Glutamate-mediated neurotoxicity

It should be noted that other types of activity, besides the increase of neurotransmitter levels, are also being explored as leads for chemotherapeutic treatment of AD. These include the prevention of glutamate-mediated neurotoxicity by antagonism ofN-methyl-D-aspartate (NMDA) receptors, antioxidants, antiinflammatories and inhibitors of fl-amyloid synthesis, but these are not covered to any extent in this chapter. 

Brain Oxidant and Antioxidant Proteins in Glutamate-Mediated Neurotoxicity... 

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 involvement of PLC in ionotropic and metabotropic glutamate receptor-mediated neurotoxicity has also been reported in primary cultures of cerebellar neurons (Miyata et al., 2003 Facchinetti et al., 1998 Nicolle et al., 1999). It is shown that l-[6-[[(17b)-3-methoxyestra-l,3, 5(10)-trien-17-yl]amino] hexyl]-lH-pyrrole-2,5-dione (U-73122) and 1 -O-octadecy 1-2-O-mcthy 1 -rac-glyccro-3-phosphocholine (Et-18-OCH3), two agents that inhibit PLC, block glutamate and... 

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