Nicotine-induced protection against glutamate cytotoxicity. Nicotinic cholinergic receptor-mediated inhibition of nitric oxide formation.
Cortical neurodegeneration in Alzheimer's disease (AD) is suggested to be attributable not only to beta-protein but also to glutamate. Although degeneration of cholinergic projection to the cerebral cortex is recognized to be one of the most prominent pathological changes in AD, there is only limited information concerning the cholinergic interaction with the cortical neurodegeneration. This study was performed to examine the protective effect of nicotine against glutamate-induced cytotoxicity using rat cultured cortical neurons. The cell viability was significantly reduced when cultures were briefly exposed to glutamate or N-methyl-D-aspartate (NMDA). The simultaneous addition of nicotine did not reduce glutamate cytotoxicity. In contrast, the simultaneous application of NMDA receptor antagonists such as MK-801 reduced glutamate cytotoxicity. Incubating the cultures with nicotine (10 microM) for 0.5-24 h prior to glutamate exposure reduced its cytotoxicity. Neuroprotection by nicotine was dependent on both the concentration and incubation period. In contrast to nicotine, muscarine (10 microM) weakly potentiated glutamate cytotoxicity. The neuroprotective effect of nicotine against glutamate cytotoxicity was antagonized by hexamethonium but not by artopine. Nicotine prevented NMDA cytotoxicity but did not affect cytotoxicity induced by either kainate or alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA). Cell viability was significantly reduced by a brief exposure of cultures to ionomycin, a calcium ionophore. Ionomycin-induced cytotoxicity was abolished by removing Ca2+ from incubating medium. S-nitrosocysteine (SNOC), which spontaneously releases nitric oxide (NO), also induced delayed cell death. Nicotine prevented ionomycin-induced cytotoxicity without affecting SNOC-induced cytotoxicity. These results suggest that nicotinic cholinergic receptor stimulation induces neuroprotection against glutamate cytotoxicity by its inhibitory action on NO-formation. Therefore, we propose that acetylcholine, acting through nicotinic cholinergic receptors, can function as a putative neuroprotective factor against neurodegeneration caused by the excessive release of glutamate and/or NMDA receptor activation.
Shimohama
S
S
Department of Neurology, Faculty of Medicine, Kyoto University, Japan. i53367@sakura.kudpc.kyoto-u.ac.jp
Akaike
A
A
Kimura
J
J
D000818:Animals; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000166:cytology / Q000187:drug effects; D018698:Glutamic Acid / Q000494:pharmacology*; D009474:Neurons / Q000187:drug effects; D018696:Neuroprotective Agents / Q000494:pharmacology*; D009498:Neurotoxins / Q000494:pharmacology*; D009538:Nicotine / Q000494:pharmacology*; D009569:Nitric Oxide / Q000037:antagonists & inhibitors*; D051381:Rats / Q000196:embryology; D011978:Receptors, Nicotinic / Q000502:physiology*
D018696:Neuroprotective Agents; D009498:Neurotoxins; D011978:Receptors, Nicotinic; D009569:Nitric Oxide; D018698:Glutamic Acid; D009538:Nicotine