Oxidative stress-induced neuronal damage has been implicated to play a dominant role in neurodegenerative disorders, such as Alzheimer’s disease (AD). Nicotine, a principal additive compound for tobacco users, is thought as a candidate to attenuate amyloid-β-mediated neurotoxicity and NMDA-induced excitotoxicity. Previous studies demonstrated that nicotine exerted this neuroprotective action on oxidative stress. However, the mechanisms underlying how nicotine contributes on oxidative injury in immortalized hippocampal HT-22 cells remain largely unknown. Therefore, in this study we investigated that the potential effects of nicotine on hydrogen peroxide (H₂O₂)-induced oxidative injury and underlying mechanisms in HT-22 cells. We found that pretreatment with nicotine at low concentrations markedly recovered the cell cycle that was arrested at the G2/M phase in the presence of H₂O₂ through reduced intracellular ROS generation. Moreover, nicotine attenuated H₂O₂-induced mitochondrial dysfunctions. Mechanistically, the application of nicotine significantly upregulated the levels of phosphorylated Erk1/2. The neuroprotective effects of nicotine, in turn, were abolished by PD0325901, a selective Erk1/2 inhibitor. Further obtained investigation showed that nicotine exerted its neuroprotective effects via specifically activating α7 nicotinic acetylcholine receptors (α7-nAChRs). A selective inhibitor of α7-nAChRs, methyllycaconitine citrate (MLA), not only completely prevented nicotine-mediated antioxidation but also abolished expression of p-Erk1/2. Taken together, our findings suggest that nicotine suppresses H₂O₂-induced HT-22 cell injury through activating the α7-nAChR/Erk1/2 signaling pathway, which indicates that nicotine may be a novel strategy for the treatment of neurodegenerative disorders.

氧化应激诱导的神经元损伤被认为在神经退行性疾病如阿尔茨海默氏病（AD）中起主要作用。尼古丁是烟草使用者的主要添加剂化合物，被认为是减轻淀粉样β介导的神经毒性和NMDA诱导的兴奋性毒性的候选药物。先前的研究表明，尼古丁对氧化应激发挥了这种神经保护作用。然而，在永生化的海马HT-22细胞中，尼古丁如何促进氧化损伤的潜在机制仍然未知。因此，在这项研究中，我们调查了尼古丁对过氧化氢（H ₂ O ₂诱导的HT-22细胞氧化损伤及其潜在机制。我们发现低浓度尼古丁预处理可通过减少细胞内ROS的产生显着恢复在H ₂ O ₂存在下停滞在G2 / M期的细胞周期。而且，尼古丁减轻了H ₂ O ₂诱导的线粒体功能障碍。从机理上讲，尼古丁的应用显着上调了磷酸化Erk1 / 2的水平。选择性Erk1 / 2抑制剂PD0325901取消了尼古丁的神经保护作用。进一步的研究表明尼古丁发挥了神经保护作用通过特异性激活α7烟碱乙酰胆碱受体（α7-nAChRs）。选择性的α7-nAChRs抑制剂，柠檬酸甲基卡卡尼碱（MLA），不仅可以完全阻止尼古丁介导的抗氧化作用，而且可以消除p-Erk1 / 2的表达。两者合计，我们的发现表明，尼古丁通过激活α7-nAChR/ Erk1 / 2信号通路抑制H ₂ O ₂诱导的HT-22细胞损伤，这表明尼古丁可能是治疗神经退行性疾病的一种新策略。