH abuse leads to neurodegenerative changes in the human brain. These include damage to dopamine and serotonin axons, ...https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2731235/table/T3/?report=objectonlySummary of studies showing evidences of METH toxicity in miceRole of Dopamine and Oxidative Stress in METH toxicityThe toxic effects of METH are thought to depend on the similarity of its chemical structure to DA, which allows the drug to enter DA axons (Iversen, 2006), followed by DA release from synaptic vesicles into cytoplasm and by reverse transport into the synaptic cleft (Sulzer et al., 2005). Indeed, numerous studies have conclusively shown that DA is an important component of the mechanisms that subserve METH neurotoxicity (Figure 1). For example, agents that decrease DA levels in the brain, such as the TH inhibitor, α-methyl-p-tyrosine, also protect against METH-induced damage to striatal DA axons (Axt et al., 1990; Gibb and Kogan, 1979; Hotchkiss and Gibb, 1980; Schmidt et al., 1985a; Thomas et al., 2008; Wagner et al., 1983), whereas treatment with immediate DA precursor, L-DOPA, that restores cytoplasmic DA levels, reverses this protective effect and enhances drug toxicity (Gibb and Kogan, 1979; Schmidt et al., 1985a; Thomas et al., 2008) (Figure 1). Pretreatment with L-DOPA alone which causes ~50% increase in striatal DA levels prior to METH injections also exacerbates drug-induced DA depletion at 2, 7 and 14 days after treatment (Thomas et al., 2008; Weihmuller et al., 1993). In addition, the MAO inhibitors, pargyline and clorgyline, which cause increases in cytoplasmic DA levels, exacerbate METH neurotoxicity (Kita et al., 1995; Thomas et al., 2008; Wagner and Walsh, 1991) (Figure 1). The role for DA in the mediation of METH toxicity is also supported by studies showing that it causes reactive oxygen species (ROS) production and oxidative stress in ventral midbrain cultures that contain DA neurons, but not in cultures of cells obtained in the nucleus accumbens that do not contain DA neurons (Cubells et al., 1994). The observations of METH-induced ROS in normal but not in DA-depleted striatal synaptosomes (Pubill et al., 2005) further support the involvement of DA in METH toxicity.METHAMPHETAMINE TOXICITY AND MESSENGERS OF DEATHMethamphetamine (METH) is an illicit psychostimulant that is widely abused in the world. Several lines of evidence suggest that chronic METH abuse leads to neurodegenerative changes in the human brain. These include damage to dopamine and serotonin axons, ...https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2731235/figure/F1/?report=objectonlySchematic rendering of cellular and molecular events involved in METH-induced DA terminal degeneration and neuronal apoptosis within the striatum. The figure summarizes findings of various studies that have addressed the role of DA, oxidative stress, ...Studies have also emerged to show that DA plays an important role in the toxic effects of METH towards 5-HT axons. For example, α-methyl-p-tyrosine, which was shown to protect against METH-induced toxicity towards DA axons, also prevents long-term decrease in TPH activity (Hotchkiss and Gibb, 1980; Schmidt et al., 1985a) and reductions in 5-HT levels (Axt et al., 1990; Schmidt et al., 1985a) in the striatum and hippocampus. However, when cytoplasmic DA levels were restored by pretreatment with L-DOPA, α-methyl-p-tyrosine failed to protect against decreases in TPH activity and 5-HT concentrations caused by METH treatment (Schmidt et al., 1985a). In addition, α-methyl-p-tyrosine also blocked METH-induced decreases in 5-HT levels in the rat somatosensory cortex (Axt et al., 1990; Commins and Seiden, 1986). Together, these findings support the idea that DA participates in METH-induced 5-HT toxicity in the rodent brain.After its displacement to the cytoplasm by METH, DA rapidly auto-oxidizes to form potentially toxic substances including superoxide radicals, hydroxyl radicals, hydrogen peroxide and DA quinones (Acikgoz et al., 1998; Cubells et al., 1994; Kita et al., 1999; Larsen et al., 2002; LaVoie and Hastings, 1999; Lazzeri et al., 2007; Miyazaki et al., 2006; Stokes et al., 1999). Stone et al. (1989) were among the first investigators to report that METH can reduce the activity of TPH in the rat hippocampus within 1 hour after treatment by causing oxidation of thiol groups of the enzyme, therefore suggesting a role for ROS and oxidative stress in the deleterious effects of the drug. Later, LaVoie and Hastings (1999) found that administration of neurotoxic doses of METH to rats caused DA oxidation to DA quinones that bind to cysteinyl residues on proteins, leading to an increase in protein cysteinyl-DA levels in the striatum. Increases in DA oxidation occurred only under conditions resulting in toxicity, suggesting that the oxidation of DA may contribute to the mechanism of METH-induced damage to DA terminals (LaVoie and Hastings, 1999). DA metabolism by MAO is also accompanied by increased production of hydrogen peroxide which interacts with metal ions such as iron, whose level is elevated by METH treatment (Melega et al., 2007), to form toxic hydroxyl radicals (Cadet and Brannock, 1998). Indeed, METH has been shown to induce increased levels of 2,3-dihydroxybenzoic acid, a marker for hydroxyl radical production, in the rat striatum 2 hours after treatment (Giovanni et al., 1995). The accumulated evidence indicates that METH can also cause oxidative stress by switching the balance between ROS production and the capacity of antioxidant enzyme systems to scavenge ROS (Chen et al., 2007; Gluck et al., 2001; Harold et al., 2000; Iwazaki et al., 2006; Jayanthi et al., 1998; Kobeissy et al., 2008; Li et al., 2008). For example, METH administration causes decreases in the levels of CuZnSOD, catalase, glutathione, and peroxiredoxins in the brain (Chen et al., 2007; Gluck et al., 2001; Harold et al., 2000; Iwazaki et al., 2006; Jayanthi et al., 1998; Kobeissy et al., 2008; Li et al., 2008) accompanied by elevated lipid peroxidation and substantial increases in the levels of protein carbonyls (Chen et al., 2007; Gluck et al., 2001; Harold et al., 2000; Iwazaki et al., 2006; Jayanthi et al., 1998; Kobeissy et al., 2008; Li et al., 2008). Increased levels of the lipid peroxidation products, 4-hydroxynonenal and malonedialdehyde observed in the brains of chronic METH addicts provide evidence for the generation of ROS by the drug and subsequent oxidative damage in the brains of human addicts (Fitzmaurice et al., 2006). The elevated levels of antioxidants, such as CuZnSOD and glutathione, in the brains of METH abusers also suggest compensatory responses to oxidative stress (Mirecki et al., 2004). Excessive production of ROS that overwhelm this protective antioxidant system can damage cellular components such as lipids, proteins, mitochondrial and nuclear DNA (Potashkin and Meredith, 2006). These deleterious effects might be responsible, in part, for both METH-induced terminal degeneration and neuronal apoptosis (Figure 1).A potent role for oxidative mechanisms in METH toxicity is also consistent with findings that pretreatment with antioxidants such as N-acetyl-L-cysteine, ascorbic acid and vitamin E affords protection against psychostimulant-induced depletion of monoaminergic axons (De Vito and Wagner, 1989; Fukami et al., 2004; Hashimoto et al., 2004; Wagner et al., 1985). The involvement of superoxide radicals in the neurotoxic effects of METH on DA terminals was tested by injecting the drug to transgenic mice that overexpress the human CuZnSOD, a cytosolic enzyme that catalyzes the breakdown of superoxide radicals (Cadet et al., 1994a, 1994b; Hirata et al., 1996; Jayanthi et al., 1998). These mice which have much higher CuZnSOD enzyme activity in the cytosol than control wild-type animals (Jayanthi et al., 1998) were protected against METH toxicity (Cadet et al., 1994a, 1994b; Hirata et al., 1996). METH neurotoxicity is also attenuated in striatum of mice that overexpress human manganese superoxide dismutase (MnSOD) that catalyzes detoxification of superoxide radicals within mitochondria (Maragos et al., 2000). These data are consistent with the demonstration that METH-induced depletions of DA and 5-HT levels in the rat striatum are exacerbated by the SOD inhibitor, diethyldithiocarbamate (De Vito and Wagner, 1989). In addition, the fact that the scavenger of hydroxyl radicals, bromocriptine, also protects against METH-related DA depletion in the brain supports a role for these radicals in causing the toxicity associated with the use of the drug (Kondo et al., 1994). The idea that oxygen-based free radicals are involved in METH neurotoxicity is further strengthened by reports that the drug can reduce the levels of glutathione (Harold et al., 2000; Moszczynska et al., 1998) and of antioxidant enzymes (Chen et al., 2007; D'Almeida et al., 1995; Iwazaki et al., 2006; Jayanthi et al., 1998; Kobeissy et al., 2008; Li et al., 2008), can induce lipid peroxidation (Acikgoz et al., 1998; Gluck et al., 2001; Jayanthi et al., 1998), and can cause the formation of protein carbonyls (Gluck et al., 2001). Together, these findings support the proposition that METH-induced DA release is accompanied by redox cycling of DA quinones and consequent formation of superoxide and hydroxyl radicals.In addition to their potential participation in damaging monoaminergic axons, ROS formation and associated oxidative stress may be involved in METH-related neuronal apoptosis because psychostimulant-induced poly (ADP-ribose) polymerase (PARP) cleavage, increase in caspase-3 activity, and neuronal death are all attenuated in the striata of CuZnSOD transgenic mice (Deng and Cadet, 2000) (see Figure 1). METH-induced death in CATH.a cells is also attenuated by the antioxidant, glutathione, and by inhibitors of DA synthesis and release (Choi et al., 2002). Moreover, overexpression of glutathione peroxidase in PC12 cells protects against drug-related increases in ROS production, lipid peroxidation and cell death (Hom et al., 1997). The idea that oxidative stress may play a role in METH-induced cell death is also supported by findings showing that decline in mitochondrial membrane potential, increase in the levels of ROS and apoptosis in human dopaminergic neuroblastoma SH-SY5Y cell line are attenuated by vitamin E (Wu et al., 2007).Attempts to further identify mechanisms that underlie METH-induced oxidative stress have revealed that the drug causes DA-dependent production of ROS in striatal synaptosomes, and that ROS production can be suppressed by antioxidants and by inhibitors of nNOS and protein kinase C (Pubill et al., 2005). EGTA and the antagonist of α7 nicotinic acetylcholine receptors, methylcaconitine, also prevented increased production of ROS, thus implicating Ca2+ and α7 nicotinic receptors in METH toxicity (Escubedo et al., 2005; Pubill et al., 2005). Together, these studies suggest that METH-induced ROS production might depend, in part, on the activation of α7 nicotinic receptors which stimulate increases in intrasynaptosomal Ca2+ (Escubedo et al., 2005; Pubill et al., 2005). This could lead to nNOS activation and stimulation of protein kinase C, with oxidation of cytosolic DA and subsequent ROS formation (Escubedo et al., 2005; Pubill et al., 2005).Role of DAT, VMAT-2 and 5-HTT in METH-induced ToxicityAs mentioned above, METH is known to interact with both the DAT and VMAT-2 to release DA withing the cytosol of DA terminals and into the extracellular space (Sulzer et al., 2005). Thus, it was not surprising to suggest that these proteins might play an important role in METH neurotoxicity. Indeed, the involvement of DAT in METH toxicity is supported by studies showing that the DAT inhibitor, amphoneic acid, was able to protect against drug-induced striatal DA depletion (Marek et al., 1990) and decrease in striatal TH activity (Schmidt and Gibb, 1985a) by blocking reversed transport of DA into the synaptic cleft (Figure 1). A role of DAT in METH toxicity is also supported by studies using DAT knockout mice that are protected against drug-induced DA depletion, reactive astrocytosis, and ROS production in the striatum (Fumagalli et al., 1998). Further studies have shown that administration of the DAT inhibitor, methylphenidate, 1 hour after METH treatment could reverse decreases in vesicular DA uptake, reductions in VMAT-2 ligand binding and decreases in VMAT-2 immunoreactivity in vesicular subcellular fractions 6 hours after injections of the drugs (Sandoval et al., 2003). The methylphenidate post-treatment also protected against long-term DA deficits, suggesting that alterations in VMAT-2 functions might contribute to METH toxicity (Sandoval et al., 2003). A role for VMAT-2 in METH-induced damage to striatal DA terminals is also supported by studies showing that pretreatment with the irreversible inhibitor of vesicular transport, reserpine, exacerbates toxicity of the psychostimulant (Albers and Sonsalla, 1995; Kuhn et al., 2008; Thomas et al., 2008; Wagner et al., 1983) although these observations might be more related to the DA depletion associated with such treatments (Figure 1). Further evidence of the involvement of VMAT-2 in METH-induced terminal degeneration is provided by observations that decreases in DA concentrations and reductions in DAT protein levels are potentiated in the striata of VMAT-2 heterozygote mice (Fumagalli et al., 1999). METH also causes increased degeneration of DA neurites and accumulation of ROS in ventral midbrain neuronal cultures derived from VMAT-2 deficient mice in comparison to cultures obtained from wild-type animals (Larsen et al., 2002). Other supportive studies on the role of VMAT-2 in METH toxicity have shown that the administration of the alkaloid, lobeline (Eyerman and Yamamoto, 2005), after injections of METH could reverse the decreases in synaptosomal, membrane-associated and vesicular VMAT-2 immunoreactivity 24 hours after psychostimulant treatment and was able to protect against striatal DA depletion measured 7 days later. Taken together, these results suggest that dysregulation of VMAT-2 function and/or trafficking is important for manifestation of persistent DA deficits caused by METH treatment.Several studies have also focused on the role of 5-HTT in METH-induced damage to 5-HT axons. A number of 5-HTT inhibitors that include fluoxetine, citalopram, and chlorimipramine, have been shown to block METH-induced reductions in TPH activity and to prevent 5-HT depletion in the striatum, hippocampus and cortex (Hotchkiss and Gibb, 1980; Ricaurte et al., 1983; Schmidt and Gibb, 1985b), suggesting a role for 5-HTT in mechanisms of drug toxicity towards 5-HT terminals. However, 5-HTT inhibitors failed to prevent decreases in striatal TH activity and DA levels caused by METH treatment (Ricaurte et al., 1983; Schmidt and Gibb, 1985b). Thus, this area deserves further investigations in view of the fact that human subsects exhibit substantial decreases in 5-HTT markers in several brain regions (Kish et al., 2008; Sekine et al., 2006).Role of Dopamine Receptors in METH ToxicityThe review has so far demonstrated a significant involvement of presynaptic elements in METH-induced toxicity. Interestingly, several investigators have also demonstrated that DA receptors located on striatal cells post-synaptic to DA terminals are also involved in METH toxicity against striatal DA and 5-HT terminals (Angulo et al., 2004; Jayanthi et al., 2005; O'Dell et al., 1993; Sonsalla et al., 1986, Xu et al., 2005) (Figure 1). Specifically, pretreatment with DA D1 receptor antagonist, SCH23390, given before each of 5 METH injections was able to attenuate drug-induced decreases in TH activity and DA levels in the rat striatum and reductions in TPH activity and 5-HT levels in the striatum and cortex measured 18–20 hours after METH treatment (Sonsalla et al., 1986). Interestingly, the DA D2 receptor antagonist, sulpiride, also blocked METH-induced toxic effects on DA systems without affording any protection to striatal and cortical 5-HT terminals (Sonsalla et al., 1986). Similarly, treatment with either the D1 antagonist, SCH23390, or the D2 antagonist, eticlopride, before each of binge METH injections completely prevented reductions in striatal DA levels measured 7 days later (O'Dell et al., 1993). In addition, a single injection of the DA D1 receptor antagonist, SCH23390, or DA D2 receptor antagonist, raclopride, prior to a single high-dose METH injection also attenuated long-term decreases in DA levels (Jayanthi et al., 2005), reductions in DAT binding, depletion in TH protein levels and reactive astrocytosis (Xu et al., 2005). SCH23390 also protected against METH-induced cell death in the striatum (Jayanthi et al., 2005; Xu et al., 2005). These neuroprotective effects might depend, in part, on changes in DA release because DA receptor antagonists were reported by one group of investigators to partially block METH-related increases in DA release in the striatum (O'Dell et al., 1993). Specifically, microdialysis experiments have revealed that multiple METH doses injected 2 hours apart caused marked increases in extracellular DA levels in the rat stiatum which reached ~950% of control levels 1.5 hours after cessation of drug treatment (O'Dell et al., 1993). This dramatic increase in DA release was attenuated by pretreatment with the DA receptor antagonists, SCH23390 and eticlopride, prior to each of METH injections (O'Dell et al., 1993). The protection afforded by SCH23390 against METH-mediated cell death may also depend on the Fas/FasL death pathway because pretreatment with the antagonist caused significant inhibition of increases in the expression of FasL and caspase-3 caused by METH treatment in rat striatal cells (Jayanthi et al., 2005). Because the dose of SCH23390 used in that study completely blocks METH-induced decreases in DA levels while providing only partial protection against death of striatal neurons (Jayanthi et al., 2005), the possibility exists that drug-related cell death might involve additional mechanisms independent of stimulation of DA D1 receptors. Some of these factors might include METH-induced excitotoxicity via gluatamate release in the striatum. These are discussed below.METH Toxicity and ExcitotoxicityMETH neurotoxicity has also been shown to involve excitotoxic damage following glutamate release and activation of glutamate receptors (Yamamoto and Bankson, 2005). The role for glutamate in METH toxicity is supported by findings that the psychostimulant causes glutamate release in the brain (Abekawa et al., 1994; Baldwin et al., 1993; Mark et al., 2004; Marshall et al., 1993; Nash and Yamamoto, 1992; Nash et al., 1988; Stephan sand Yamamoto, 1994). It has been reported that some glutamate receptor antagonists, including MK-801 and dizocilpine, can reduce METH-induced degeneration of DA and 5-HT terminals in different brain regions (Battaglia et al., 2002; Bowyer et al., 2001; Chipana et al., 2008; Farfel et al., 1992; Fuller et al., 1992; Golembiowska et al., 2003; Green et al., 1992; Ohmori et al., 1993; Sonsalla et al., 1989, 1991; Weihmuller et al., 1992). These drugs can protect against METH-induced death in PC12 cells (Uemura et al., 2003) and can also attenuate inhibition of mitochondrial complex II caused by METH treatment in the striatum (Brown et al., 2005). However, because MK-801 and dizocilpine also block hyperthermia which plays an important role in METH toxicity (Albers and Sonsalla, 1995; Bowyer et al., 1994; Farfel and Seiden, 1995), these results suggest that neuroprotection afforded by glutamate receptor antagonists might depend, in part, on inhibition of METH-mediated hyperthermic responses. It is to be noted that administration of low, non-neurotoxic concentrations of NMDA together with non-neurotoxic doses of METH exacerbates drug toxicity causing reduction in DA levels in mouse striatum (Sonsalla et al., 1998), further supporting the idea that DA and gluatame might interact to cause toxic effects towards striatal DA terminals. Reports that chronic stress can increase METH-induced glutamate concentrations and thereby, exacerbate damage to striatal DA and 5-HT terminals (Quinton and Yamamoto, 2007; Tata and Yamamoto, 2008) also support the involvement of glutamate in METH toxicity. The observation that treatment with the corticosterone synthesis inhibitor, metyrapon, which attenuates stress-induced enhanced glutamate release, can also reduce METH neurotoxicity (Tata and Yamamoto, 2008) provides further support for the excitotoxicity hypothesis.It is important to note that unlike METH-induced striatal DA release, which occurs via reversed transport (Sulzer et al., 2005), glutamate release in the striatum is thought to be initiated by DA D1 receptor-dependent stimulation of striatonigral GABAergic pathway that causes increases in GABA release in the substantia nigra pars reticulata, inhibition of nigrothalamic GABAergic outflow via activation of GABAA receptors, followed by disinhibition of thalamocortical afferents with consequent increases in striatal glutamate release (Mark et al., 2004). METH has also been shown to increase the synthesis and expression of vesicular glutamate transporters that enhance vesicular glutamate uptake and can sustain increases in striatal glutamate release (Mark et al., 2007). Glutamate toxicity may depend, in part, on the production of superoxide radicals and nitric oxide (NO) because METH-induced increase in glutamate release might lead to excessive activation of NMDA receptors and subsequent formation of superoxide radicals and NO (Gunasekar et al., 1995; Lafon-Cazal et al., 1993). This suggestion is supported by observations that knockout mice deficient in nNOS or mice that overexpress CuZnSOD are protected against METH toxicity (Cadet et al., 1994b; Hirata et al., 1996; Imam et al., 2001c; Itzhak et al., 1998). The first evidence that NO might be involved in METH toxicity was reported by the Cadet’s laboratory which showed that NOS inhibitors, Nw-nitro-L-arginine and monomethyl-L-arginine, attenuated drug-induced cell death in primary mecencephalic cultures (Sheng et al., 1996). The selective nNOS inhibitor, 7-nitroindazole, also protects against METH-induced DA and 5-HT depletion in the striatum (Ali and Itzhak, 1998; Di Monte et al., 1996; Itzhak and Ali, 1996). The participation of NO in METH neurotoxicity is also supported by findings that another nNOS inhibitor, S-methyl-L-thiocitrulline, blocks METH-related VMAT-2 protein oxidation and decreases in VMAT-2 immunoreactivity in striatal synaptosomes (Eyerman and Yamamoto, 2007). NO can react with superoxide radicals to form the strong oxidant and major neurotoxin, peroxynitrite (Pacher et al., 2007). NO-mediated toxicity is accompanied by an increased production of 3-nitrotyrosine, which is used as a marker for peroxynitrite production (Pacher et al., 2007). Imam et al. (2001a) have reported METH-induced increases in 3-nitrotyrosine in vitro and in vivo models of toxicity. The antioxidants, selenium and melatonin, have been reported to completely block the formation of 3-nitrotyrosine and striatal DA depletion (Imam et al., 2001a). The free radical scavenger, edaravone, also blocked METH-related increases in 3-nitrotyrosine immunoreactivity and attenuated striatal DA depletion and reduction in TH immunoreactivity caused by the drug (Kawasaki et al., 2006). The involvement of NO and peroxynitrite in METH effects is further supported by a study showing that the peroxynitrite scavenger, 5,10,15,20-tetrakis (2,4,6-trimethyl-3,5-sulphonatophenyl) porphinato iron III, prevents drug-induced inhibition of complex II–III of the mitochondrial electron transport chain in the rat striatum (Brown et al., 2005). Of interest to this topic are the findings that Nurr 1 heterozygote mice which show increased METH toxicity in comparison to wild-type animals also demonstrate greater drug-induced increases in nNOS activity and 3-nitrotyrosine levels (Imam et al., 2005).In addition to the role in the damage of monoaminergic axons, NO and peroxynitrite may be involved in METH-related apoptotic mechanisms because nNOS knockout mice are protected against increases in the levels of pro-apoptotic protein, p53, and decreases in anti-apoptotic protein, Bcl-2 caused by the psychostimulant treatment in the striatum (Imam et al., 2001b). When taken together, these observations implicate interactions between glutamate/superoxide and glutamate/NO pathways in METH-induced neuronal damage (Imam et al., 2001c; Itzhak and Ali, 2006; Itzhak et al., 1998; Yamamoto and Bankson, 2005).METH Toxicity and Temperature RegulationTemperature dysregulation appears to be also an important factor in the mediation of some toxic responses to METH. Several groups of investigators carried in-depth studies of the potential connections between the hyperthermic and neurotoxic actions of the drug (Albers and Sonsalla, 1995; Bowyer et al., 1994; Farfel and Seiden, 1995; Miller and O'Callaghan, 1994; Yuan et al., 2006). Conditions that cause hypothermia or prevent increases in core body temperature are, at least, partially protective against METH toxicity (Albers and Sonsalla, 1995; Ali et al., 1996; Bowyer et al., 1994; Tata et al., 2007). This protection is probably related to hypothermia-induced inhibitory effects on oxidative insults (Hsu et al., 2006; Zhao et al., 2007). Indeed, prevention of METH-induced hyperthermia by keeping animals at low ambient temperature blocked increases in DA oxidation products without affecting DA release while preventing long-term drug toxicity towards striatal DA and 5-HT terminals (LaVoie and Hastings, 1999). Similarly, prevention of hyperthermia blocked METH-induced increase in a marker of hydroxyl radicals, dihydroxybenzoic acid, and attenuated decrease in TPH activity 1 hour after drug treatment (Fleckenstein et al., 1997). In contrast, hyperthermia has been shown to exacerbate METH toxicity (Albers and Sonsalla, 1995; Bowyer et al., 1992), in part, because it causes increased intracellular accumulation of METH by potentiating DAT function (Xie et al., 2000). Hyperthrmia-induced increased production of free radicals in the brain (Kil et al., 1996) and its potentiation of their toxic effects (Lin et al., 1991) are also possible factors. These ideas are supported by the fact that hyperthermia significantly increases the formation of DA quinones (LaVoie and Hastings, 1999) which can cause inactivate TH (Kuhn et al., 1999), cause dysregulation of DAT function (Whitehead et al., 2001), inhibit proteasomal proteins participating in detoxification mechanisms (Zafar et al., 2006), and damage DA neurons (Montine et al., 1997; Spencer et al., 2002). Together, these data strongly suggest that hyperthermia facilitates METH-induced ROS production and that increased oxidation of DA is associated with neurotoxic effects of this drug.Nevertheless, some pharmacological and genetic manipulations can block METH toxicity without influencing the drug-induced thermal responses (Callahan et al., 2001; Deng et al., 2002b; Itzhak et al., 2000; Ladenheim et al., 2000; Sanchez et al., 2003). For example, nNOS inhibition using S-methylthiocitrulline, 7-nitroindazole, or AR-R17477AR blocks METH toxicity without preventing hyperthermia (Itzhak et al., 2000; Sanchez et al., 2003). DA uptake inhibitors also show protection that seems to be independent of any effects on temperature (Callahan et al., 2001). Interleukin-6 knockout mice that are protected against drug-induced DA and 5-HT axonal degeneration, cell death, and microgliosis still show hyperthermia in response to METH injections (Ladenheim et al., 2000). Knockout mice that are partially deficient of c-Jun are also protected against METH-induced neuronal apoptosis, in a manner independent of temperature regulation (Deng et al., 2002b). Thus, it appears that METH-related changes in body temperature are not sine qua non to the manifestations of its toxicity.Although METH-dependent increases in temperature are thought to contribute to neurotoxic effects of the drug, the mechanisms involved remain to be determined. DA release and activation of DA receptors seem to be critical for METH-induced hyperthermia because this thermic response can be attenuated by DA D1 and D2 receptor antagonists (Albers and Sonsalla, 1995; Broening et al., 2005; He et al., 2004). This idea is also supported by reports that administration of the D1 agonist, SKF38393, can induce hyperthermia in mice (Sanchez, 1989; Verma and Kulkarni, 1993; Zarrindast and Tabatabai, 1992), an effect which is blocked by the D1 antagonist, SCH23390 (Sanchez, 1989; Zarrindast and Tabatabai, 1992). The involvement of DA receptors is further supported by the demonstration that METH-induced hyperthermia is less prominent in D1 and D2 receptor knockout mice (Ito et al., 2008).The role of DAT and 5-HTT in METH-associated hyperthermia has been studied using DAT and/or 5-HTT knockout mice (Numachi et al., 2007). METH administration caused hyperthermia even in animals with a single gene copy of DAT and no 5-HTT (DAT+/−5-HTT−/− mice), whereas mice with no DAT copies and a single gene copy of 5-HTT (DAT−/−5-HTT+/− mice) showed reduced hyperthermia after drug treatment, suggesting that METH can exert a hyperthermic effect through its action on the DAT or via its interactions with the 5-HTT in the absence of the DAT protein (Numachi et al., 2007). The observations that DAT/5-HTT double knockout mice actually exhibited hypothermia in response to METH suggests the possibility that the thermic response to the drug is mediated by multiple systems that can either promote hyperthermia or hypothermia depending on the presence or absence of DA and/or 5-HT terminals (Numachi et al., 2007). Another proposed mechanism of METH-induced hyperthermia involves increases in hypothalamic concentrations of interleukin-1β (Bowyer et al., 1994) which is thought to be the major endogenous pyrogen (Leon, 2002). METH does indeed cause induction of hypothalamic interleukin-1β mRNA in mice (Halladay et al., 2003; Numachi et al., 2007) and rats (Yamaguchi et al., 1991) whereas interleukin-1 receptor antagonist reduces the hyperthermic effects of the psychostimulant (Bowyer et al., 1994). A possible role for interleukin-1β in drug-induced hypertherma is supported by the fact that it can cause a hyperthermic response when administered into the brain (Dascombe et al., 1989). Finally, the skeletal muscle uncoupling mitochondrial protein 3 (UCP-3) may also be involved in mediating METH-induced hyperthermia because UCP-3-deficient mice treated with the drug showed blunted thermic responses (Sprague et al., 2004). It is also possible that hyperthermia might potentiate some of the deleterious effects of METH by causing adverse effects on the blood-brain barrier.Role of Blood-Brain Barrier Dysfunction in METH ToxicitySeveral recent papers have examined the effects of METH on the blood-brain barrier (BBB) and their potential relationships to METH toxicity (Bowyer and Ali, 2006; Bowyer et al., 2008; Kiyatkin et al., 2007; Sharma and Ali, 2006; Sharma and Kiyatkin, 2009; Sharma et al., 2007). Using protein tracers and albumin immunohistochemistry, METH was shown to cause marked disruption of BBB at the levels of the cortex, hippocampus, thalamus, hypothalamus, cerebellum and amygdala (Bowyer and Ali, 2006; Kiyatkin et al., 2007; Sharma et al., 2007). METH-induced BBB breakdown was evidenced by diffusion of Evans blue dye and by leakage of serum albumin into the brain tissue (Kiyatkin et al., 2007; Sharma et al., 2007). Doses of METH that cause BBB disturbances also induce neuronal damage, myelin degeneration, and reactive astrocytosis in the parietal and occipital cortices (Sharma et al., 2007). These doses also cause extensive degeneration of pyramidal cells and activation of microglia in amygdala and hippocampus of rats (Bowyer and Ali, 2006). These effects appear to be temperature-dependent because magnitude of METH-induced diffusion of Evans blue dye into brain tissue and albumin immunoreactivity tightly correlated with intensity of hyperthermia (Kiyatkin et al., 2007; Sharma and Kiyatkin, 2009) and because the psychostimulant failed to induce BBB damage and neurodegeneration in the brains of animals that did not show increased temperature (Bowyer and Ali, 2006). Interestingly, mild BBB dysfunction found in the caudate-putamen after METH treatment was exacerbated by hyperthermia (Bowyer et al., 2008). In addition, a recent study has also shown distortion of neurons, damage to gilial cells, vesiculation of myelin and alterations in vascular endothelium and epithelium that occur in the cortex, hippocampus, thalamus and hypothalamus within 30–80 min following METH treatment (Sharma and Kiyatkin, 2009). Electron microscopy studies revealed acute degeneration of cellular elements, condensed cytoplasm and irregular folding of nuclear membrane, which were evident in all cell types, with the most affected cells being the epithelial cells of the choroid plexus, a critical element of blood-CSF barrier (Sharma and Kiyatkin, 2009). These acute morphological abnormalities also tightly correlated with METH-induced hyperthermia and increased BBB permeability (Sharma and Kiyatkin, 2009). It is interesting to point out that leakage of serum albumin into brain tissue caused by METH administration is attenuated by pretreatment with antioxidant, H-290/51, suggesting the involvement of free radicals in BBB damage (Sharma et al., 2007). Also of interest is the fact the antioxidant was able to attenuate METH-induced hyperthermia, neuronal damage, myelin degradation and glial response (Sharma et al., 2007).Inflammation, Microglial Reactions and METH ToxicityMicroglia are the resident immune cells within CNS that protect the brain against injury and damage (Raivich, 2005). In the healthy brain, microglial cells exist in a resting ramified state and monitor the neuronal environment (Block et al., 2007; Raivich, 2005). However, in response to inflammation or brain damage, microglial cells increase in size, migrate to the site of the injury, and cause phagocytosis of dying and dead cells (Block et al., 2007; Raivich, 2005). While microglial activation is essential for immune responses and neuronal survival, the overactivation of microglial cells can result in neurotoxic consequences. Indeed, multiple lines of evidence have suggested that activated microglia might release a variety of cytokines, reactive oxygen and nitrogen species and prostaglandins that are known to cause neuronal damage (Block et al., 2007; Perry et al., 2007), and, therefore, might be involved in neurodegeneration through inflammatory processes. Specifically, microglial cells appear to play role in the progress of many neurodegenerative disorders, including Parkinson’s (Kim and Joh, 2006), Alzheimer’s (Xiang et al., 2006), and Huntington’s (Sapp et al., 2001) diseases as well as AIDS-related neurological deficits (Gonzalez-Scarano and Martin-Garcia, 2005).Microglial activation appears to be an early event in the neurotoxic cascades initiated by METH treatment. Specifically, METH induces a substantial microglial response in the areas of the brain that show neuronal degeneration (Escubedo et al., 1998; Guilarte et al., 2003; LaVoie et al., 2004; Pubill et al., 2002, 2003; Thomas and Kuhn, 2005a; Thomas et al., 2004a, 2004c). In addition, reserpine and clorgyline that exacerbate METH toxicity also cause further increases in METH-induced microglial activation in the mouse striatum (Thomas et al., 2008). In contrast, attenuation of METH neurotoxicity by MK-801, dextromethorphan and α-methyl-p-tyrosine is accompanied by inhibition of microglial activation (Thomas et al., 2008; Thomas and Kuhn, 2005b). The anti-inflammatory drugs, ketoprofen and indometacin, and the second-generation tetracycline, minocycline, afford protection against METH-induced microgliosis and neurotoxicity (Asanuma et al., 2003, 2004; Zhang et al., 2006). Nevertheless, because attenuation of microglial activation by itself is not sufficient to protect against METH neurotoxicity (Sriram et al., 2006), much more remains to be done in order to further clarify the role of microglia in psychostimulant-induced terminal degeneration and cell death.Microglial cells might potentiate METH-related damage by releasing toxic substances such as superoxide radicals and NO which have already been implicated in drug neurotoxicity (see discussion above). In addition, METH causes increases in the levels of interleukin-1β (Numachi et al., 2007; Yamaguchi et al., 1991), pro-inflammatory cytokine that can also contribute to toxicity of the drug. Consistent with these findings, METH neurotoxicity and an increase in a marker for microglial activation PK11195 binding were attenuated in interleukin-6 null mice (Ladenheim et al., 2000). In fact, oxidative mechanisms and cytokines might exert their physiological and pathological effects by influencing the expression of several transcriptional factors with long-term consequences on the brain’s molecular programming (Malemud and Miller, 2008; Planas et al., 2006; Poli et al., 2004; Potashkin and Meredith, 2006).Involvement of Activator Protein 1 (AP-1) in METH-induced NeurotoxicityIn order to establish to what extent METH administration might influence the transcriptional profiles, several investigators have studied the effects of the drug on gene expression in the brain (Asanuma et al., 2004; Barrett et al., 2001; Cadet et al., 2001, 2002; Thomas et al., 2004b). For example, it has been reported that METH injections can cause increases in the expression of several members of the AP-1 family of transcription factors which include c-jun, c-fos, junB, and junD (Cadet et al., 2001). These changes, in turn, might be related to METH-induced generation of ROS because ROS participate in cellular signaling processes, which include the regulation of transcription factors (Poli et al., 2004; Potashkin and Meredith, 2006). In particular, ROS are critical in the regulation of transcription factors in the AP-1, NF-κB, and AP-2 families that play crucial role in responses to neuronal injury, in the control of death and survival signals; they also participate in mounting cellular defense mechanisms, immunological responses, and in the regulatated expression of cytokines and cell adhesion molecules (Dalton et al., 1999; Poli et al., 2004). Induction or suppression of transcription factors with subsequent activation or repression of genes that encode proteins involved in various neuronal functions might be critical steps in METH-related cascades of toxic events. The potential role for c-fos in METH-induced neuropathological changes has been confirmed by using c-fos heterozygote mice that demonstrate increased degeneration of DA axons in the striatum as shown by reduction of DAT binding, decrease in DAT protein levels and in TH immunoreactivity in comparison to wild-type mice 1 week after drug administration (Deng et al., 1999). In addition, c-fos mutant mice showed increased cell death in the striatum and cortex 3 days after drug treatment (Deng et al., 1999). Exacerbation of METH neurotoxicity in c-fos heterozygote mice was independent of temperature regulation (Deng et al., 1999). Microarray analyses have also revealed marked differences between wild-type and c-fos heterozygote mice after drug administration (Cadet et al., 2002). Specifically, METH caused downregulation of fos-related antigen-1 (Fra-1) and FosB, which are members of AP-1 family of transcription factors, in wild-type, but not in c-fos mutant mice (Cadet et al., 2002). In addition, METH induced increases in the expression of several DNA repair genes such as APEX, PolB, LIG1, nibrin, DDB1 and DNA mismatch repair proteins MSH3 and PMS1 only in wild-type, but not in the mutant mice, implicating deficient DNA repair process in the exacerbated drug toxicity in c-fos knockout animals (Cadet et al., 2002). These findings support a protective role for c-fos against METH damage and suggest that c-fos might be involved in mechanisms of DNA repair (Cadet et al., 2002). The other factors that could be involved in this protection include cell adhesion receptors such as integrins, intrercellular adhesion molecules 1 and 2 as well as the ephrin receptor A1 because c-fos heterozygote mice show decreased basal levels of these transcripts and because METH treatment caused further reduction of their expression (Betts et al., 2002; Cadet et al., 2002). This idea is also supported by the observations that integrins promote cell survival after injury and apoptotic insults through stimulation of the PI3K-Akt pathway which leads to phosphorylation of the pro-apoptotic protein, BAD, thereby enhancing the anti-apoptotic effects of Bcl-2 (Gilcrease, 2006). The involvement of the integrins in METH-induced cell death is also supported by the report that inhibition of integrins increases apoptotic cell death (Gilcrease, 2006).Fra-2 is another protein that might play a role in protective mechanisms against METH toxicity. Unlike other AP-1 transcription factors such as c-fos and c-jun, which are transiently expressed, Fra-2 expression is increased for a longer period of time after METH administration, starting at 3 days post-treatment and returning to basal levels by day 5 (Pennypacker et al., 2000). This effect seems to depend on METH-induced hyperthermia, because decreasing body temperature prevented drug toxicity and also blocked Fra-2 induction in the mouse striatum (Pennypacker et al., 2000). Because the non-neurotoxic amphetamine, dexfenfluramine, does not cause Fra-2 induction, it has been suggested that this transcription factor may play role in the initial regulation of regeneration and repair mechanisms activated during the early days of METH toxicity (Pennypacker et al., 2000).C-jun is an AP-1 transcription factor that might contribute to the induction of METH toxicity because c-jun knockout mice show partial protection against damaging effects of the drug (Deng et al., 2002b). Specifically, c-jun mutant mice showed lower induction of apoptotic markers poly(ADP-ribose) polymerase (PARP) and cleaved caspase-3 as well as reduced DNA fragmentation in their brains after METH treatment (Deng et al., 2002b). Because c-jun knockout mice and their wild-type littermates demonstrate similar degree of dopaminergic toxicity after METH treatment, c-jun appears to only play role in the mediation of neuronal apoptosis in cells postsynaptic to DA axons (Deng et al., 2002b). Moreover, temperature regulation does not seem to play role in the partial protection against METH neurotoxicity afforded by c-jun +/− genotype because wild-type and c-jun knockout mice showed no differences in drug-induced hyperthermia (Deng et al., 2002b). The role for c-jun in the mechanisms underlying METH neurotoxicity is also supported by the findings that METH-induced expression of c-Jun, phosphorylated c-Jun at Ser63 and Ser73 and phosphorylated Jun-N-terminal kinases (JNK) at Thr183 and Tyr185 is associated with cell death in vivo (Deng et al., 2002b; Jayanthi et al., 2002; O'Dell and Marshall, 2005) and in vitro (Wang et al., 2008); by data showing that phosphorylated c-Jun colocalized with markers of DNA fragmentation and cell death in the striatum (Deng et al., 2002b); and by observations that the JNK-specific inhibitor, SP600125, can attenuate JNK phosphorylation, activation of caspase-3 and cell death caused by psychostimulant treatment in human neuroblastoma cells (Wang et al., 2008). METH-mediated activation of the JNK-Jun pathway appears to involve several signaling events. Specifically, increased expression of Src, Cas and Crk after METH treatment in the striatum suggests a role for the Src-dependent upstream pathway (Jayanthi et al., 2002), because Src can stimulate JNK activity (Feng et al., 2001) and because Src-dependent events are mediated by the assembly of the signal transduction complex that involves Cas and Crk (Yoshizumi et al., 2000). In addition, inhibition of METH-induced JNK phosphorylation and apoptosis in differentiated human mesencephalic neuron-derived cells with the mixed-lineage kinases inhibitor, CEP1347, implies that the upstream mixed-lineage kinase signaling might also contribute to JNK-Jun pathway activation (Lotharius et al., 2005). This proposition is supported by findings showing that expression of MKK7 which mediates JNK activation by mixed-lineage kinases is increased after METH treatment (Jayanthi et al., 2002). Additionally, the finding that pretreatment with antioxidant vitamin E prevents METH-associated JNK phosphorylation suggests that the drug can cause JNK activation via ROS-depenent mechanisms (Wang et al., 2008), which can induce DNA damage such as DNA strand breaks and base excision (Barzilai, 2007; Fishel et al., 2007).Role of DNA Damage in METH ToxicityAs mentioned earlier, METH can cause neuronal apoptosis in several brain regions, including the striatum, cortex, hippocampus and olfactory bulb (Deng and Cadet, 2000; Deng et al., 2001, 2007; Ladenheim et al., 2000; Zhu et al., 2005; 2006a, 2006b). Because METH administration is associated with ROS production and because ROS can cause apoptosis and DNA damage (Li and Trush, 1993), it is thus possible that METH might induce neuronal apoptosis through ROS-mediated DNA damage. This suggestion is supported by data obtained using microarray analyses which have shown changes in the expression of a number of genes that participate in DNA repair, including APEX, PolB, LIG1 and DNA mismatch repair proteins MSH3 and PMS1 after toxic doses of the drug (Cadet et al., 2002).The role of DNA damage in METH toxicity is supported by the report that METH treatment causes increased DNA oxidation in the striatum, substantia nigra, hippocampus and cortex (Jeng et al., 2006). This effect appears to depend on prostaglandin H synthase-dependent increases in ROS formation and ROS-mediated DNA damage (Jeng et al., 2006). In addition, exposure to the drug during embryonic and fetal development is associated with increased DNA oxidation in the mouse brain (Jeng et al., 2005).Involvement of Mitochondrial Pathways in METH-induced NeurodegenerationMETH is a cationic lipophilic molecule that can diffuse into mitochondria and be retained by these organelles (Asanuma et al., 2000; Davidson et al., 2001). Accumulation of positively charged molecules in the mitochondria results in dissipation of the electrochemical gradient established by oxidative phosphorylation and inhibit ATP synthesis, causing energy deficiency and subsequent mitochondrial dysfunction (Wallace, 2005). METH is capable of inducing decreases in mitochondrial membrane potential and disturbances in mitochondrial biogenesis in neuroblastoma cell lines (Wu et al., 2007). METH has been also shown to cause rapid decreases in the activity of complex II (Brown et al., 2005) and complex IV of the mitochondrial electron transport chain, which is associated with a reduction in ATP stores in the brain (Burrows et al., 2000). In addition to reduced ATP generation, mitochondrial defects can cause increased ROS production (Wu et al., 2007), suggesting that mitochondria affected by the drug may constitute an important sources of ROS that cause damage to lipids (Jayanthi et al., 1998), and DNA (Jeng et al., 2006; Jeng et al., 2005).In addition to the participation of mitochondrial mechanisms in METH-induced terminal degeneration, drug-related neuronal apoptosis also involves the mitochondria-dependent death pathway (Deng et al., 2002a; Jayanthi et al., 2001, 2004). Specifically, METH has been shown to cause increases in proapoptotic proteins, Bax, Bad and Bid, but decreases in antiapoptotic proteins Bcl-2 and Bcl-XL(Deng et al., 2002a; Jayanthi et al., 2001). METH-induced alterations in their levels cause the formation of channels that result in mitochondrial membrane potential loss and lead to the release of mitochondrial proteins such as cytochrome c and apoptosis inducing factor (AIF) into the cytosol (Breckenridge and Xue, 2004). Indeed, AIF and Smac/DIABLO released from mitochondria have also been shown to participate in apoptosis caused by METH treatment in the striatum (Jayanthi et al., 2004). Release of cytochrome c is followed by activation of caspases 9 and 3, and the proteolysis of several target proteins, including PARP, lamins and DNA fragmentation factor 45 kDA subunit (DFF-45) (Deng et al., 2002a; Jayanthi et al., 2004). Cleaved capase-3, in turn, can contribute to METH-induced cytoskeletal damage because it was shown to mediate proteolysis of cytoskeletal proteins spectrin and tau in vitro (Warren et al., 2005; Warren et al., 2007a) and in vitro (Warren et al., 2007b). This discussion is consistent with the observations that overexpression of Bcl-2 (Cadet et al., 1997), as well as inhibition of caspases (Jimenez et al., 2004; Uemura et al., 2003) and PARP (Iwashita et al., 2004) can protect against METH-induced cell death. It is also consistent with our demonstration that METH causes cell death through interaction of the mitochondria- and ER-dependent death pathways (Jayanthi et al., 2004).Endoplasmic Reticulum, Calcium-Dependent Mechanisms, and METH-induced Cell DeathThe accumulated evidence had suggested that METH-induced oxidative stress can trigger neuronal damage by causing dysfunctions of cellular organelles such as the endoplasmic reticulum (ER) (Jayanthi et al., 2004) (Figure 1). In addition to regulating synthesis, folding, and transport of proteins, ER also constitutes the main intracellular store for Ca2+, whose excess can contribute to cell death (Gorlach et al., 2006). At physiological levels, Ca2+ released from the ER is taken up by mitochondria to enhance metabolite flow on the outer mitochondrial membrane and to increase ATP production (Kroemer et al., 2007). However, sustained release of Ca2+ from the ER stores may initiate calcium-dependent apoptosis via the permeabilization of the outer mitochondrial membrane (Kroemer et al., 2007). ER stress and dysregulation of calcium homeostasis appear to participate in METH-induced cell death because the drug can cause activation of calpain (Jayanthi et al., 2004), a calcium-responsive cytosolic protease involved in ER-dependent apoptosis (Nakagawa and Yuan, 2000). Indeed, METH has been shown to cause cell death consequent to increases in calpain activity in spinal cord motoneurons and cortical neurons (Samantaray et al., 2006). Pretreatment with the calpain inhibitor, calpeptin, attenuated METH-induced cell death in these models (Samantaray et al., 2006). Exposure to METH is accompanied by calpain-mediated proteolysis of cytoskeletal scaffolding protein, spectrin, in primary cerebrocortical neuronal cultures (Warren et al., 2007b), in the rat cortex (Warren et al., 2005, 2007a), hippocampus (Warren et al., 2005) and striatum (Staszewski and Yamamoto, 2006). In addition to spectrin proteolysis, METH-induced increases in the cleaved form of cytoskeletal protein tau, which functions to stabilize microtubules (Hernandez and Avila, 2007), in primary cerebrocortical neuronal cultures (Warren et al., 2007b) as well as in the cortex, striatum and hippocampus (Straiko et al., 2007; Wallace et al., 2003; Warren et al., 2005), also appear to depend on calpain activation (Warren et al., 2007b). These findings strongly implicate ER stress and calpain activation in the mechanisms of METH neuronal degeneration.A role for the ER in METH toxicity is further supported by the findings that neurotoxic doses of the drug can increase the expression of proteins, such as caspase-12, GRP78/BiP and CHOP/GADD153 (Jayanthi et al., 2004) that participate in ER-induced apoptosis (Marciniak and Ron, 2006). This METH-related ER stress might be secondary to oxidative stress (Cadet et al., 1994a; Jayanthi et al., 1998) and to increases in BAX/Bcl-2 ratios caused by this illicit drug (Jayanthi et al., 2001).Role of Fas Ligand (FasL)/Fas Cell Death Pathway in METH-induced ApoptosisIn addition to the ER- and mitochondria-dependent death pathways, METH-induced neuronal apoptosis has been linked to stimulation of the FasL/Fas-mediated cell death pathway (Cadet and Krasnova, 2007; Cadet et al., 2007; Jayanthi et al., 2005). FasL is a member of the tumor necrosis factor (TNF) superfamily of cytokines that is involved in mechanisms of neuronal apoptosis observed in various models of brain injury (Choi and Benveniste, 2004). FasL expression is regulated by transcription factors AP-1, Egr and Nurr77 (Droin et al., 2003; Toth et al., 2001), all of which are induced by toxic doses of METH in the rat striatum (Jayanthi et al., 2005). Accordingly, METH was shown to elicit the expression of FasL in striatal neurons (Jayanthi et al., 2005). METH-induced activation of FasL/Fas apoptotic pathway in the striatum depends on upregulation of calcenurin activity as well as dephosphorylation and nuclear translocation of nuclear factor of activated T cells (NFAT) (Jayanthi et al., 2005), that are known to be involved in FasL regulation (Luoma and Zirpel, 2008; Shioda et al., 2007). In addition, METH injections caused cleavage of caspases 8 and 3, both of which are mediators of FasL/Fas apoptosis pathway (Thorburn, 2004). These changes in the FasL/Fas pathway and drug-induced apoptosis were attenuated by pretreatment with DA D1 receptor antagonist, SCH23390 (Jayanthi et al., 2005), suggesting a role for DA system in the activation of Fas-mediated cell death pathway. Because NFATs are known to participate in the regulation of Ca2+ and calcineurin-mediated transcriptional activity in the nervous system (Hogan et al., 2003) and because pretreatment with SCH23390 also blocked METH-induced increase in calcineurin expression and NFAT nuclear translocation (Jayanthi et al., 2005), it is possible to suggest that DA system is involved in the regulation of FasL/Fas apoptotic pathway via calcineurin-NFAT-dependent mechanism. METH treatment caused increase in FasL protein expression and apoptosis in striatal GABA- and enkephalin-positive neurons without inducing damage to substance P-expressing medium spiny neurons or somatostatin- and choline acetyltransferase-positive interneurons (Jayanthi et al., 2005).Role of Autophagy and Ubiquitin/Proteasome System in METH ToxicityAutophagy is the process through which abnormal protein aggregates and damaged cellular organelles are enwrapped within an endoplasmic reticulum-derived double membrane vesicle called autophagosome and then delivered to lysosomes for degradation (Yorimitsu and Klionsky, 2005). Several studies have shown that neurotoxic doses of METH can cause autophagy in vitro and in vivo (Castino et al., 2008; Fornai et al., 2004b; Kanthasamy et al., 2006; Larsen et al., 2002; Lazzeri et al., 2006). For example, midbrain neuronal cells exposed to METH develop vacuolation of endocytic compartments and formation of autophagic granules within their cytoplasm (Cubells et al., 1994; Larsen et al., 2002). Kanthasamy et al. (2006) have also reported drug-related autophagic changes in mesencephalic DA cell cultures. Immortalized mesencephalic cells treated with METH also show characteristic vacuoles in their cytoplasm (Cadet et al., 1997). METH-induced accumulation of cytoplasmic inclusions resembling autophagic vacuoles has also been reported in PC12 cells, in nigrostriatal DA neurons and in striatal GABAergic neurons (Fornai et al., 2004b; Lazzeri et al., 2006). The formation of these inclusions appears to be related to inhibition of the ubiquitin-proteasome system, which is a major pathway for degradation of abnormal or nonfunctional proteins within cells (Lazzeri et al., 2006, 2007).It appears that DA may play role in METH-induced dysfunction of the ubiquitin-proteasome system and in the formation of cytplasmic inclusions because both are attenuated by inhibition of DA synthesis with the TH inhibitor, α-methyp-p-tyrosine (Fornai et al., 2004b) This effect was reversed with L-DOPA, which restored intracellular DA levels (Fornai et al., 2004b). Similarly, METH failed to produce cytoplasmic inclusions in primary striatal cell cultures which do not contain DA, while exposure of these cultures to DA led to the appearance of intracellular inclusions and cell death (Lazzeri et al., 2007). The DA D1 receptor agonist, SKF38393, also caused the appearance of cytoplasmic inclusions in striatal cultures in a fashion similar to those caused by DA (Lazzeri et al., 2007). These inclusions were blocked by the DA D1 receptor antagonist, SCH23390 (Lazzeri et al., 2007). METH-induced formation of cytoplasmic inclusions appears to depend on ROS production because it is prevented by treatment with the antioxidant, S-apomorphine (Fornai et al., 2004b).Further investigations of signaling pathways underlying METH-induced formation of cytplasmic inclusions using PC12 cells have revealed a potential role for β-arrestin, which is involved in ubiquitination and degradation of G-protein coupled receptors (Fornai et al., 2008). Exposure to the DA receptor agonist, apomorphine, caused rapid ubiquitination of β-arrestin in PC12 cells similar to that induced by METH whereas treatment with the DA D2 receptor antagonist, eticlopride and to the non-selective DA receptor antagonist, flufenazine, reduced both METH-induced β-arrestin ubiquitination and cytoplasmic inclusion formation, thus providing further support for the involvement of DA receptors in these effects (Fornai et al., 2008). The role for β-arrestin in mediating the appearance of intracellular inclusions is also supported by findings that the number of METH-induced cytplasmic bodies was reduced in cells transfected with β-arrestin dominant-negative mutant and increased by the persistently ubiquitinated β-arrestin-ubiquitin fusion protein (Fornai et al., 2008). It is interesting to note that DA receptor antagonists inhibited the formation of 50% of cytoplasmic bodies, which is in contrast with the full protection observed after DA depletion (Fornai et al., 2004b, 2008). Together, these data suggest that DA receptors play only a partial role in the formation of cytplasmic inclusions caused by METH in PC12 cells and point to additional pathways that might be triggered by DA. Indeed, prevous studies have shown that cytosolic DA causes inhibition of ubiquitin-proteasome system (Keller et al., 2000) and formation of nigrostriatal inclusions (Fornai et al., 2003). This DA-dependent mechanism might apply to the formation of cytplasmic bodies in both nigrostriatal DA neurons and striatal GABA neurons expressing DA receptors. Indeed, METH-induced activation of DA receptors may be involved in causing the appearance of cytplasmic inclusions in striatal postsynaptic GABA neurons, while drug-related increases of free cytosolic DA levels in nigrostriatal terminals might account for the formation of intracellular bodies in nigrostriatal DA neurons (Fornai et al., 2008).Interestingly, METH-induced cytplasmic inclusions that are positive for protein markers of autophagy-lysosomal sysem Rab24, microtubule-associated protein light chain 3 (LC3) and belcin 1 also stain for α-synuclein, parkin and proteins that belong to the ubiquitin-proteasome pathway (Castino et al., 2008; Fornai et al., 2004a, 2004b, 2005; Lazzeri et al., 2007), suggesting morphological and functional identity of autophagic vacuoles with α-synuclein- and ubiquitin-proteasome-positive inclusions (Castino et al., 2008). In line with these findings, recent studies employing proteomic approaches to identify pathways involved in METH toxicity have reported increases in the expression of autophagy-linked LC3, α-synuclein, ubiquitin-conjugating enzyme E2N, and ubiquitin carboxy-terminal hydrohylase-L1 in the striatum and cortex of drug-treated rats (Kobeissy et al., 2008; Li et al., 2008; Liao et al., 2005). Because autophagy plays a critical role in the degradation of oxidatively damaged proteins (Yorimitsu and Klionsky, 2005), it is possible that METH-induced DA-dependent production of ROS promotes protein misfolding and aggregation, resulting in the upregulation of autophagic degradation in DA neurons as a part of the protective mechanism against drug toxicity (Castino et al., 2008). This idea is supported by findings showing that suppression of autophagy with 3-methyladenine caused Bax oligomerization, mitochondria permeabilization and apoptosis in METH-treated PC12 cells, the toxic effects which were prevented by caspase inhibitor ZVAD-fmk (Castino et al., 2008).Concluding RemarksIn summary, the brains of human METH addicts, who abuse large doses of the drug, are characterized by a variety of neuropathological changes. These include degeneration of monoaminergic terminals, dysregulation of energy metabolism, evidence of oxidative stress, as well as microgliosis and reactive astrogliosis. The deleterious effects of the drug have been consistently replicated in animal models. These studies have helped to identify some of the pathways that form the mechanistic substrates for METH-induced damage to monoaminergic terminals. Similarly, recent investigations have clarified the bases for neuronal apoptosis caused by METH exposure in various regions of the mammalian brain. This knowledge is just beginning to impact on the thinking regarding how to best approach the development of potentially effective therapeutic strategies that will address the neurological and psychiatric deterioration observed in some METH addicts. The use of therapeutic agents that address solely the addictive properties of METH might not be sufficient to attenuate the varied neuropathological end-points caused by the use of the drug. One possibility might be the need to combine therapeutic anti-addictive drugs with neuroprotective agents within the same clinical setting where these patients are being treated. The combination of anti-addictive agents with the anti-manic drug, lithium, that has been shown to have neuroprotective properties (Chuang, 2004), might be a fruitful approach to the treatment of METH abusers. In any case, more studies are needed in order to further clarify strategies that might serve to promote recovery of monoaminergic systems in models of METH toxicity.AcknowledgementsThis paper is supported by the Intramural Research Program of the National Institute on Drug Abuse, NIH, DHHS. The authors recognize and thank wholeheartedly two reviewers for their helpful comments on an original version of this review.FootnotesPublisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.Article informationBrain Res Rev. Author manuscript; available in PMC 2010 May 1.Published in final edited form as:https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&retmode=ref&cmd=prlinks&id=19328213Published online 2009 Mar 25. doi: 10.1016/j.brainresrev.2009.03.002PMCID: PMC2731235NIHMSID: NIHMS105133PMID: 19328213Irina N. Krasnova and Jean Lud CadetMolecular Neuropsychiatry Reasearch Branch, Intramural Research Program, NIDA/NIH/DHHS, Baltimore, MD 21224, USACorrespondence: Jean Lud Cadet M.D., Chief, Molecular Neuropsychiatry Reasearch Branch, Intramural Research Program, NIDA/NIH/DHHS, 251 Bayview Boulevard, Baltimore, MD 21224, USA, vog.hin.adin.artni@tedacj, Tel: 443-740-2656, Fax: 443-740-2856PMC Copyright NoticePMC Copyright Notice This page has information about general copyright restrictions that apply to the material that is available through the PubMed Central (PMC) site. There also are links to some Publisher Specific Copyright Information . 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Public Domain Material The following PMC participating journals are U.S. Government publications: Addiction Science & Clinical Practice (vol. 1 throughhttps://www.ncbi.nlm.nih.gov/pmc/about/copyright/METHAMPHETAMINE TOXICITY AND MESSENGERS OF DEATHMethamphetamine (METH) is an illicit psychostimulant that is widely abused in the world. Several lines of evidence suggest that chronic METH abuse leads to neurodegenerative changes in the human brain. These include damage to dopamine and serotonin axons, ...https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2731235/#FN1The publisher's final edited version of this article is available at Brain Res RevSee other articles in PMC that cite the published article.ReferencesAbekawa T, Ohmori T, Koyama T. Effects of repeated administration of a high dose of methamphetamine on dopamine and glutamate release in rat striatum and nucleus accumbens. Brain Res. 1994;643:276–281. [PubMed] [Google Scholar]Achat-Mendes C, Ali SF, Itzhak Y. 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