Maiti Arpan Kumar, Saha Nimai Chandra, More Sunil S, Panigrahi Ashish Kumar, Paul Goutam
Environmental Physiology Laboratory, Department of Physiology, University of Kalyani, Kalyani, West Bengal, 741235, India.
Department of Biological Sciences, School of Basic and Applied Sciences, Dayananda Sagar University, Shavige Malleshwara Hills, Kumaraswamy Layout, Bangalore, 560078, India.
Neurotox Res. 2017 Apr;31(3):358-372. doi: 10.1007/s12640-016-9692-7. Epub 2017 Jan 3.
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 O. However, dimethylsulphoxide and catalase failed to provide protection signifying the noninvolvement of OH and HO 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.
铅（Pb）是最具污染性的金属之一，会在脑线粒体中蓄积，破坏线粒体的结构和功能。尽管活性氧介导的氧化应激仍然是铅神经毒性最被认可的机制，但一些报告表明一氧化氮（NO）和活性氮物质参与了铅诱导的神经毒性。但是铅神经毒性对线粒体呼吸酶复合物的影响仍然未知，没有相关报告强调过氧亚硝酸盐（ONOO）在其中的作用。在此，我们通过口服MitoQ（一种已知的具有ONOO清除活性的线粒体特异性抗氧化剂），在体内大鼠模型中研究了这些影响。有趣的是，MitoQ有效减轻了ONOO介导的线粒体复合物II、III和IV的抑制，增加了线粒体ATP的产生，并恢复了线粒体膜电位。MitoQ降低了铅暴露后增强的半胱天冬酶3和9的活性，还抑制了突触体脂质过氧化和蛋白质氧化，同时伴随着亚硝酸盐产生和蛋白质结合的3-硝基酪氨酸的减少。为了确定我们在体内关于线粒体功能障碍的研究结果，我们在体外SHSY5Y细胞系模型中，在不同抗氧化剂和自由基清除剂存在的情况下进行了类似的实验。与巯基乙基胍、N-硝基-L-精氨酸甲酯和超氧化物歧化酶相比，MitoQ提供了更好的保护，这表明与NO和O相比，ONOO起主要作用。然而，二甲基亚砜和过氧化氢酶未能提供保护，这表明OH和HO在此过程中不参与。MitoQ在SHSY5Y细胞中提供更好保护的原因可能是MitoQ靶向线粒体，而巯基乙基胍、N-硝基-L-精氨酸甲酯和超氧化物歧化酶主要靶向细胞质而非线粒体。综上所述，本研究结果清楚地表明了MitoQ对抗铅暴露后ONOO诱导的毒性的潜力，表明其在金属毒性方面的治疗潜力。
