Molecular basis of glutamate toxicity in retinal ganglion cells

Molecular basis of glutamate toxicity in retinal ganglion cells Loss of retinal ganglion cells (RGCs) is a hallmark of many ophthalmic diseases including glaucoma, retinal ischemia due to central artery occlusion, anterior ischemic optic neuropathy and may be significant in optic neuritis, optic nerve trauma, and AIDS. Recent research indicates that neurotoxicity is caused by excessive stimulation of receptors for excitatory amino acids (EAAs). In particular, the amino acid glutamate has been shown to act as a neurotoxin which exerts its toxic effect on RGCs predominantly through the N -methyl- d -aspartate (NMDA) subtype of glutamate receptor. NMDA-receptor-mediated toxicity in RGCs is dependent on the influx of extracellular Ca 2+ . The increase in (Ca 2+ ) i acts as a second messenger that sets in motion the cascade leading to eventual cell death. Glutamate stimulates its own release in a positive feedback loop by its interaction with the non-NMDA receptor subtypes. Ca 2+ -induced Ca 2+ release and further influx of Ca 2+ through voltage-gated Ca 2+ channels after glutamate-induced depolarization contribute to glutamate toxicity. In vitro and in vivo studies suggest that the use of selective NMDA receptor antagonists or Ca 2+ channel blockers should be useful in preventing or at least abating neuronal loss in the retina. Of particular importance for future clinical use of NMDA receptor antagonists in the treatment of acute vascular insults is the finding that some drugs can prevent glutamate-induced neurotoxicity, even when administered a few hours after the onset of retinal ischemia. http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Vision Research Elsevier

Molecular basis of glutamate toxicity in retinal ganglion cells

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Publisher
Elsevier
Copyright
Copyright © 1997 Elsevier Ltd
ISSN
0042-6989
eISSN
1878-5646
DOI
10.1016/S0042-6989(97)00047-3
Publisher site
See Article on Publisher Site

Abstract

Loss of retinal ganglion cells (RGCs) is a hallmark of many ophthalmic diseases including glaucoma, retinal ischemia due to central artery occlusion, anterior ischemic optic neuropathy and may be significant in optic neuritis, optic nerve trauma, and AIDS. Recent research indicates that neurotoxicity is caused by excessive stimulation of receptors for excitatory amino acids (EAAs). In particular, the amino acid glutamate has been shown to act as a neurotoxin which exerts its toxic effect on RGCs predominantly through the N -methyl- d -aspartate (NMDA) subtype of glutamate receptor. NMDA-receptor-mediated toxicity in RGCs is dependent on the influx of extracellular Ca 2+ . The increase in (Ca 2+ ) i acts as a second messenger that sets in motion the cascade leading to eventual cell death. Glutamate stimulates its own release in a positive feedback loop by its interaction with the non-NMDA receptor subtypes. Ca 2+ -induced Ca 2+ release and further influx of Ca 2+ through voltage-gated Ca 2+ channels after glutamate-induced depolarization contribute to glutamate toxicity. In vitro and in vivo studies suggest that the use of selective NMDA receptor antagonists or Ca 2+ channel blockers should be useful in preventing or at least abating neuronal loss in the retina. Of particular importance for future clinical use of NMDA receptor antagonists in the treatment of acute vascular insults is the finding that some drugs can prevent glutamate-induced neurotoxicity, even when administered a few hours after the onset of retinal ischemia.

Journal

Vision ResearchElsevier

Published: Dec 1, 1997

References

  • Responses mediated by excitatory amino acid receptors in solitary retinal ganglion cells from rat
    Aizenman, E.; Frosch, M.P.; Lipton, S.A.
  • Expression of NMDA and high-affinity kainate receptor subunit mRNAs in the retina
    Brandstatter, J.H.; Hartveit, E.; Sassoe-Pognetto, M.; Wässle, H.
  • Calcium channels in solitary retinal ganglion cells from post-natal rat
    Karschin, A.; Lipton, S.A.
  • Differential role of two Ca 2+ -permeable non-NMDA glutamate channels in rat retinal ganglion cells: kainate-induced cytoplasmic and nuclear Ca 2+ signals
    Leinders-Zufall, T.; Rand, M.N.; Waxman, S.G.; Kocsis, J.D.
  • Calcium channel antagonists and human immunodeficiency virus coat protein-mediated neuronal injury
    Lipton, S.A.
  • Voltage-dependent conductances of solitary ganglion cells dissociated from the rat retina
    Lipton, S.A.; Tauck, D.L.
  • Delayed administration of memantine prevents N -methyl- d -aspartate receptor-mediated neurotoxicity
    Pellegrini, J.W.; Lipton, S.A.
  • Redox modulatory site of the NMDA receptor-channel complex: regulation by oxidized glutathione
    Sucher, N.J.; Lipton, S.A.
  • Functional architecture of the mammalian retina
    Wässle, H.; Boycott, B.B.

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