Activation of α7-nAChRs protects SH-SY5Y cells from 1-methyl-4-phenylpyridinium-induced apoptotic cell death via ERK/p53 signaling pathway.

Abstract

Epidemiologic studies have shown a reduced risk of developing Parkinson's disease (PD) among cigarette smokers. Nicotine, as a key component in tobacco products, is thought as a possible candidate for action of smoking in neuroprotection. α7 nicotinic acetylcholine receptors (α7-nAChRs) is one of the most abundant nAChRs in the mammalian brain. Although nicotine is thought to exert this protective action by acting on nicotinic receptors, including the α7-nAChRs; the mechanisms underlying how α7-nAChRs protect against dopaminergic neuron loss are highly complex. Using nicotine and a selective α7-nAChR agonist PNU-282987, we first confirmed that their addition to SH-SY5Y cells challenged with 1-methyl-4-phenylpyridinium (MPP+ ) could afford neuroprotection and result in a reduction in apoptotic cell death. Then, we found that the pretreatment with nicotine and PNU-282987 showed the neuroprotective antiapoptotic effects via activating the α7-nAChRs/MAPK/p53 axis. Furthermore, we used RNA interference to silence the expression of α7-nAChRs in SH-SY5Y cells and found that suppressing α7-nAChR expression diminished the antiapoptotic effects of nicotine and PNU-282987, not the toxic effects of MPP+ . Moreover, α7-nAChR knockdown could only decrease the inhibitory effects of nicotine and PNU-282987 on the phosphorylated extracellular signal-regulated kinase (ERK), not c-Jun amino-terminal kinase and p38. Therefore, our findings indicate the important roles of ERK/MAPK signaling in the neuroprotective effects of α7-nAChRs and suggest that α7-nAChR agonists may be validated as novel treatments for PD.