title: Attenuation of Magnesium Sulfate on CoCl₂-Induced Cell Death by Activating ERK1/2/MAPK and Inhibiting HIF-1α via Mitochondrial Apoptotic Signaling Suppression in a Neuronal Cell Line.
abstract: Magnesium sulfate (MgSO₄) ameliorates hypoxia/ischemia-induced neuronal apoptosis in a rat model. This study aimed to investigate the mechanisms governing the anti-apoptotic effect of MgSO₄ on cobalt chloride (CoCl₂)-exposed NB41A3 mouse neuroblastoma cells. MgSO₄ increased the viability of NB41A3 cells treated with CoCl₂ in a dose-dependent manner. MgSO₄ treatment was shown to lead to an increase in the anti-apoptotic Bcl-2 family proteins, with a concomitant decrease in the pro-apoptotic proteins. MgSO₄ also attenuated the CoCl₂-induced disruption of mitochondrial membrane potential (ΔΨ(m)) and reduced the release of cytochrome c form the mitochondria to the cytosol. Furthermore, exposure to CoCl₂ caused activation of the hypoxia-inducible factor 1α (HIF-1α). On the other hand, MgSO₄ markedly reduced CoCl₂-induced HIF-1α activation and suppressed HIF-1α downstream protein BNIP3. MgSO₄ treatment induced ERK1/2 activation and attenuated CoCl₂-induced activation of p38 and JNK. Addition of the ERK1/2 inhibitor U0126 significantly reduced the ability of MgSO₄ to protect neurons from CoCl₂-induced mitochondrial apoptotic events. However, incubation of cultures with the p38 and JNK inhibitors did not significantly affect MgSO₄-mediated neuroprotection. MgSO₄ appears to suppress CoCl₂-induced NB41A3 cell death by activating ERK1/2/ MAPK pathways, which further modulates the role of Bcl-2 family proteins and mitochondria in NB41A3 cells. Our data suggest that MgSO₄ may act as a survival factor that preserves mitochondrial integrity and inhibits apoptotic pathways.
authors.affiliation: Graduate Institute of Basic Medical Science, China Medical University, Taichung 40402, Taiwan, Republic of China.|Department of Health and Nutrition Biotechnology, Asia University, Taichung 41354, Taiwan, Republic of China.
authors.forename: Chih-Yang
authors.initials: CY
authors.lastname: Huang
authors.affiliation: Department of Health and Nutrition Biotechnology, Asia University, Taichung 41354, Taiwan, Republic of China.
authors.forename: You-Liang
authors.initials: YL
authors.lastname: Hsieh
authors.affiliation: Department of Neurological Surgery, Tri-Service General Hospital National Defense Medical Center, Taipei 11472, Taiwan, Republic of China.
authors.forename: Da-Tong
authors.initials: DT
authors.lastname: Ju
authors.affiliation: Orthopaedic Departmrnt, Armed Forces General Hospital, Taichung 41168, Taiwan, Republic of China.
authors.forename: Chien-Chung
authors.initials: CC
authors.lastname: Lin
authors.affiliation: Laboratory of Exercise Biochemistry, Taipei Physical Education College, Taipei 11153, Taiwan, Republic of China.
authors.forename: Chia-Hua
authors.initials: CH
authors.lastname: Kuo
authors.affiliation: Graduate Institute of Basic Medical Science, China Medical University, Taichung 40402, Taiwan, Republic of China.
authors.forename: Yi-Fan
authors.initials: YF
authors.lastname: Liou
authors.affiliation: Chinese Medicine Department, China Medical University Beigang Hospital, Yunlin 65152, Taiwan, Republic of China.
authors.forename: Tsung-Jung
authors.initials: TJ
authors.lastname: Ho
authors.affiliation: Department of Healthcare Administration, Asia University, Taichung 41354, Taiwan, Republic of China.
authors.forename: Chang-Hai
authors.initials: CH
authors.lastname: Tsai
authors.affiliation: Department of Pediatrics, Medical Research and Medical Genetics, China Medical University, Taichung 40402, Taiwan, Republic of China.
authors.forename: Fuu-Jen
authors.initials: FJ
authors.lastname: Tsai
authors.affiliation: Department of Medical Imaging and Radiological Science, Central Taiwan University of Science and Technology, Taichung 40601, Taiwan, Republic of China.
authors.forename: Jing-Ying
authors.initials: JY
authors.lastname: Lin
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D045744:Cell Line, Tumor; D003035:Cobalt / Q000494:pharmacology*; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism*; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000037:antagonists & inhibitors*; D008278:Magnesium Sulfate / Q000494:pharmacology*; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D051379:Mice; D017382:Reactive Oxygen Species / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects*
chemical_list: D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D017382:Reactive Oxygen Species; D003035:Cobalt; D008278:Magnesium Sulfate; D048049:Extracellular Signal-Regulated MAP Kinases; C018021:cobaltous chloride