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Nicotine Prevents Oxidative Stress-Induced Hippocampal Neuronal Injury Through ?7-nAChR/Erk1/2 Signaling Pathway.

ABSTRACT: 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-?-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 ?7 nicotinic acetylcholine receptors (?7-nAChRs). A selective inhibitor of ?7-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 ?7-nAChR/Erk1/2 signaling pathway, which indicates that nicotine may be a novel strategy for the treatment of neurodegenerative disorders.

SUBMITTER: Dong Y

PROVIDER: S-EPMC7717967 | biostudies-literature | 2020

REPOSITORIES: biostudies-literature

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Nicotine Prevents Oxidative Stress-Induced Hippocampal Neuronal Injury Through α7-nAChR/Erk1/2 Signaling Pathway.

Dong Yun Y Bi Wenchuan W Zheng Kai K Zhu Enni E Wang Shaoxiang S Xiong Yiping Y Chang Junlei J Jiang Jianbing J Liu Bingfeng B Lu Zhonghua Z Cheng Yongxian Y

Frontiers in molecular neuroscience 20201112

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 i ...[more]

PMID: 33328880

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Project description:α-Conotoxins potently inhibit isoforms of nicotinic acetylcholine receptors (nAChRs), which are essential for neuronal and neuromuscular transmission. They are also used as neurochemical tools to study nAChR physiology and are being evaluated as drug leads to treat various neuronal disorders. A number of experimental studies have been performed to investigate the structure-activity relationships of conotoxin/nAChR complexes. However, the structural determinants of their binding interactions are still ambiguous in the absence of experimental structures of conotoxin-receptor complexes. In this study, the binding modes of α-conotoxin ImI to the α7-nAChR, currently the best-studied system experimentally, were investigated using comparative modeling and molecular dynamics simulations. The structures of more than 30 single point mutants of either the conotoxin or the receptor were modeled and analyzed. The models were used to explain qualitatively the change of affinities measured experimentally, including some nAChR positions located outside the binding site. Mutational energies were calculated using different methods that combine a conformational refinement procedure (minimization with a distance dependent dielectric constant or explicit water, or molecular dynamics using five restraint strategies) and a binding energy function (MM-GB/SA or MM-PB/SA). The protocol using explicit water energy minimization and MM-GB/SA gave the best correlations with experimental binding affinities, with an R2 value of 0.74. The van der Waals and non-polar desolvation components were found to be the main driving force for binding of the conotoxin to the nAChR. The electrostatic component was responsible for the selectivity of the various ImI mutants. Overall, this study provides novel insights into the binding mechanism of α-conotoxins to nAChRs and the methodological developments reported here open avenues for computational scanning studies of a rapidly expanding range of wild-type and chemically modified α-conotoxins.

Dataset Information

Nicotine Prevents Oxidative Stress-Induced Hippocampal Neuronal Injury Through ?7-nAChR/Erk1/2 Signaling Pathway.

Publications

Nicotine Prevents Oxidative Stress-Induced Hippocampal Neuronal Injury Through α7-nAChR/Erk1/2 Signaling Pathway.

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