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

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.