title: Minocycline prevents paraquat-induced cell death through attenuating endoplasmic reticulum stress and mitochondrial dysfunction.
abstract: Paraquat (PQ) was demonstrated to induce dopaminergic neuron death and is used as a Parkinson's disease (PD) mimetic; however, its mechanism remains contradictory. Alternatively, minocycline is a second-generation tetracycline and is undergoing clinical trials for treating PD with an unresolved mechanism. We thus investigated the molecular mechanism of minocycline in preventing PQ-induced cytotoxicity. In this study, minocycline was effective in preventing PQ-induced apoptotic cell death, which involves the cleavages of poly (ADP-ribose) polymerase (PARP) and caspase 3 and increased fluorescence intensity of annexin V-FITC. In addition, PQ also quickly induced alterations of unfolded protein responses (UPRs) and subsequently dysfunction of the mitochondria (such as the decrease in membrane potential and increase in membrane permeability and superoxide formation). Finally, the mechanism of minocycline in preventing PQ-induced apoptosis might be mediated by attenuating endoplasmic reticulum (ER) stress and mitochondrial dysfunction, which respectively results in caspase-12 activation and the release of H2O2, HtrA2/Omi, and Smac/Diablo. Thus, minocycline could possibly be used to treat other neurodegenerative disorders with similar pathologic mechanisms.
authors.affiliation: Medical Research Center, Cardinal Tien Hospital, Hsintien, New Taipei City, Taiwan, ROC.
authors.forename: Chuen-Lin
authors.initials: CL
authors.lastname: Huang
authors.forename: Yi-Chao
authors.initials: YC
authors.lastname: Lee
authors.forename: Ying-Chen
authors.initials: YC
authors.lastname: Yang
authors.forename: Tsun-Yung
authors.initials: TY
authors.lastname: Kuo
authors.forename: Nai-Kuei
authors.initials: NK
authors.lastname: Huang
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D015153:Blotting, Western; D053454:Caspase 12 / Q000378:metabolism; D016923:Cell Death / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D004721:Endoplasmic Reticulum / Q000187:drug effects* / Q000378:metabolism; D006540:Herbicides / Q000633:toxicity*; D007150:Immunohistochemistry; D007425:Intracellular Membranes / Q000378:metabolism; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D008911:Minocycline / Q000494:pharmacology*; D008928:Mitochondria / Q000187:drug effects*; D033681:Mitochondrial Membrane Transport Proteins / Q000378:metabolism; D000083162:Mitochondrial Permeability Transition Pore; D018384:Oxidative Stress / Q000187:drug effects*; D016716:PC12 Cells; D010269:Paraquat / Q000633:toxicity*; D010539:Permeability; D051381:Rats; D017382:Reactive Oxygen Species / Q000378:metabolism
chemical_list: D006540:Herbicides; D033681:Mitochondrial Membrane Transport Proteins; D000083162:Mitochondrial Permeability Transition Pore; D017382:Reactive Oxygen Species; C506443:Casp12 protein, rat; D053454:Caspase 12; D008911:Minocycline; D010269:Paraquat