Nicotine blocks ethanol-induced apoptosis in primary cultures of rat cerebral cortical and cerebellar granule cells.
Nicotine's counteraction of adverse effects of ethanol on cognitive function and motor coordination may play a major role in the observed high incidence of smoking among alcoholics. Previously, we have observed protective effects of nicotine against ethanol-induced neurotoxicity in cultured cortical and cerebellar granule cells as determined by lactate dehydrogenase assay. Ethanol-induced apoptosis may be a contributory mechanism to its neuronal toxicity. In this study we sought to determine whether ethanol induces formation of caspase 3 (reflective of apoptosis) in these cells and whether these effects may be blocked by nicotine pretreatment. Primary cultures of cerebral cortical and cerebellar granule cells were prepared from the brains of 20 day old Sprague-Dawley fetuses. Exposure of cells to ethanol (10-100 mM) for 3 days resulted in a dose-dependent increase in caspase 3 activity and cytotoxicity. Pretreatment with nicotine (5-20 microM) dose dependently attenuated these effects of ethanol. Complete block of ethanol effects was achieved by the highest dose of nicotine (20 microM). Nicotine, at concentrations administered, did not affect caspase activity or neuronal viability. These results suggest that at least some of the neurotoxic effects of ethanol may be mediated by apoptosis and that pretreatment with nicotine can prevent these effects of ethanol. Anti-apoptotic effects of nicotine in this model may be suggestive of potential use of nicotinic agonists in neurotoxic insults and/or neurodegenerative disorders.
Tizabi
Yousef
Y
Department of Pharmacology, Howard University, Washington, DC 20059,USA. ytizabi@howard.edu
Manaye
Kebreten F
KF
Taylor
Robert E
RE
D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D053148:Caspase 3; D020169:Caspases / Q000378:metabolism; D002478:Cells, Cultured; D002492:Central Nervous System Depressants / Q000037:antagonists & inhibitors* / Q000633:toxicity*; D002531:Cerebellum / Q000166:cytology* / Q000187:drug effects*; D002540:Cerebral Cortex / Q000166:cytology* / Q000187:drug effects*; D000431:Ethanol / Q000037:antagonists & inhibitors* / Q000633:toxicity*; D005260:Female; D009474:Neurons / Q000187:drug effects*; D009538:Nicotine / Q000494:pharmacology*; D018722:Nicotinic Agonists / Q000494:pharmacology*; D011247:Pregnancy; D051381:Rats; D017207:Rats, Sprague-Dawley
D002492:Central Nervous System Depressants; D018722:Nicotinic Agonists; D000431:Ethanol; D009538:Nicotine; C505410:Casp3 protein, rat; D053148:Caspase 3; D020169:Caspases