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 Ca2+. The increase in [Ca2+]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 Ca2+ release and further influx of Ca2+ through voltage-gated Ca2+ 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 Ca2+ 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.
Sucher
N J
NJ
Department of Neurology, Children's Hospital, Boston, MA 02115, USA.
Lipton
S A
SA
Dreyer
E B
EB
D000818:Animals; D002118:Calcium / Q000502:physiology*; D016923:Cell Death; D005246:Feedback; D018698:Glutamic Acid / Q000633:toxicity*; D016202:N-Methylaspartate / Q000187:drug effects*; D009498:Neurotoxins / Q000494:pharmacology*; D051381:Rats; D012165:Retinal Ganglion Cells / Q000187:drug effects* / Q000378:metabolism; D015290:Second Messenger Systems
D009498:Neurotoxins; D018698:Glutamic Acid; D016202:N-Methylaspartate; D002118:Calcium