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Inexcitotoxicity,nerve cells suffer damage or death when the levels of otherwise necessary and safeneurotransmitters such asglutamate become pathologically high, resulting in excessive stimulation ofreceptors.[2] For example, whenglutamate receptors such asNMDA receptors orAMPA receptors encounter excessive levels of the excitatory neurotransmitter, glutamate, significant neuronal damage might ensue. Different mechanisms might lead to increased extracellular glutamate concentrations, e.g. reduced uptake byglutamate transporters (EAATs), synaptic hyperactivity, or abnormal release from different neural cell types.[3][4] Excess glutamate allows high levels ofcalcium ions (Ca2+) to enter thecell. Ca2+ influx into cells activates a number of enzymes, includingphospholipases,endonucleases, andproteases such ascalpain. These enzymes go on to damage cell structures such as components of thecytoskeleton,membrane, and DNA.[1][5] In evolved,complex adaptive systems such as biological life it must be understood that mechanisms are rarely, if ever, simplistically direct. For example, NMDA, in subtoxic amounts, can block glutamate toxicity and induce neuronal survival.[6][7] In addition to abnormally high neurotransmitter concentrations, also elevation of the extracellular potassium concentration, acidification and other mechanisms may contribute to excitotoxicity.
Excitotoxicity may be involved incancers,spinal cord injury,stroke,traumatic brain injury,hearing loss (throughnoise overexposure orototoxicity), and inneurodegenerative diseases of thecentral nervous system such asmultiple sclerosis,Alzheimer's disease,amyotrophic lateral sclerosis (ALS),Parkinson's disease,alcoholism,alcohol withdrawal orhyperammonemia and especially over-rapidbenzodiazepine withdrawal, and alsoHuntington's disease.[8][9] Other common conditions that cause excessive glutamate concentrations around neurons arehypoglycemia. Blood sugars are the primary energy source for glutamate removal from inter-synaptic spaces at the NMDA and AMPA receptor site. Persons in excitotoxic shock must never fall into hypoglycemia. Patients should be given 5% glucose (dextrose) IV drip during excitotoxic shock to avoid a dangerous build up of glutamate.[citation needed] When 5% glucose (dextrose) IV drip is not available high levels of fructose are given orally. Treatment is administered during the acute stages of excitotoxic shock along with glutamate receptorantagonists. Dehydration should be avoided as this also contributes to the concentrations of glutamate in the inter-synaptic cleft[10] and "status epilepticus can also be triggered by a build up of glutamate around inter-synaptic neurons."[11]
The harmful effects of glutamate on thecentral nervous system were first observed in 1954 by T. Hayashi, a Japanese scientist who stated that direct application of glutamate causedseizure activity,[12] though this report went unnoticed for several years.[citation needed]D. R. Lucas andJ. P. Newhouse, after noting that "single doses of [20–30 grams ofsodium glutamate in humans] have ... been administered intravenously without permanent ill-effects", observed in 1957 that asubcutaneous dose described as "a little less than lethal", destroyed the neurons in the inner layers of theretina in newbornmice.[13] In 1969,John Olney discovered that the phenomenon was not restricted to the retina, but occurred throughout thebrain, and coined the term excitotoxicity. He also assessed thatcell death was restricted topostsynaptic neurons, that glutamateagonists were asneurotoxic as their efficiency to activate glutamate receptors, and that glutamateantagonists could stop the neurotoxicity.[14]
In 2002,Hilmar Bading and co-workers found that excitotoxicity is caused by the activation ofNMDA receptors located outside synaptic contacts.[15] The molecular basis for toxicextrasynaptic NMDA receptor signaling was uncovered in 2020 when Hilmar Bading and co-workers described a death signaling complex that consists ofextrasynaptic NMDA receptor andTRPM4.[16] Disruption of this complex usingNMDAR/TRPM4 interface inhibitors (also known as 'interface inhibitors') rendersextrasynaptic NMDA receptor non-toxic.[citation needed]
Excitotoxicity can occur from substances produced within the body (endogenous excitotoxins). Glutamate is a prime example of an excitotoxin in the brain, and it is also the major excitatory neurotransmitter in the central nervous system of mammals.[17] During normal conditions, glutamateconcentration can be increased up to 1mM in thesynaptic cleft, which is rapidly decreased in the lapse of milliseconds.[18] When the glutamate concentration around the synaptic cleft cannot be decreased or reaches higher levels, the neuron kills itself by a process calledapoptosis.[19][20]
This pathologic phenomenon can also occur afterbrain injury andspinal cord injury. Within minutes after spinal cord injury, damaged neural cells within the lesion site spill glutamate into the extracellular space where glutamate can stimulate presynaptic glutamate receptors to enhance the release of additional glutamate.[21]Brain trauma orstroke can causeischemia, in whichblood flow is reduced to inadequate levels. Ischemia is followed by accumulation of glutamate andaspartate in theextracellular fluid, causing cell death, which is aggravated by lack ofoxygen andglucose. Thebiochemical cascade resulting from ischemia and involving excitotoxicity is called theischemic cascade. Because of the events resulting from ischemia and glutamate receptor activation, a deepchemical coma may be induced in patients with brain injury to reduce the metabolic rate of the brain (its need for oxygen and glucose) and save energy to be used to remove glutamateactively. (The main aim in induced comas is to reduce theintracranial pressure, not brainmetabolism).[citation needed]
Increased extracellular glutamate levels leads to the activation of Ca2+ permeable NMDA receptors on myelin sheaths andoligodendrocytes, leaving oligodendrocytes susceptible to Ca2+ influxes and subsequent excitotoxicity.[22][23] One of the damaging results of excess calcium in the cytosol is initiating apoptosis through cleavedcaspase processing.[23] Another damaging result of excess calcium in the cytosol is the opening of themitochondrial permeability transition pore, a pore in the membranes ofmitochondria that opens when the organelles absorb too much calcium. Opening of the pore may cause mitochondria to swell and releasereactive oxygen species and other proteins that can lead toapoptosis. The pore can also cause mitochondria to release more calcium. In addition, production ofadenosine triphosphate (ATP) may be stopped, andATP synthase may in fact beginhydrolysing ATP instead of producing it,[24] which is suggested to be involved in depression.[25]
InadequateATP production resulting from brain trauma can eliminateelectrochemical gradients of certain ions.Glutamate transporters require the maintenance of these ion gradients to remove glutamate from the extracellular space. The loss of ion gradients results in not only the halting of glutamate uptake, but also in the reversal of the transporters. The Na+-glutamate transporters on neurons and astrocytes can reverse their glutamate transport and start secreting glutamate at a concentration capable of inducing excitotoxicity.[26] This results in a buildup of glutamate and further damaging activation of glutamate receptors.[27]
On themolecular level, calcium influx is not the only factor responsible for apoptosis induced by excitoxicity. Recently,[28] it has been noted that extrasynaptic NMDA receptor activation, triggered by both glutamate exposure or hypoxic/ischemic conditions, activate aCREB (cAMP response element binding)protein shut-off, which in turn caused loss ofmitochondrial membrane potential and apoptosis. On the other hand, activation of synaptic NMDA receptors activated only the CREBpathway, which activatesBDNF (brain-derived neurotrophic factor), not activating apoptosis.[28][29]
Exogenous excitotoxins refer to neurotoxins that also act at postsynaptic cells but are not normally found in the body. These toxins may enter the body of an organism from the environment through wounds, food intake, aerial dispersion etc.[30] Common excitotoxins include glutamate analogs that mimic the action of glutamate at glutamate receptors, including AMPA and NMDA receptors.[31]
The L-alanine derivative β-methylamino-L-alanine (BMAA) has long been identified as aneurotoxin which was first associated with theamyotrophic lateral sclerosis/parkinsonism–dementia complex (Lytico-bodig disease) in theChamorro people of Guam.[32] The widespread occurrence of BMAA can be attributed tocyanobacteria which produce BMAA as a result of complex reactions under nitrogen stress.[33] Following research, excitotoxicity appears to be the likely mode of action for BMAA which acts as aglutamate agonist, activatingAMPA andNMDA receptors and causing damage to cells even at relatively low concentrations of 10 μM.[34] The subsequent uncontrolled influx of Ca2+ then leads to the pathophysiology described above. Further evidence of the role of BMAA as an excitotoxin is rooted in the ability of NMDA antagonists like MK801 to block the action of BMAA.[32] More recently, evidence has been found that BMAA is misincorporated in place of L-serine in human proteins.[35][36] A considerable portion of the research relating to the toxicity of BMAA has been conducted onrodents. A study published in 2016 with vervets (Chlorocebus sabaeus) in St. Kitts, which are homozygous for the apoE4 (APOE-ε4) allele (a condition which in humans is a risk factor for Alzheimer's disease), found that vervets orally administered BMAA developed hallmark histopathology features of Alzheimer's Disease including amyloid beta plaques and neurofibrillary tangle accumulation. Vervets in the trial fed smaller doses of BMAA were found to have correlative decreases in these pathology features. This study demonstrates that BMAA, an environmental toxin, can trigger neurodegenerative disease as a result of a gene/environment interaction.[37] While BMAA has been detected in brain tissue of deceased ALS/PDC patients, further insight is required to trace neurodegenerative pathology in humans to BMAA.[citation needed]