title: Melatonin Ameliorates Arsenite-Induced Neurotoxicity: Involvement of Autophagy and Mitochondria.
abstract: In the present study, the neuroprotective effect of melatonin on arsenite-induced neurotoxicity was investigated in rat primary cultured cortical neurons. Incubation of melatonin prevented arsenite-induced neuronal cell loss in a concentration-dependent manner. Furthermore, melatonin significantly attenuated arsenite-induced elevation in microtubule-associated protein light chain 3 (LC3)-II levels, a biomarker of autophagy. Our fluorescent staining assay showed that melatonin decreased arsenite-induced elevation of co-localized fluorescent puncta of monodansylcadaverine (a specific marker of autophagic vacuoles) and lysotracker red (a specific marker of lysosomes), indicating that melatonin is capable of inhibiting arsenite-induced autophagy and autolysosome formation. Because 3-methyladenine (an autophagic inhibitor) attenuated the arsenite-reduced α-synuclein levels (a protein essential for the neurite outgrowth and synaptic plasticity), melatonin via inhibiting autophagy attenuated the arsenite-reduced α-synuclein levels. At the same time, melatonin ameliorated the arsenite-induced reduction in growth associated protein 43 (a hallmark protein of neurite outgrowth) and discontinuous neurites of rat primary cultured cortical neurons. In addition, melatonin was found to prevent arsenite-induced decreases in cytochrome c oxidase levels (a biomarker of mitochondrial mass) and elevation in co-localized fluorescent puncta of autolysosomes and cytochrome c oxidase. Moreover, melatonin prevented arsenite-induced reduction in peroxisome proliferator-activated receptor gamma co-activator 1 α, a transcriptional co-activator of mitochondrial biosynthesis. Taken together, melatonin may exert its neuroprotective action via inhibiting arsenite-induced autophagy and enhancing mitochondrial biogenesis and thus restoring α-synuclein levels, neuronal integrity, and mitochondrial mass in rat primary cultured cortical neurons.
authors.affiliation: Institute of Physiology, National Yang-Ming University, Taipei, Taiwan.
authors.forename: Y C
authors.initials: YC
authors.lastname: Teng
authors.forename: Y I
authors.initials: YI
authors.lastname: Tai
authors.forename: H J
authors.initials: HJ
authors.lastname: Huang
authors.forename: A M Y
authors.initials: AM
authors.lastname: Lin
mesh_terms: D000225:Adenine / Q000031:analogs & derivatives / Q000494:pharmacology; D000818:Animals; D000975:Antioxidants / Q000494:pharmacology / Q000627:therapeutic use*; D018053:Arsenites / Q000633:toxicity*; D001343:Autophagy / Q000187:drug effects*; D015415:Biomarkers; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000166:cytology; D004305:Dose-Response Relationship, Drug; D003576:Electron Transport Complex IV / Q000032:analysis; D005260:Female; D008247:Lysosomes / Q000187:drug effects; D008550:Melatonin / Q000494:pharmacology / Q000627:therapeutic use*; D008928:Mitochondria / Q000187:drug effects* / Q000502:physiology; D009419:Nerve Tissue Proteins / Q000378:metabolism; D009474:Neurons / Q000187:drug effects*; D018696:Neuroprotective Agents / Q000494:pharmacology / Q000627:therapeutic use*; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; D011247:Pregnancy; D051381:Rats; D017207:Rats, Sprague-Dawley; D017670:Sodium Compounds / Q000633:toxicity*; D014157:Transcription Factors / Q000378:metabolism; D051844:alpha-Synuclein / Q000378:metabolism
chemical_list: D000975:Antioxidants; D018053:Arsenites; D015415:Biomarkers; D009419:Nerve Tissue Proteins; D018696:Neuroprotective Agents; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; C501429:Ppargc1a protein, rat; D017670:Sodium Compounds; D014157:Transcription Factors; D051844:alpha-Synuclein; C017947:sodium arsenite; C025946:3-methyladenine; D003576:Electron Transport Complex IV; D000225:Adenine; D008550:Melatonin