Skip to main content
SpringerLink
Log in

Oxidative mechanisms involved in kainate-induced cytotoxicity in cortical neurons

  • Original Articles
  • Published:
Neurochemical Research Aims and scope Submit manuscript

Abstract

In our previous experiments, evidence of free radical formation has been demonstrated in gerbil brain after kainic acid (KA) administration. In the present study, the mechanisms involved in KA-induced free radical formation and subsequent cell degeneration were investigated using high density cortical neuron cultures. A free radical trapping agent,a-phenyl-N-tert-butyl-nitrone (PBN), as well as the combined action of superoxide dismutase and catalase attenuated KA neurotoxic effect. Calpain-induced xanthine oxidase (XO) activation may play an important role in KA excitotoxicity since calpain inhibitor I as well as allopurinol, a selective XO inhibitor, significantly protected the cortical neurons from KA-induced cell death. However, XO activation may not be the only source producing free radicals, other free radical generating systems such as nitric oxide synphase may also play a role in KA insult.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

  1. Rothman, S. M., and Olney, J. W. 1987. Excitotoxicity and the NMDA receptor. Trends Neurosoci. 10:229–302.

    Google Scholar 

  2. Young, A. B. 1991. Roles of Excitotoxins in heredito-degenerative neurological diseases. Research Publication — Association for Research in Nervous & Mental Diseases 71:175–89.

    Google Scholar 

  3. Choi, D. W. 1989. Glutamate neurotoxicity and diseases of the nervous system. Neuron. 1:623–34.

    Google Scholar 

  4. Hayes, R. L., Jenkins, L. W., and Lyeth, B. G. 1992. Neurotransmitter-mediated mechanisms of traumatic brain injury: Acetylcholine and excitatory amino acids. J. Neurotrauma 9(Suppl. 1):S173–87.

    PubMed  Google Scholar 

  5. Beal, M. F., Kowall, N. W., Ellison, N. W., Mazurek, M. F., Swartz, K. J., and Martin, J. B. 1986. Replication of the neurochemical characteristics of Huntington's disease by quinolinic acid. Nature 321:168–71.

    PubMed  Google Scholar 

  6. Watkins, K. C., Curtis, D. R., and Biscoe, T. J. 1966. Central effects of b-N-oxalyl-a,b-diaminopropionic acid and other lathyrus factors. Nature 211:637.

    Google Scholar 

  7. Olney, J. W., Misra, C. H., and Rhee, V. 1976. Brain and retinal damage from lathyrus excitotoxin, b-N-oxalyl-L-a,b-diaminopropionic acid. Nature 264:659–61.

    PubMed  Google Scholar 

  8. Weiss, J. H., and Choi, D. W. 1990. Slow non-NMDA receptor mediated neurotoxicity and amyotrophic lateral sclerosis. Advance Neurol. 56:311–8.

    Google Scholar 

  9. Davies, P., Katzman, R., and Terry, R. D. 1980. Reduced somatostatin-like immunoreactivity in cerebral cortex from cases of Alzheimer's disease and Alzheimer's senile dementia. Nature 288:279–80.

    PubMed  Google Scholar 

  10. Koh, J-Y., Goldberg, M. P., Hartley, D. M., and Choi, D. W. 1990. Non-NMDA receptor-mediated neurotoxicity in cortical culture. J. Neurosci. 10:693–705.

    PubMed  Google Scholar 

  11. Kato, K., Puttfarcken, P. S., Lyons, W. E., and Coyle, J. T. 1991. Developmental time course and ionic dependence of kainate-mediated toxicity in rat cerebellar granule cell cultures. J. Pharm. Exp. Therap. 265:402–11.

    Google Scholar 

  12. Schousboe, A., Frandsen, A., and Kregsgaard-Larsen, P. 1992. Pharmacological and functional characterization of excitatory amino acid mediated cytotoxicity in cerebral cortical neurons. Cell. Biol. & Toxicology 8:93–100.

    Google Scholar 

  13. Rothman, S. M., Thurston, J. H., and Hauhart, R. E. 1987. Delayed neurotoxicity of excitatory amino acids in vitro. Neurosci. 22:471–80.

    Google Scholar 

  14. MacDermott, A. B., Mayer, M. L., Westbrook, G. L., Smith, S. J., and Barker, J. L. 1986. NMDA receptor activation increases cytoplasmic calcium concentration in cultured spinal cord neurons. Nature 321:519–22.

    PubMed  Google Scholar 

  15. Garthwaite, G., and Garthwaite, J. 1986. Neurotoxicity of excitatory amino acid receptor agonists in rat cerebellar slices: dependence of calcium concentration. Neurosci. Lett. 66:193–8.

    PubMed  Google Scholar 

  16. Weiss, J. H., Hartley, D. M., Koh, J., and Choi, D. W. 1990. The calcium channel blocker nifedipine attenuates slow excitatory amino acid neurotoxicity. Science 247:1474–7.

    PubMed  Google Scholar 

  17. Kontos, H. A., Wei, E. P., Povlishock, T. J., Dietrich, W. D., Margiera, C. J., and Ellis, E. F. 1980. Cerebral arteriolar damage by arachidonic acid and prostaglandin G2. Science 209:1242–4.

    PubMed  Google Scholar 

  18. Lynch, M. A., and Bliss, T. V. P. 1986. Long term potentiation of synaptic transmission in the hippocampus of the rat; effect of calmodulin and oleoyl-acetyl-glycerol on release of3H-glutamate. Neurosci. Lett. 65:171–6.

    PubMed  Google Scholar 

  19. Connor, J. A., Wadman, W. J., Hockberger, P. E., and Wong, R. K. S. 1988. Sustained dentritic gradients of Ca2+ induced by excitatory amino acids in CA1 hippocampus neurons. Science 240:649–53.

    PubMed  Google Scholar 

  20. Orrenius, S., McConkey, D. J., Bellomo, G., and Nicotera, P. 1989. Role of Ca2+ in toxic cell killing. Trends Pharmacol. Sci. 10:281–5.

    PubMed  Google Scholar 

  21. Garthwaite, J., Charles, S. L., and Chess-Williams, R. 1988. Endothelium-derived relaxing factor release on activation of the NMDA receptors suggests role as intercellular messenger in the brain. Nature 336:385–6.

    PubMed  Google Scholar 

  22. Melloni, E., and Portremoli, S. 1989. The calpains. Trends Neurosci. 12:438–44.

    PubMed  Google Scholar 

  23. Orrenius, S., Burkitt, M. J., Kass, G. E., Dypbukt, J. M., and Nicotera, P. 1992. Calcium ions and oxidative cell injury. Annals Neurol. 32(Suppl.):S33–42.

    Google Scholar 

  24. Sun, A. Y., Cheng, Y., Bu, Q., and Oldfield, F. 1992. The Biochemical mechanisms of the excitotoxicity of kainic acid. Mol. Chem. Neuropath. 17:51–63.

    Google Scholar 

  25. Dichter, A. 1978. Rat cortical neurons in cell culture: Culture methods, cell morphology, electrophysiology, and synapse formation. Brain Res. 149:279–93.

    PubMed  Google Scholar 

  26. Bergmeyer, H. U., and Bernt, E. 1974. Lactate Dehydrogenase, in Methods of Enzymatic Analysis. (Bergmeyer, HU. eds. 2nd. ed.), Academic Press, Inc., New York & London.

    Google Scholar 

  27. McCord, J. M. 1987. Oxygen-derived radicals: A link between reperfusion injury and inflammation. Fed. Proc. 46:2402–6.

    PubMed  Google Scholar 

  28. Coyle, J. T., and Puttfarcken, P. 1993. Oxidative stress, glutamate, and neurodegenerative disorders. Science 262:689–95.

    PubMed  Google Scholar 

  29. Giffard, R. G., Bruno, V. M. G., Amagasu, S. M., Choi, D. W., and Dugan, L. L. 1992. NMDA receptor activation results in hydroxl radical production in primary murine cortical cultures. Soc Neurosci (Abstracts) 18:646.

    Google Scholar 

  30. Chan, P. H., Chu, L., Chen, S. F., Carlson, E. J., and Epstein, C. J. 1990. Reduced neurotoxicity in transgenic mice overexpressing human copper-zinc-superoxide dismutase. Stroke 21(suppl. 3):80–82.

    Google Scholar 

  31. Zweier, J. L., Kuppusamy, P., Thompson-Gorman, S., Klunk, D., and Lutty, G. A. 1994. Measurement and characterization of free radical generation in reoxygenated human endothelial cells. Am. J. Physiol. 266:C700-C708.

    PubMed  Google Scholar 

  32. Lipton, S. A., and Rosenberg, P. 1994. Excitatory amino acids as a final common pathway for neurologic disorders. New Engl. J. Med. 330:613–22.

    PubMed  Google Scholar 

  33. Ahmad, F. F., Cowan, D. L., and Sun, A. Y. 1989. Spin trapping studies of the influence of alcohol on lipid peroxidation. In “Molecular Mechanisms of Alcohol” (G. Y. Sun, P. K. Rudeen, W. G. Wood, Y. H. Wei, and A. Y. Sun, eds) Humana Press, Clifton, NJ., pp. 257–78.

    Google Scholar 

  34. Carney, J. M., and Floyd, R. A. 1991. Protection against oxidative damage to CNS by a-phenyl-tert-butyl nitrone (PBN) and other spin-trapping agents: a novel series of nonlipid free radical scavenger. J. Molecular Neurosci. 3:47–57.

    Google Scholar 

  35. Choi, D. W. 1992. Excitotoxic cell death. J. Neurobiol. 23:1261–76.

    PubMed  Google Scholar 

  36. Goldberg, M. P., Gifford, R. G., Kurth, M. C., and Choi, D. W. 1989. Role of extracellular calcium and magnesium in ischemic neuronal injury in vitro. Neurology 39(suppl. 1):217.

    Google Scholar 

  37. Michaels, R. L., and Rothman, S. M. 1990. Glutamate neurotoxicity in vitro: Antagonist pharmacology and intracellular calcium concentrations. J. Neurosci. 10:283–92.

    PubMed  Google Scholar 

  38. Sun, A. Y., Cheng, Y., and Sun, G. Y. 1992. Kainic acid-induced excitotoxicity in neurons and glial cells. Prog. Brain Res. 94:271–80.

    PubMed  Google Scholar 

  39. Dumuis, a., Sebben, M., Haynes, L., Pin, L-P., and Bockaert, J. 1988. NMDA receptors activate the arachidonate cascade system in striatal neurons. Nature 336:68–70.

    PubMed  Google Scholar 

  40. Lazarewicz, J. W., Wroblewski, J. T., and Costa, E. 1990. NMDA-sensitive glutamate receptors induce calcium-mediated arachidonic acid release in primary cultures of cerebellar granule cells. J. Neurochem. 55:1875–81.

    PubMed  Google Scholar 

  41. Seubert, P. Larson, J., Oliver, M., Jung, M. W., Baudry, M., and Lynch, G. 1988. Stimulation of NMDA receptors induces proteolysis of spectrin in hippocampus. Brain Res. 459:233–40.

    PubMed  Google Scholar 

  42. Siman, R., and Noszek, J. C. 1988. Excitatory amino acids activate calpain and induce structure protein breakdown in vivo. Neuron. 1:279–87.

    PubMed  Google Scholar 

  43. Arai, A., Kessler, M., Lee, K., and Lynch, G. 1990. Calpain inhibitors improve the recovery of synaptic transmission from hypoxia in hippocampal slices. Brain Res. 532:63–8.

    PubMed  Google Scholar 

  44. Manev, H., Favaron, M., Siman, R., Guidotti, A., and Costa, E. 1991. Glutamate neurotoxicity is independent of calpain I inhibition in primary cultures of cerebellar granule cells. J. Neurochem. 57:1288–95.

    PubMed  Google Scholar 

  45. Dawson, V. L., Dawson, T. M., London, E. D., Bredt, D.S., and Snyder, S. H. 1991. Nitric oxide mediates glutamate neurotoxicity in primary cortical cultures. Proc. Natl. Acad. Sci. USA 88:6368–74.

    PubMed  Google Scholar 

  46. Buttelli, M. G., Lorenzoni, E., and Stirpe, F. 1973. Milk xanthine oxidase type D (dehydrogenase) and type O (oxidase). Biochem. J. 131:191–98.

    PubMed  Google Scholar 

  47. Retz, K. C., and Coyle, J. T. 1982. The effects of kainic acid on high energy metabolites in the mouse striatum. J. Neurochem. 38:196–203.

    PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Pharmacology, University of Missouri-Columbia School of Medicine, 65212, Columbia, Missouri

    Yu Cheng & Albert Y. Sun

Authors
  1. Yu Cheng
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Albert Y. Sun
    View author publications

    You can also search for this author in PubMed Google Scholar

Rights and permissions

Reprints and permissions

About this article

Cite this article

Cheng, Y., Sun, A.Y. Oxidative mechanisms involved in kainate-induced cytotoxicity in cortical neurons. Neurochem Res 19, 1557–1564 (1994). https://doi.org/10.1007/BF00969006

Download citation

  • Accepted:

  • Issue Date:

  • DOI: https://doi.org/10.1007/BF00969006

Key Words

Search

Navigation