Neurotoxicity, glutamate-induced mediation

During ischaemia, NOS is activated by calcium influx or by cytokines like tumour necrosis factor (TNF) or by lipopolysaccharide (LPS) and NO is produced in excess. It has been proposed that the excitotoxic effect of glutamate, which contributes to ischaemia-induced neuronal damage, is mediated by increased production of NO via a chain of events that includes increases in intracellular calcium (via glutamate activation of NMDA receptors), calcium activation of NOS, production of NO and peroxynitrite, and induction of lipid peroxidation. In fact, N-nitro-L-atginine, a selective inhibitor of NOS, has been shown to prevent glutamate-induced neurotoxicity in cortical cell cultures (Dawson rf /., 1991). 

Attention then turned to the mechanism of glutamate-induced neurotoxicity in the brain. Evidence was provided that NO mediates glutamate neurotoxicity in primary cortical cultures (Dawson et ai, 1991). NO synthase inhibitors and hemoglobin prevented NMDA- and glutamate-induced neurotoxicity on the other hand, L-arginine reversed the effect of NO synthase inhibitors, and sodium nitroprusside (which decomposes to NO) caused neurotoxicity that paralleled cyclic GMP formation. In the cerebral cortex, NO synthase immunoreactivity was found to be confined to a discrete population of aspiny neurons comprising... 

During neurotoxicity induced by KA, glutamate release is stimulated (Stein-Behrens et al., 1992). The released glutamate may exert positive feedback to potentiate the action of KA by acting at the NMDA receptor, which produces a further increase in the entry of extracellular Ca2+ through receptor-operated ion channels, thus compounding the Ca2+-mediated neuronal damage. 

Piani, D., Frei, K., Do, K. Q., Cuenod, M., and Fontana, A., Murine brain macrophages induce NMDA receptor mediated neurotoxicity in vitro by secreting glutamate, Neurosci. Lett., 133, 159, 1991. 

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