title: Neuroprotective Efficacy of Mitochondrial Antioxidant MitoQ in Suppressing Peroxynitrite-Mediated Mitochondrial Dysfunction Inflicted by Lead Toxicity in the Rat Brain.
abstract: Lead (Pb) is one of the most pollutant metals that accumulate in the brain mitochondria disrupting mitochondrial structure and function. Though oxidative stress mediated by reactive oxygen species remains the most accepted mechanism of Pb neurotoxicity, some reports suggest the involvement of nitric oxide (•NO) and reactive nitrogen species in Pb-induced neurotoxicity. But the impact of Pb neurotoxicity on mitochondrial respiratory enzyme complexes remains unknown with no relevant report highlighting the involvement of peroxynitrite (ONOO-) in it. Herein, we investigated these effects in in vivo rat model by oral application of MitoQ, a known mitochondria-specific antioxidant with ONOO-scavenging activity. Interestingly, MitoQ efficiently alleviated ONOO--mediated mitochondrial complexes II, III and IV inhibition, increased mitochondrial ATP production and restored mitochondrial membrane potential. MitoQ lowered enhanced caspases 3 and 9 activities upon Pb exposure and also suppressed synaptosomal lipid peroxidation and protein oxidation accompanied by diminution of nitrite production and protein-bound 3-nitrotyrosine. To ascertain our in vivo findings on mitochondrial dysfunction, we carried out similar experiments in the presence of different antioxidants and free radical scavengers in the in vitro SHSY5Y cell line model. MitoQ provided better protection compared to mercaptoethylguanidine, N-nitro-L-arginine methyl ester and superoxide dismutase suggesting the predominant involvement of ONOO-compared to•NO and O2•-. However, dimethylsulphoxide and catalase failed to provide protection signifying the noninvolvement of•OH and H2O2in the process. The better protection provided by MitoQ in SHSY5Y cells can be attributed to the fact that MitoQ targets mitochondria whereas mercaptoethylguanidine, N-nitro-L-arginine methyl ester and superoxide dismutase are known to target mainly cytoplasm and not mitochondria. Taken together the results from the present study clearly brings out the potential of MitoQ against ONOO--induced toxicity upon Pb exposure indicating its therapeutic potential in metal toxicity.
authors.affiliation: Environmental Physiology Laboratory, Department of Physiology, University of Kalyani, Kalyani, West Bengal, 741235, India. arpankumar.maiti@gmail.com.|Department of Biological Sciences, School of Basic and Applied Sciences, Dayananda Sagar University, Shavige Malleshwara Hills, Kumaraswamy Layout, Bangalore, 560078, India. arpankumar.maiti@gmail.com.
authors.forename: Arpan Kumar
authors.initials: AK
authors.lastname: Maiti
authors.affiliation: Additional Director of Public Instruction, Govt. of West Bengal, Education Directorate, Bikash Bhavan, Salt Lake, Kolkata, 700091, India.
authors.forename: Nimai Chandra
authors.initials: NC
authors.lastname: Saha
authors.affiliation: Department of Biological Sciences, School of Basic and Applied Sciences, Dayananda Sagar University, Shavige Malleshwara Hills, Kumaraswamy Layout, Bangalore, 560078, India.
authors.forename: Sunil S
authors.initials: SS
authors.lastname: More
authors.affiliation: Department of Zoology, University of Kalyani, West Bengal, 741235, India.
authors.forename: Ashish Kumar
authors.initials: AK
authors.lastname: Panigrahi
authors.affiliation: Environmental Physiology Laboratory, Department of Physiology, University of Kalyani, Kalyani, West Bengal, 741235, India.
authors.forename: Goutam
authors.initials: G
authors.lastname: Paul
mesh_terms: D000818:Animals; D000975:Antioxidants / Q000494:pharmacology; D001921:Brain / Q000187:drug effects* / Q000378:metabolism; D016923:Cell Death; D002478:Cells, Cultured; D005260:Female; D006801:Humans; D018836:Inflammation Mediators / Q000378:metabolism; D007854:Lead / Q000633:toxicity*; D015227:Lipid Peroxidation / Q000187:drug effects; D008297:Male; D008928:Mitochondria / Q000187:drug effects* / Q000378:metabolism; D018696:Neuroprotective Agents / Q000494:pharmacology*; D009943:Organophosphorus Compounds / Q000494:pharmacology*; D030421:Peroxynitrous Acid / Q000009:adverse effects*; D051381:Rats; D013574:Synaptosomes / Q000187:drug effects / Q000378:metabolism; D014451:Ubiquinone / Q000031:analogs & derivatives* / Q000494:pharmacology
chemical_list: D000975:Antioxidants; D018836:Inflammation Mediators; D018696:Neuroprotective Agents; D009943:Organophosphorus Compounds; D014451:Ubiquinone; D030421:Peroxynitrous Acid; D007854:Lead; C429014:mitoquinone
keywords: Lead; MitoQ; Mitochondrial electron transport chain; Neurotoxicity; Nitrosative stress; Peroxynitrite