Role of Nitric Oxide in neuronal death and its modulation by neuroprotective factors

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The purpose of this study was to elucidate the mechanism underlying neuronal death in neurodegeneration diseases in central nervous system (CNS), such as cerebrovascular disease and Alzheimer's disease. We studied the mechanisms underlying glutamate neurotoxicity mediated by nitric oxide (NO) and protective effect of nicotine against glutamate neurotoxicity using cultured rat cortical neurons. 1.We examined the protective effect on nicotine. The cell viability was markedly reduced when cultures were briefly exposed to glutamate or N-methyl-D-aspartate (NMDA). Incubating the cultures with nicotine (10muM) prior to glutamate exposure reduced its cytotoxicity. The neuroprotective effect of nicotine against glutamate neurotoxicity was antagonized by hexamethonium, an antagonist specific to nicotinic acetylcholine receptor. Both brief exposures to ionomycin, a calcium ionophore, and S-nitrosocysteine (SNOC), an NO donor, induced delayd neuronal death. Nicotine prevented ionomycin-induced cy … More totoxicity without affecting SNOC-induced cytotoxicity. These results suggest that the nicotinic receptor stimulation induces neuroprotection against glutamate cytotoxicity by reducing NO-formation. 2.We have previously shown that anti-phospholipase C-delta (PLC-delta) antibody produced intense staining of neurofibrillary tangles, the neurite surrounding senile plaque cores and neuropil threads in the brain of patients with Alzheimer's disease. We examined the influence of glutamate on PLC-delta immunoreactivity in the cultures using anti-PLC-delta antibody. Exposure to glutamate exhibited increased immunostaining with the anti-PLC-delta antibody. The increase in PLC-delta immunoreactivity was prevented by both application of MK-801, an NMDA receptor antagonist, and N^<omega>-nitro-L-arginine, an NO synthase inhibitor. These results suggest that NO formation secondary to NMDA receptor activation by glutamate leads to similar modifications of PLC-delta to those seen in Alzheimer's disease. The results in this study will offer basic materials to drive forward developmental research for neuroprotective drugs. Less