Alpha7 nicotinic receptor activation inhibits ethanol-induced mitochondrial dysfunction, cytochrome c release and neurotoxicity in primary rat hippocampal neuronal cultures.
Primary hippocampal neuronal cultures exhibited a concentration- and time-dependent loss of cells when exposed to ethanol (EtOH). EtOH-induced neurotoxicity was attenuated by 2,4-dimethoxybenzilidene anabaseine (DMXB) which selectively activates alpha7 nicotinic receptors in a concentration-dependent manner. We further investigated the mechanisms of the protective effect of DMXB on EtOH- induced neurotoxicity. We found that EtOH decreased the mitochondrial membrane potential and released cytochrome c from mitochondria at neurotoxic concentrations. DMXB (3 microm) attenuated both of these actions in a manner that was in turn blocked with the nicotinic antagonist methyllyconitine (MLA) 100 nm. Neither DMXB nor MLA alone affected these parameters. These results suggest that the neuroprotection conferred by alpha7 nicotinic receptor activation may be mediated, at least in part, through preventing the decrease in the mitochondrial membrane potential and the increase in the release of cytochrome c caused by EtOH.
Li
Yangxin
Y
Department of Internal Medicine, School of Medicine, Southern Illinois University, Springfield, IL 62707, USA. yli3@siumed.edu
Meyer
Edwin M
EM
Walker
Don W
DW
Millard
William J
WJ
He
Yun-Ju
YJ
King
Michael A
MA
D000818:Animals; D001597:Benzylidene Compounds / Q000494:pharmacology; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D003574:Cytochrome c Group / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D000431:Ethanol / Q000633:toxicity*; D006624:Hippocampus / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D007425:Intracellular Membranes / Q000502:physiology; D008564:Membrane Potentials / Q000187:drug effects; D008928:Mitochondria / Q000187:drug effects*; D009474:Neurons / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism*; D018722:Nicotinic Agonists / Q000494:pharmacology; D011725:Pyridines / Q000494:pharmacology; D051381:Rats; D011978:Receptors, Nicotinic / Q000187:drug effects / Q000378:metabolism*; D064569:alpha7 Nicotinic Acetylcholine Receptor
D001597:Benzylidene Compounds; C579165:Chrna7 protein, rat; D003574:Cytochrome c Group; D018722:Nicotinic Agonists; D011725:Pyridines; D011978:Receptors, Nicotinic; D064569:alpha7 Nicotinic Acetylcholine Receptor; D000431:Ethanol; C088936:3-(2,4-dimethoxybenzylidene)anabaseine