Investigating the receptor-independent neuroprotective mechanisms of nicotine in mitochondria.
Although nicotine has been associated with a decreased risk of developing Parkinson disease, the underlying mechanisms are still unclear. By using isolated brain mitochondria, we found that nicotine inhibited N-methyl-4-phenylpyridine (MPP(+)) and calcium-induced mitochondria high amplitude swelling and cytochrome c release from intact mitochondria. Intra-mitochondria redox state was also maintained by nicotine, which could be attributed to an attenuation of mitochondria permeability transition. Further investigation revealed that nicotine did not prevent MPP(+)- or calcium-induced mitochondria membrane potential loss, but instead decreased the electron leak at the site of respiratory chain complex I. In the presence of mecamylamine hydrochloride, a nonselective nicotinic acetylcholine receptor inhibitor, nicotine significantly postponed mitochondria swelling and cytochrome c release induced by a mixture of neurotoxins (MPP(+) and 6-hydroxydopamine) in SH-SY5Y cells, suggesting that there is a receptor-independent nicotine-mediated neuroprotective effect of nicotine. These results show that interaction of nicotine with mitochondria respiratory chain together with its antioxidant effects should be considered in the neuroprotective effects of nicotine.
Xie
Yu-Xiang
YX
State Key Laboratory of Brain and Cognitive Science, Institute of Biophysics, Academia Sinica, Beijing, China.
Bezard
Erwan
E
Zhao
Bao-Lu
BL
D015655:1-Methyl-4-phenylpyridinium / Q000494:pharmacology*; D000818:Animals; D001665:Binding Sites; D015153:Blotting, Western; D001921:Brain / Q000378:metabolism*; D002118:Calcium / Q000378:metabolism; D002460:Cell Line; D045744:Cell Line, Tumor; D045304:Cytochromes c / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004583:Electrons; D005609:Free Radicals; D049452:Green Fluorescent Proteins / Q000378:metabolism; D006801:Humans; D006861:Hydrogen Peroxide / Q000494:pharmacology; D007425:Intracellular Membranes / Q000378:metabolism; D008297:Male; D008564:Membrane Potentials; D018613:Microscopy, Confocal; D008928:Mitochondria / Q000378:metabolism*; D008933:Mitochondrial Swelling; D009538:Nicotine / Q000378:metabolism / Q000494:pharmacology*; D016627:Oxidopamine / Q000494:pharmacology; D010100:Oxygen / Q000378:metabolism; D010539:Permeability; D010957:Plasmids / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D013053:Spectrophotometry; D013997:Time Factors
D005609:Free Radicals; D049452:Green Fluorescent Proteins; D009538:Nicotine; D016627:Oxidopamine; D045304:Cytochromes c; D006861:Hydrogen Peroxide; D015655:1-Methyl-4-phenylpyridinium; D010100:Oxygen; D002118:Calcium