Excitotoxicity

Low Ca2+ buffering and excitotoxicity under physiological stress and pathophysiological conditions in motor neuron (MNs). Low Ca2+ buffering in amyotrophic lateral sclerosis (ALS) vulnerable hypoglossal MNs exposes mitochondria to higher Ca2+ loads compared to highly buffered cells. Under normal physiological conditions, the neurotransmitter opens glutamate, NMDA and AMPA receptor channels, and voltage dependent Ca2+ channels (VDCC) with high glutamate release, which is taken up again by EAAT1 and EAAT2. This results in a small rise in intracellular calcium that can be buffered in the cell. In ALS, a disorder in the glutamate receptor channels leads to high calcium conductivity, resulting in high Ca2+ loads and increased risk for mitochondrial damage. This triggers the mitochondrial production of reactive oxygen species (ROS), which then inhibit glial EAAT2 function. This leads to further increases in the glutamate concentration at the synapse and further rises in postsynaptic calcium levels, contributing to the selective vulnerability of MNs in ALS. Jaiswal et al., 2009.[1]

In excitotoxicity, nerve cells suffer damage or death when the levels of otherwise necessary and safe neurotransmitters such as glutamate become pathologically high, resulting in excessive stimulation of receptors. For example, when glutamate receptors such as the NMDA receptor or AMPA receptor encounter excessive levels of the excitatory neurotransmitter, glutamate, significant neuronal damage might ensue. Excess glutamate allows high levels of calcium ions (Ca2+) to enter the cell. Ca2+ influx into cells activates a number of enzymes, including phospholipases, endonucleases, and proteases such as calpain. These enzymes go on to damage cell structures such as components of the cytoskeleton, membrane, and DNA.[1][2] 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 induces neuronal survival of otherwise toxic levels of glutamate.[3][4]

Excitotoxicity may be involved in cancers, spinal cord injury, stroke, traumatic brain injury, hearing loss (through noise overexposure or ototoxicity), and in neurodegenerative diseases of the central nervous system such as multiple sclerosis, Alzheimer's disease, amyotrophic lateral sclerosis (ALS), Parkinson's disease, alcoholism, alcohol withdrawal or hyperammonemia and especially over-rapid benzodiazepine withdrawal, and also Huntington's disease.[5][6] Other common conditions that cause excessive glutamate concentrations around neurons are hypoglycemia. Blood sugars are the primary glutamate removal method 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 around NMDA and AMPA neurons.[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 antagonists. Dehydration should be avoided as this also contributes to the concentrations of glutamate in the inter-synaptic cleft[7] and "status epilepticus can also be triggered by a build up of glutamate around inter-synaptic neurons."[8]

  1. ^ a b Jaiswal MK, Zech WD, Goos M, Leutbecher C, Ferri A, Zippelius A, et al. (June 2009). "Impairment of mitochondrial calcium handling in a mtSOD1 cell culture model of motoneuron disease". BMC Neuroscience. 10: 64. doi:10.1186/1471-2202-10-64. PMC 2716351. PMID 19545440.
  2. ^ Manev H, Favaron M, Guidotti A, Costa E (July 1989). "Delayed increase of Ca2+ influx elicited by glutamate: role in neuronal death". Molecular Pharmacology. 36 (1): 106–112. PMID 2568579.
  3. ^ Zheng S, Eacker SM, Hong SJ, Gronostajski RM, Dawson TM, Dawson VL (July 2010). "NMDA-induced neuronal survival is mediated through nuclear factor I-A in mice". The Journal of Clinical Investigation. 120 (7): 2446–2456. doi:10.1172/JCI33144. PMC 2898580. PMID 20516644.
  4. ^ Chuang DM, Gao XM, Paul SM (August 1992). "N-methyl-D-aspartate exposure blocks glutamate toxicity in cultured cerebellar granule cells". Molecular Pharmacology. 42 (2): 210–216. PMID 1355259.
  5. ^ Kim AH, Kerchner GA, and Choi DW. Blocking Excitotoxicity or Glutamatergic Storm. Chapter 1 in CNS Neuroprotection. Marcoux FW and Choi DW, editors. Springer, New York. 2002. Pages 3-36
  6. ^ Hughes JR (June 2009). "Alcohol withdrawal seizures". Epilepsy & Behavior. 15 (2): 92–97. doi:10.1016/j.yebeh.2009.02.037. PMID 19249388. S2CID 20197292.
  7. ^ Camacho A, Massieu L (January 2006). "Role of glutamate transporters in the clearance and release of glutamate during ischemia and its relation to neuronal death". Archives of Medical Research. 37 (1): 11–18. doi:10.1016/j.arcmed.2005.05.014. PMID 16314180.
  8. ^ Fujikawa DG (December 2005). "Prolonged seizures and cellular injury: understanding the connection". Epilepsy & Behavior. 7 (Suppl 3): S3-11. doi:10.1016/j.yebeh.2005.08.003. PMID 16278099. S2CID 27515308.