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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 H2O2 in 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.

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Acknowledgements

The authors thank Jhargram Raj College, West Bengal, India, along with the Department of Zoology and Department of Physiology, University of Kalyani, West Bengal, India, Pin-741235, for providing necessary permission and laboratory infrastructure for carrying out the research work. This research work has been funded by the departmental research grant of the Department of Physiology, University of Kalyani, West Bengal, India.

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Correspondence to Arpan Kumar Maiti.

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Maiti, A.K., Saha, N.C., More, S.S. et al. Neuroprotective Efficacy of Mitochondrial Antioxidant MitoQ in Suppressing Peroxynitrite-Mediated Mitochondrial Dysfunction Inflicted by Lead Toxicity in the Rat Brain. Neurotox Res 31, 358–372 (2017). https://doi.org/10.1007/s12640-016-9692-7

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Keywords

  • Mitochondrial electron transport chain
  • MitoQ
  • Lead
  • Neurotoxicity
  • Peroxynitrite
  • Nitrosative stress