Advertisement

Excitotoxicity and Stroke

  • D. W. Choi

Abstract

The development of effective interventional treatments for stroke has been an important research goal for many years. Major effort to date has appropriately focused on insult limitation, for example, utilizing thrombolytic therapy in the minutes to hours after the onset of symptoms to restore blood flow in a clogged cerebral artery. However, a complementary approach is to reduce the intrinsic vulnerability of brain parenchyma to hypoxic-ischemic damage. This latter parenchymal approach has gained both momentum and specific form from recent data suggesting that the toxic overactivation of neuronal glutamate receptors ‘excitotoxicity’- may contribute to the pathogenesis of hypoxicischemic neuronal death (Meldrum 1985; Rothman and Olney 1987; Choi 1988). Pharmacological agents directed at antagonizing excitotoxicity may provide a new class of neuroprotective drugs useful in reducing the brain damage associated with acute stroke.

Keywords

NMDA Receptor Glutamate Receptor Glutamate Release Excitatory Amino Acid NMDA Antagonist 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References

  1. Albers GW, Goldberg MP, Choi DW (1989) N-methyl-D-aspartate antagonists: ready for clinical trial in brain ischemia? Ann Neurol 25: 398–403PubMedCrossRefGoogle Scholar
  2. Albers GW, Goldberg MP, Choi DW (1992) Do NMDA antagonists prevent neuronal injury? Yes. Arch Neurol 49: 418–420PubMedGoogle Scholar
  3. Beckman JS, Beckman TW, Chen J, Marshall PA, Freeman BA (1990) Apparent hydroxyl radical production by peroxynitrite: implications for endothelial injury from nitric oxide and superoxide. Proc Natl Acad Sci USA 87: 1620–1624PubMedCrossRefGoogle Scholar
  4. Benveniste H, Drejer J, Schousboe A, Diemer NH (1984) Elevation of the extracellular concentrations of glutamate and aspartate in rat hippocampus during transient cerebral ischemia monitored by intracerebral microdialysis. J Neurochem 43: 1369–1374PubMedCrossRefGoogle Scholar
  5. Braughler JM, Hall ED (1989) Central nervous system trauma and stroke. I. Biochemical considerations for oxygen radical formation and lipid peroxidation. J Free Radic Biol Med 6: 289–301CrossRefGoogle Scholar
  6. Buchan AM (1990) Do NMDA antagonists protect against cerebral ischemia: are clinical trials warranted? Cerebrovasc Brain Metab Rev 2: 1–26PubMedGoogle Scholar
  7. Buchan AM (1992) Do NMDA antagonists prevent neuronal injury? No. Arch Neurol 49: 420–421PubMedGoogle Scholar
  8. Chan PH, Fishman RA, Longar S, Chen S, Yu A (1985) Cellular and molecular effects of polyunsaturated fatty acids in brain ischemia and injury. Prog Brain Res 63: 227–235PubMedCrossRefGoogle Scholar
  9. Choi DW (1988) Glutamate neurotoxicity and diseases of the nervous system. Neuron 1: 623–634PubMedCrossRefGoogle Scholar
  10. Choi DW (1990a) Methods for antagonizing glutamate neurotoxicity. Cerebrovasc Brain Metab Rev 2: 105–147PubMedGoogle Scholar
  11. Choi DW (1990b) Cerebral hypoxia - some new approaches and unanswered questions. J Neurosci 10: 2493–2501PubMedGoogle Scholar
  12. Choi DW (1992) Excitotoxic cell death. J Neurobiol 23: 1261–1276PubMedCrossRefGoogle Scholar
  13. Choi DW, Koh J, Peters S (1988) Pharmacology of glutamate neurotoxicity in cortical cell culture: attenuation by NMDA antagonists. J Neurosci 8: 185–196PubMedGoogle Scholar
  14. Collins RC, Olney JW (1982) Focal cortical seizures cause distant thalamic lesions. Science 218: 177–179PubMedCrossRefGoogle Scholar
  15. Dawson VL, Dawson TM, London ED, Bredt DS, Snyder SH (1991) Nitric oxide mediates glutamate neurotoxicity in primary cortical cultures. Proc Natl Acad Sci USA 88: 6368–6371PubMedCrossRefGoogle Scholar
  16. Dykens JA, Stern A, Trenkner E (1987) Mechanism of kainite toxicity to cerebellar neurons in vitro is analogous to reperfusion tissue injury. J Neurochem 49: 1222–1228PubMedCrossRefGoogle Scholar
  17. Faden Al, Simon RP (1988) A potential role for excitotoxins in the pathophysiology of spinal cord injury. Ann Neurol 23: 623–626CrossRefGoogle Scholar
  18. Faden Al, Demediuk P, Panter SS, Vink R (1989) The role of excitatory amino acids and NMDA receptors in traumatic brain injury. Science 244: 798–800CrossRefGoogle Scholar
  19. Frandsen A, Drejer J, Schousboe A (1989) Direct evidence that excitoxicity in cultured neurons is mediated via N-methyl- D-aspartate (NMDA) as well as non-NMDA receptors. J Neurochem 53: 297–299PubMedCrossRefGoogle Scholar
  20. Garthwaite J, Charles SL, Chess-Willians R (1988) Endothelium-derived relaxing factor release on activation of NMDA receptors suggests role as intercellular messenger in the brain. Nature 336: 385–388PubMedCrossRefGoogle Scholar
  21. Giffard RG, Monyer H, Choi DW (1990a) Selective vulnerability of cultured cortical glia to injury by extracellular acidosis. Brain Res 530: 138–141PubMedCrossRefGoogle Scholar
  22. Giffard RG, Monyer H, Christine CW, Choi DW (1990b) Acidosis reduces NMDA receptor activation glutamate neurotoxicity and oxygen-glucose deprivation neuronal injury in cortical cultures. Brain Res 506: 339–342PubMedCrossRefGoogle Scholar
  23. Globus MY, Busto R, Dietrich WD, Martinez E, Valdes I, Ginsberg MD (1988) Effect of ischemia on the in vivo release of striatal dopamine, glutamate and gamma-aminobutyric acid studied by intracerebral microdialysis. J Neurochem 51: 1455–1464PubMedCrossRefGoogle Scholar
  24. Goldman SA, Pulsinelli WA, Clarke WY, Kraig RP, Plum F (1989) The effects of extracellular acidosis on neurons and glia in vitro. J Cerebr Blood Flow Metab 9: 471–477CrossRefGoogle Scholar
  25. Hollman M, O’Shea-Greenfield A, Rogers SW, Heinemann S (1989) Cloning by functional expression of a member of the glutamate receptor family. Nature 342: 643–648CrossRefGoogle Scholar
  26. Hume RI, Dingledine R, Heinemann SF (1991) Identification of a site in glutamate receptor subunits that controls calcium permeability Science 253: 1028–1031PubMedCrossRefGoogle Scholar
  27. lino M, Ozawa S, Tsuzuki (1990) Permeation of calcium through excitatory amino acid receptor channels in cultured rat hippocampal neurons. J Physiol (Lond) 424: 151–165Google Scholar
  28. Kaku DA, Goldberg MP, Choi DW (1991) Antagonism of non- NMDA receptors augments the neuroprotective effect of NMDA receptor blockade in cortical cultures subjected to prolonged deprivation of oxygen and glucose. Brain Res 554: 344–347PubMedCrossRefGoogle Scholar
  29. Koh J, Choi DW (1991) Selective blockade of non-NMDA receptors does not block rapidly triggered glutamateinduced neuronal death. Brain Res 548: 318–321PubMedCrossRefGoogle Scholar
  30. Koh J, Goldberg MP, Hartley DM, Choi DW (1990) Non- NMDA receptor-mediated neurotoxicity in cortical culture. J Neurosci 10: 693–705PubMedGoogle Scholar
  31. Koh JY, Palmer E, Cotman CW (1991) Activation of the metabotropic glutamate receptor attenuates N-methyl- D-aspartate neurotoxicity in cortical cultures. Proc Natl Acad Sci USA 88: 9431–9435PubMedCrossRefGoogle Scholar
  32. Lee KS, Frank S, Vanderklish P, Arai A, Lynch G (1991) Inhibition of proteolysis protects hippocampal neurons from ischemia. Proc Natl Acad Sci USA 88: 7233–7237PubMedCrossRefGoogle Scholar
  33. MacDermott AB, Mayer ML, Westbrook GL, Sith SJ, Barker JL (1986) NMDA-receptor activation increases cytoplasmic calcium concentration in cultured spinal cord neurons. Nature 321: 519–522PubMedCrossRefGoogle Scholar
  34. Manev H, Favaron M, Guidotti A, Costa E (1989) Delayed increase of Ca2+ influx elicited by glutamate: role in neuronal death. Mol Pharmacol 36: 106–112PubMedGoogle Scholar
  35. Masu M, Tanabe Y, Tsuchida K, Shigemoto R, Nakanishi S (1991) Sequence and expression of a metabotropic glutamate receptor. Nature 349: 760–765PubMedCrossRefGoogle Scholar
  36. Mattson MP, Murrain M, Guthrie PB, Kater SB (1989) Fibroblast growth factor and glutamate: opposing roles in the generation and degeneration of hippocampal neuroarchitecture. J Neurosci 9: 3728–3740PubMedGoogle Scholar
  37. Meldrum B (1985) Possible therapeutic applications of antagonists of excitatory amino acid neurotransmitters. Clin Sci 68: 113–122PubMedGoogle Scholar
  38. Michaels RL, Rothman SM (1990) Glutamate neurotoxicity in vitro: antagonist pharmacology and intracellular calcium concentrations. J Neurosci 10: 283–292PubMedGoogle Scholar
  39. Monyer H, Hartley DM, Choi DW (1990) 21-Aminosteroids attenuate excitotoxic neuronal injury in cortical cell cultures. Neuron 5:121–126Google Scholar
  40. Morad M, Dichter M, Tang CM (1988) The NMDA activated current in hippocampal neurons is highly sensitive to [H+]0. Soc Neurosci Abs 14: 791Google Scholar
  41. Moriyoshi K, Masu M, Ishii T, Shigemoto R, Mizuno N, Nakanishi S (1991) Molecular cloning and characterization of the rat NMDA receptor. Nature 354: 31–37PubMedCrossRefGoogle Scholar
  42. Nicoletti F, Wroblewski JT, Novelli A, Alho H, Guidotti A, Costa E (1986) The activation of inositol phospholipid metabolism as a signal-transducing system for excitatory amino acids in primary cultures of cerebellar granule cells. J Neurosci 6: 1905–1911PubMedGoogle Scholar
  43. Norenberg MD, Mozes LW, Gregorios JB, Norenberg LB (1987) Effects of lactic acid on astrocytes in primary culture. J Neuropathol Exp Neurol 46: 154–166PubMedCrossRefGoogle Scholar
  44. Olney JW, Labruyere J, Price MT (1989) Pathological changes induced in cerebrocortical neurons by phencyclidine and related drugs. Science 244: 1360–1362PubMedCrossRefGoogle Scholar
  45. Olney JW, Labruyere J, Wang G, Wozniak DF, Price MT, Sesma MA (1991) NMDA antagonist neurotoxicity: mechanism and prevention. Science 254: 1515–1518PubMedCrossRefGoogle Scholar
  46. Pellegrini-Giampietro DE, Cherici G, Alesiani M, Carla V, Moroni F (1988) Excitatory amino acid release from rat hippocampal slices as a consequence of free-radical formation. J Neurochem 51: 1960–1963PubMedCrossRefGoogle Scholar
  47. Plum F (1983) What causes infarction in ischemic brain? The Robert Wartenberg Lecture. Neurology 33: 222–233PubMedGoogle Scholar
  48. Rose K, Bruno VMG, Oliker R, Choi DW (1990) Nordihydroguaiaretic acid (NDGA) attenuates slow excitatory amino acid-induced neuronal degeneration in cortical cultures. Soc Neurosci Abs 16: 288Google Scholar
  49. Rosenberg PA, Aizenman E (1989) Hundred-fold increase in neuronal vulnerability to glutamate toxicity in astrocytepoor cultures of rat cerebral cortex. Neurosci Lett 103: 162–168PubMedCrossRefGoogle Scholar
  50. Rothman SM, Olney JW (1987) Excitotoxicity and the NMDA receptor. Trends Neurosci 10: 299–302CrossRefGoogle Scholar
  51. Sheardown MJ, Nielsen EO, Hansen AJ, Jacobsen P, Honore T, (1990) 2,3,-Dihydroxy-6-nitro-7-sulfamoyl-benzo (F) quinoxaline: a neuroprotectant for cerebral ischemia. Science 247:571–574Google Scholar
  52. Siesjo BK (1989) Free radicals and brain damage. Cerebrovasc Brain Metab Rev 1: 165–211PubMedGoogle Scholar
  53. Siman R, Noszek JC, Kegerise C (1989) Calpain I activation is specifically related to excitatory amino acid induction of hippocampal damage. J Neurosci 9: 1579–1590PubMedGoogle Scholar
  54. Sladeczek F, Pin JP, Recasens M, Bockaert J, Weiss S (1985) Glutamate stimulates inositol phosphate formation in striatal neurons. Nature 317: 717–719PubMedCrossRefGoogle Scholar
  55. Sommer B, Seeburg PH (1992) Glutamate receptor channels: novel properties and new clones. Trends Neurosci 13: 291–296Google Scholar
  56. Tanabe Y, Masu M, Ishii T, Shigemoto R, Nakanishi S (1992) A family of metabotropic glutamate receptors. Neuron 8: 169–179PubMedCrossRefGoogle Scholar
  57. Tecoma ES, Monyer H, Goldberg MP, Choi DW (1989) Traumatic neuronal injury in vitro is attenuated by NMDA antagonists. Neuron 2: 1541–1545PubMedCrossRefGoogle Scholar
  58. Tombaugh GC, Sapolsky RM (1990) Mild acidosis protects hippocampal neurons from injury induced by oxygen and glucose deprivation. Brain Res 506: 343–345PubMedCrossRefGoogle Scholar
  59. Turetsky DM, Goldberg MP, Choi DW (1992) Kainate-activated cobalt uptake identifies a subpopulation of cultured cortical neurons that are preferentially vulnerable to kainate- induced damage. Soc Neurosci Abs 18: 81Google Scholar
  60. Uematsu D, Araki N, Greenberg JH, Sladky J, Reivich M (1991) Combined therapy with MK-801 and nimodipine for protection of ischemic brain damage. Neurology 41: 88–94PubMedGoogle Scholar
  61. Verdoorn TA, Burnashev N, Monyer H, Seeburg PH, Sakmann B (1991) Structural determinants of ion flow through recombinant glutamate receptor channels. Science 252: 1715–1718PubMedCrossRefGoogle Scholar
  62. Watkins JC, Olverman JH (1987) Agonists and antagonists for excitatory amino acid receptors. Trends Neurosci 10: 265–272CrossRefGoogle Scholar
  63. Watkins JC, Krogsgaard-Larsen P, Honore T (1990) Structureactivity relationships in the development of excitatory amino acid receptor agonists and competitive antagonists. Trends Pharmacol Sci 11: 25–33PubMedCrossRefGoogle Scholar
  64. Wieloch T (1985) Hypoglycemia-induced neuronal damage prevented by an N-methyl-D-aspartate antagonist. Science 230: 681–683PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag London Limited 1995

Authors and Affiliations

  • D. W. Choi

There are no affiliations available

Personalised recommendations