Neurotoxicity, glutamate-induced

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... 

The precise mechanism by which NO causes glutamase neurotoxicity is unknown. Calcium must be required because of the requirement for NMDA- and glutamate-induced NO formation in brain tissue (Garthwaite etal., 1988). Although both NMDA-receptor agonists and sodium nitroprusside induce specific neurotoxicity as well as cyclic GMP formation in brain tissue (Dawson et al., 1991), it is unlikely that cyclic GMP is the ultimate cause of the neurotoxicity. Instead, NO is most likely involved in producing target cell death. One possible mechanistic pathway is that locally synthesized NO and superoxide anion react with each other to yield peroxynitrite anion (Beckman et al., 1990), which can destroy cell membranes either directly via interaction with cellular thiols (Radi et al., 1991) or indirectly via decomposition to hydroxyl and other free radicals (Beckman et al., 1990). 

Goto, Y., Niidome, T., Akaike, A., Kihara, T., and Sugimoto, H. (2006). Amyloid beta-peptide preconditioning reduces glutamate-induced neurotoxicity by promoting endocytosis of NMDA receptor. Biochem Biophys Res Commun 351, 259-265. 

F. Sureda et al.. Effects of U-83836E on glutamate-induced neurotoxicity in dissociated rat cerebellar granule cells. Toxicol. Appl. Pharmacol. 156 (1999) 1-5. 

Toriu N, Akaike A, Yasuyoshi H, Zhang S, Kashii S, et al. 2000. Lomerizine, a Ca channel blocker, reduces glutamate-induced neurotoxicity and ischemia/reperfusion damage in rat retina. Exp Eye Res 70 475-484. 

The direct alkylation of the nitrogen atom of salt 402a with l-(3-iodo-propyl)-3,7-dimethylxanthine afforded compound 403 (80%), which antagonised glutamate induced neurotoxicity [130] (Scheme 96). 

S. bitergeniana Neuroprotective Attenuation of glutamate-induced neurotoxicity [121]... 

Lindholm, D., Dechant, G., Heisenberg, C.P. and Thoenen, H. (1993) Brain derived neurotrophic factor is a survival factor for cultured rat cerebellar granule neurons and protects them against glutamate induced neurotoxicity. Eur. J. Neu-rosci. 5 1455-1464. 

Randall, R.D. and Thayer, S.A. (1992). Glutamate-induced calcium transient triggers delayed calcium overload and neurotoxicity in rat hippocampal neurons. J. Neurosci. 12 1882-1895. 

Hansen, H. S., Moesgaard, B., Hansen, H. H., Schousboe, A., and Petersen, G. (1999). Formation of 7/-acyl-phosphatidylethanolamine and iV-acylethanolamine (including anandamide) during glutamate-induced neurotoxicity. Lipids 34 Suppl., 327-330. 

Cosi C, Suzuki H, Milan D et al. PolyfADP-ribose) polymerase Early involvement in glutamate-induced neurotoxicity in cultured cerebellar granule cells. J Neurosci Res 1994 39 38-46. 

Oxindole and indole alkaloids corynoxeine, hirsutine, and hirsuteine from uncaria Uncaria rhynchophylla Miq.) as the main compounds of the extract destabilize the formation of Ap aggregates [185]. They also have a neuropro-tective effect and inhibit glutamate-induced neurotoxicity in the cells of the cerebellum [186]. 

Favit, A. Sortino, M. A. Aleppo, G. Scapagnini, U. Canonico, P. L. Protection by dihydroergocryp-tine of glutamate-induced neurotoxicity. Pharmacol. Toxicol. 1993, 73, 224—228. 

---