Immune-related mechanisms participating in resistance and susceptibility to glutamate toxicity.
Glutamate is an essential neurotransmitter in the CNS. However, at abnormally high concentrations it becomes cytotoxic. Recent studies in our laboratory showed that glutamate evokes T cell-mediated protective mechanisms. The aim of the present study was to examine the nature of the glutamate receptors and signalling pathways that participate in immune protection against glutamate toxicity. We show, using the mouse visual system, that glutamate-induced toxicity is strain dependent, not only with respect to the amount of neuronal loss it causes, but also in the pathways it activates. In strains that are genetically endowed with the ability to manifest a T cell-dependent neuroprotective response to glutamate insult, neuronal losses due to glutamate toxicity were relatively small, and treatment with NMDA-receptor antagonist worsened the outcome of exposure to glutamate. In contrast, in mice devoid of T cell-dependent endogenous protection, NMDA receptor antagonist reduced the glutamate-induced neuronal loss. In all strains, blockage of the AMPA/KA receptor was beneficial. Pharmacological (with alpha2-adrenoceptor agonist) or molecular intervention (using either mice overexpressing Bcl-2, or DAP-kinase knockout mice) protected retinal ganglion cells from glutamate toxicity but not from the toxicity of NMDA. The results suggest that glutamate-induced neuronal toxicity involves multiple glutamate receptors, the types and relative contributions of which, vary among strains. We suggest that a multifactorial protection, based on an immune mechanism independent of the specific pathway through which glutamate exerts its toxicity, is likely to be a safer, more comprehensive, and hence more effective strategy for neuroprotection. It might suggest that, because of individual differences, the pharmacological use of NMDA-antagonist for neuroprotective purposes might have an adverse effect, even if the affinity is low.
Schori
Hadas
H
Department of Neurobiology, The Weizmann Institute of Science, Rehovot, Israel.
Yoles
Eti
E
Wheeler
Larry A
LA
Raveh
Tal
T
Kimchi
Adi
A
Schwartz
Michal
M
D000818:Animals; D051017:Apoptosis Regulatory Proteins; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000172:deficiency; D016923:Cell Death / Q000187:drug effects / Q000235:genetics / Q000276:immunology; D002470:Cell Survival / Q000187:drug effects / Q000235:genetics / Q000276:immunology; D064550:Death-Associated Protein Kinases; D004198:Disease Susceptibility / Q000276:immunology; D016291:Dizocilpine Maleate / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D019254:Genes, bcl-2 / Q000502:physiology; D018698:Glutamic Acid / Q000633:toxicity*; D007113:Immunity, Innate / Q000235:genetics; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008819:Mice, Nude; D016202:N-Methylaspartate / Q000494:pharmacology; D012165:Retinal Ganglion Cells / Q000187:drug effects* / Q000201:enzymology / Q000276:immunology; D013045:Species Specificity
D051017:Apoptosis Regulatory Proteins; D018698:Glutamic Acid; D016202:N-Methylaspartate; D016291:Dizocilpine Maleate; D064550:Death-Associated Protein Kinases; D017871:Calcium-Calmodulin-Dependent Protein Kinases