Nicotine exerts neuroprotective effects against β-amyloid-induced neurotoxicity in SH-SY5Y cells through the Erk1/2-p38-JNK-dependent signaling pathway.
Epidemiological data have indicated that smoking tobacco can decrease the risk of developing Alzheimer's disease (AD). Nicotine, a main component of tobacco, has been shown to have therapeutic effects in AD. The aim of the present study was to assess the neuroprotective effects of nicotine against toxicity induced by β-amyloid (Aβ) in relation to cell apoptosis, and to elucidate the role of the activation of the Erk1/2-p38-JNK pathway and the modulation of anti-apoptotic proteins in the nicotine-induced neuroprotective effects. We performed in vitro and in vivo experiments using SH-SY5Y cells and C57BL/6 mice, respectively. The effects of nicotine on cell apoptosis were determined by flow cytmetry and microscopic observation. The effects of nicotine on the expression of anti-apoptotic proteins were also determined by western blot analysis. Our results demonstrated that nicotine protected the SH-SY5Y cells against Aβ25-35-induced toxicity by inhibiting apoptosis and upregulating the expression of anti-apoptotic proteins. As shown by our in vivo experiments, nicotine effectively ameliorated the impairment in spatial working memory induced by Aβ25-35; this was confirmed by a Morris water maze navigation test and further supported by the upregulation of Bcl-2 in the hippocampus of Aβ25-35-injected mice treated with nicotine. The phosphorylation of Erk1/2, p38 and JNK increased following treatment with nicotine in the SH-SY5Y cells, whereas caspase-3 activation was inhibited by treatment with nicotine prior to exposure to Aβ25-35. Of note, these effects of nicotine against Aβ25-35-induced damage were abolished by inhibitors of Erk1/2, p38 and JNK phosphorylation. These ﬁndings suggest that nicotine prevents Aβ25-35-induced neurotoxicity through the inhibition of neuronal apoptosis, and may thus prove to be a potential preventive or therapeutic agent for AD.
Department of Basic Medical Sciences, Medical College, Xiamen University, Xiamen, Fujian 361005, P.R. China.
Mao Qiang
MQ
Xue
Department of Basic Medical Sciences, Medical College, Xiamen University, Xiamen, Fujian 361005, P.R. China.
Xiao Xing
XX
Liu
Department of Basic Medical Sciences, Medical College, Xiamen University, Xiamen, Fujian 361005, P.R. China.
Yan Ling
YL
Zhang
Department of Basic Medical Sciences, Medical College, Xiamen University, Xiamen, Fujian 361005, P.R. China.
Feng Guang
FG
Gao
D016229:Amyloid beta-Peptides / Q000633:toxicity*; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D045744:Cell Line, Tumor; D003072:Cognition Disorders / Q000188:drug therapy / Q000503:physiopathology; D004305:Dose-Response Relationship, Drug; D004789:Enzyme Activation / Q000187:drug effects; D006801:Humans; D020935:MAP Kinase Signaling System / Q000187:drug effects*; D008297:Male; D008570:Memory, Short-Term / Q000187:drug effects; D051379:Mice; D008810:Mice, Inbred C57BL; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism*; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism*; D064549:Myeloid Cell Leukemia Sequence 1 Protein / Q000378:metabolism; D018696:Neuroprotective Agents / Q000494:pharmacology* / Q000627:therapeutic use; D009498:Neurotoxins / Q000633:toxicity; D009538:Nicotine / Q000494:pharmacology* / Q000627:therapeutic use; D010446:Peptide Fragments / Q000633:toxicity*; D013997:Time Factors; D051020:bcl-X Protein / Q000378:metabolism; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism*
D016229:Amyloid beta-Peptides; C579095:MCL1 protein, human; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D018696:Neuroprotective Agents; D009498:Neurotoxins; D010446:Peptide Fragments; C074636:amyloid beta-protein (25-35); D051020:bcl-X Protein; D009538:Nicotine; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D048051:p38 Mitogen-Activated Protein Kinases