Protective efficacy of mitochondrial targeted antioxidant MitoQ against dichlorvos induced oxidative stress and cell death in rat brain

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• 作者：Willayat Yousuf Wani^a ; Satish Gudup^c ; Aditya Sunkaria^a ; Amanjit Bal^b ; Parvinder Pal Singh^c ; Ramesh J.L. Kandimalla^a ; Deep Raj Sharma^a ; Kiran Dip Gill^a ;   ; ^{kdgill2002@yahoo.co.in}
• 关键词：Organophosphate ; Dichlorvos ; Oxidative stress ; Neurodegeneration ; MitoQ
• 刊名：Neuropharmacology
• 出版年：2011
• 出版时间：December 2011
• 年：2011
• 卷：61
• 期：8
• 页码：1193-1201
• 全文大小：1127 K

文摘

Dichlorvos is a synthetic insecticide that belongs to the family of chemically related organophosphate (OP) pesticides. It can be released into the environment as a major degradation product of other OPs, such as trichlorfon, naled, and metrifonate. Dichlorvos exerts its toxic effects in humans and animals by inhibiting neural acetylcholinesterase. Chronic low-level exposure to dichlorvos has been shown to result in inhibition of the mitochondrial complex I and cytochrome oxidase in rat brain, resulting in generation of reactive oxygen species (ROS). Enhanced ROS production leads to disruption of cellular antioxidant defense systems and release of cytochrome c (cyt c) from mitochondria to cytosol resulting in apoptotic cell death. MitoQ is an antioxidant, selectively targeted to mitochondria and protects it from oxidative damage and has been shown to decrease mitochondrial damage in various animal models of oxidative stress. We hypothesized that if oxidative damage to mitochondria does play a significant role in dichlorvos induced neurodegeneration, then MitoQ should ameliorate neuronal apoptosis. Administration of MitoQ (100?¦Ìmol/kg body wt/day) reduced dichlorvos (6?mg/kg body wt/day) induced oxidative stress (decreased ROS production, increased MnSOD activity and glutathione levels) with decreased lipid peroxidation, protein and DNA oxidation. In addition, MitoQ also suppressed DNA fragmentation, cyt c release and caspase-3 activity in dichlorvos treated rats compared to the control group. Further electron microscopic studies revealed that MitoQ attenuates dichlorvos induced mitochondrial swelling, loss of cristae and chromatin condensation. These results indicate that MitoQ may be beneficial against OP (dichlorvos) induced neurodegeneration.