title: Bupropion, an atypical antidepressant, induces endoplasmic reticulum stress and caspase-dependent cytotoxicity in SH-SY5Y cells.
abstract: Bupropion is an atypical antidepressant that is currently used as a smoking cessation aid. Bupropion interferes with monoamine reuptake and is potentially neurotoxic, although this is yet to be confirmed. In this study, we evaluated the cytotoxicity of bupropion using SH-SY5Y human catecholaminergic cells as the in vitro model. Exposure of the cells to bupropion for 24h reduced their viability in a concentration-dependent manner. Treatment of the cells with a toxic concentration of bupropion (100μg/mL) induced the phosphorylation of eukaryotic initiation factor alpha (EIF-2α), c-JUN N-terminal kinase (JNK), and p38 mitogen-activated protein kinase (MAPK) within 1h, which later declined to baseline levels. However, bupropion failed to splice X-box binding protein 1 (XBP1) mRNA. Bupropion caused mitochondrial cytochrome c release and activated caspases 9, 8, and 3 in a time-dependent manner. The reduction in cell viability was significantly inhibited by a caspase 3 inhibitor. Bupropion also induced the mRNA expression of the death receptors DR4 (TRAILR1) and DR5 (TRAILR2). However, bupropion did not increase the level of cellular oxidative stress. Taken together, our data indicate that bupropion activates caspase 3 through the induction of endoplasmic reticulum stress responses and activation of JNK, and consequently induces apoptotic cell death in SH-SY5Y cells.
authors.affiliation: Department of Pharmacology and Medicinal Toxicology Research Center, Inha Research Institute for Medical Sciences, Inha University, Incheon, Republic of Korea.
authors.forename: Eun-Hee
authors.initials: EH
authors.lastname: Jang
authors.forename: Chang-Shin
authors.initials: CS
authors.lastname: Park
authors.forename: Ju-Hee
authors.initials: JH
authors.lastname: Kang
mesh_terms: D018687:Antidepressive Agents, Second-Generation / Q000008:administration & dosage / Q000633:toxicity*; D017209:Apoptosis / Q000187:drug effects*; D016642:Bupropion / Q000008:administration & dosage / Q000633:toxicity*; D053148:Caspase 3 / Q000187:drug effects* / Q000378:metabolism; D053181:Caspase 8 / Q000378:metabolism; D053453:Caspase 9 / Q000378:metabolism; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004721:Endoplasmic Reticulum / Q000187:drug effects* / Q000378:metabolism; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism; D009447:Neuroblastoma / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D012333:RNA, Messenger / Q000378:metabolism; D013997:Time Factors
chemical_list: D018687:Antidepressive Agents, Second-Generation; D012333:RNA, Messenger; D016642:Bupropion; D048031:JNK Mitogen-Activated Protein Kinases; D053148:Caspase 3; D053181:Caspase 8; D053453:Caspase 9