title: Arecoline Induces Neurotoxicity to PC12 Cells: Involvement in ER Stress and Disturbance of Endogenous H2S Generation.
abstract: Arecoline is a major alkaloid of areca nut and has been effect on central nervous system. Although arecoline-induced neurotoxicity has been reported, the possible underlying neurotoxic mechanisms have not yet been elucidated. Increasing evidences have shown that both excessive endoplasmic reticulum (ER) stress and disturbance of hydrogen sulfide (H2S) production are involved in the pathophysiology of numerous neurodegenerative diseases. Here, the purpose of present study was to verify whether ER stress and the disturbance of endogenous H2S generation are also involved in arecoline-caused neurotoxicity. We found that treatment of PC12 cells with arecoline induced the down-regulation of cells viability and up-regulation of apoptosis and the activity of caspase-3, indicating the neurotoxic role of arecoline to PC12 cells. In addition, arecoline also increased the expression of Bax (pro-apoptotic protein) and attenuated the expression of Bcl-2 (anti-apoptotic protein) in PC12 cells. Simultaneously, arecoline caused excessive ER stress in PC12 cells, as evidenced by the up-regulations of Glucose-regulated protein 78 (GRP78), CCAAT/enhancer binding protein homologous protein (CHOP), and Cleaved caspase-12 expressions. Notably, the level of H2S in the culture supernatant and the expressions of cystathionine β-synthase and 3-mercaptopyruvate sulfurtransferase (two major enzymes for endogenous H2S generation in PC12 cells) were also reduced by arecoline treatment. These results indicate that arecoline-caused neurotoxicity to PC12 cells is involved in ER stress and disturbance of endogenous H2S generation and suggest that the modulation of ER stress and endogenous H2S generation may be potential therapeutic approach in treatment of arecoline-caused neurotoxicity.
authors.affiliation: Department of Cardiology, The Affiliated Hospital, Guangdong Medical University, 57 W Friendship Street People Avenue South, Zhanjiang, 524001, Guangdong, People's Republic of China.|Department of Physiology and Institute of Neuroscience, Medical College, University of South China, 28 W Changsheng Road, Hengyang, 421001, Hunan, People's Republic of China.
authors.forename: Jia-Mei
authors.initials: JM
authors.lastname: Jiang
authors.affiliation: Department of Anthropotomy, Medical College, University of South China, Hengyang, 421001, Hunan, People's Republic of China.
authors.forename: Li
authors.initials: L
authors.lastname: Wang
authors.affiliation: Department of Physiology and Institute of Neuroscience, Medical College, University of South China, 28 W Changsheng Road, Hengyang, 421001, Hunan, People's Republic of China.
authors.forename: Hong-Feng
authors.initials: HF
authors.lastname: Gu
authors.affiliation: Department of Cardiology, The Affiliated Hospital, Guangdong Medical University, 57 W Friendship Street People Avenue South, Zhanjiang, 524001, Guangdong, People's Republic of China. wukeng1245@hotmail.com.
authors.forename: Keng
authors.initials: K
authors.lastname: Wu
authors.affiliation: Department of Physiology and Institute of Neuroscience, Medical College, University of South China, 28 W Changsheng Road, Hengyang, 421001, Hunan, People's Republic of China.
authors.forename: Fan
authors.initials: F
authors.lastname: Xiao
authors.affiliation: Department of Physiology and Institute of Neuroscience, Medical College, University of South China, 28 W Changsheng Road, Hengyang, 421001, Hunan, People's Republic of China.
authors.forename: Ying
authors.initials: Y
authors.lastname: Chen
authors.affiliation: Department of Cardiology, The Affiliated Hospital, Guangdong Medical University, 57 W Friendship Street People Avenue South, Zhanjiang, 524001, Guangdong, People's Republic of China.
authors.forename: Run-Min
authors.initials: RM
authors.lastname: Guo
authors.affiliation: Department of Physiology and Institute of Neuroscience, Medical College, University of South China, 28 W Changsheng Road, Hengyang, 421001, Hunan, People's Republic of China. tangxq-usc@qq.com.
authors.forename: Xiao-Qing
authors.initials: XQ
authors.lastname: Tang
mesh_terms: D000818:Animals; D001115:Arecoline / Q000633:toxicity*; D002470:Cell Survival / Q000187:drug effects / Q000502:physiology; D004305:Dose-Response Relationship, Drug; D059865:Endoplasmic Reticulum Stress / Q000187:drug effects* / Q000502:physiology*; D006862:Hydrogen Sulfide / Q000378:metabolism*; D016716:PC12 Cells; D051381:Rats
chemical_list: D001115:Arecoline; D006862:Hydrogen Sulfide
keywords: Arecoline; Endoplasmic reticulum stress; Hydrogen sulfide; Neurotoxicity