title: Rotenone-induced neurotoxicity of THP-1 cells requires production of reactive oxygen species and activation of phosphatidylinositol 3-kinase.
abstract: Parkinson's disease is characterized by slow and progressive degeneration of dopaminergic neurons. Increasing evidence has suggested an important role for exposure to pesticides such as rotenone in the pathogenesis of Parkinson's disease. Although rotenone can elicit immune responses in microglia, the intracellular signaling events mediating these effects are poorly defined. Here we show that cell-free supernatants of rotenone-treated monocytic THP-1 cells induced cytotoxicity in dopaminergic neuroblastoma SH-SY5Y cells. Exposure of THP-1 cells to rotenone led to transient production of reactive oxygen species (ROS) and phosphorylation of Akt. Akt activation was also induced by exogenous hydrogen peroxide. Pretreatment of THP-1 cells with either a phosphatidylinositol 3-kinase (PI3K) inhibitor or ROS scavengers prevented Akt activation and protected SH-SY5Y cells from the cytotoxic effect of conditioned media from rotenone-treated THP-1 cells. Rotenone treatment of THP-1 cells also led to upregulation of cyclooxygenase-2 and secretion of prostaglandin E2. These results suggest that rotenone-induced activation of ROS/PI3K/Akt pathway in THP-1 cells leads to the release of factors that are toxic to SH-SY5Y cells and have implications for the onset of Parkinson's disease.
authors.affiliation: Department of Pharmacology, Shanghai Institute of Materia Medica, Shanghai Institute for Biological Sciences, Chinese Academy of Sciences, 555 Zu Chong Zhi Road, Zhangjiang Hi-Tech Park, Shanghai 201203, China. 4j44@qlink.queensu.ca
authors.forename: Jing-Hui
authors.initials: JH
authors.lastname: Hu
authors.forename: Xing-Zu
authors.initials: XZ
authors.lastname: Zhu
mesh_terms: D000704:Analysis of Variance; D002460:Cell Line; D017077:Culture Media, Conditioned / Q000494:pharmacology; D051546:Cyclooxygenase 2 / Q000378:metabolism; D015232:Dinoprostone / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004789:Enzyme Activation / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006801:Humans; D007306:Insecticides / Q000494:pharmacology*; D009000:Monocytes / Q000187:drug effects*; D009447:Neuroblastoma; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D017382:Reactive Oxygen Species / Q000378:metabolism*; D012402:Rotenone / Q000494:pharmacology*; D013778:Tetrazolium Salts; D013844:Thiazoles; D015854:Up-Regulation / Q000187:drug effects
chemical_list: D017077:Culture Media, Conditioned; D004791:Enzyme Inhibitors; D007306:Insecticides; D017382:Reactive Oxygen Species; D013778:Tetrazolium Salts; D013844:Thiazoles; D012402:Rotenone; D051546:Cyclooxygenase 2; D019869:Phosphatidylinositol 3-Kinases; C022616:thiazolyl blue; D015232:Dinoprostone