Sannadi Saritha, Kadeyala Praveen Kumar, Gottipolu Rajarami Reddy
Department of Biotechnology, Sri Venkateswara University, Tirupati 517502, A.P., India.
Int J Dev Neurosci. 2013 Nov;31(7):586-97. doi: 10.1016/j.ijdevneu.2013.07.003. Epub 2013 Jul 30.
Oxidative stress (OS) has been implicated in the pathophysiology of many neurodegenerative disorders. Several studies have shown that exposure to arsenic (As) and lead (Pb) produces oxidative stress, one of the most noted molecular mechanisms for the neurotoxicity of these metals. In the present study, we examined the effect of combined exposure to these metals (As and Pb) on the activity levels of antioxidant enzymes and apoptotic marker enzymes in brain regions (cerebral cortex, hippocampus and cerebellum) of rats at postnatal day (PND) 21, 28 and 3 months age and compared the toxicity levels with individual metals (As or Pb). Further, we also evaluated the therapeutic efficacy of a chelating agent, monoisoamyl dimercaptosuccinic acid (MiADMSA) against arsenic and lead induced developmental neurotoxicity. Pregnant rats were exposed to sodium meta-arsenite (50 ppm) and lead acetate (0.2%) individually, and in combination (As=25 ppm+Pb=0.1%) via drinking water throughout perinatal period (GD 6 to PND 21). MiADMSA (50 mg/kg, orally through gavage) was given for three consecutive days to the PND 18 pups (i.e., PND 18 to PND 20). Exposure to metal mixture resulted in a significant decrease in the activity levels of antioxidant enzymes such as manganese-superoxide dismutase (Mn-SOD), Cu/Zn superoxide dismutase (Cu/Zn-SOD), catalase (CAT) and glutathione peroxidase (GPx) while the malondialdehyde (MDA) levels and mRNA expression levels of caspase-3 and caspase-9 were significantly increased in all the three brain regions. The observed alterations were greater with exposure to metal mixture than individual metals (As or Pb) and the changes were more prominent at PND 28 and greater in cerebral cortex than hippocampus and cerebellum. Interestingly, chelation therapy with MiADMSA showed significant recovery in antioxidant enzymes, lipid peroxidation and gene expression levels of caspase-3 and caspase-9. From these findings, it can be concluded that combined exposure to As and Pb showed an additive effect on antioxidant enzymes than individual metal exposure and chelation therapy with MiADMSA significantly reversed the As and Pb induced apoptosis and oxidative stress, a major contributing factor to neurotoxicity.
氧化应激（OS）与许多神经退行性疾病的病理生理学有关。多项研究表明，接触砷（As）和铅（Pb）会产生氧化应激，这是这些金属神经毒性最显著的分子机制之一。在本研究中，我们检测了在出生后第21天、28天和3个月龄时，联合暴露于这些金属（As和Pb）对大鼠脑区（大脑皮层、海马体和小脑）抗氧化酶和凋亡标记酶活性水平的影响，并将毒性水平与单独暴露于金属（As或Pb）的情况进行比较。此外，我们还评估了螯合剂单异戊基二巯基丁二酸（MiADMSA）对砷和铅诱导的发育性神经毒性的治疗效果。在整个围产期（妊娠第6天至出生后第21天），将怀孕大鼠分别、联合暴露于偏亚砷酸钠（50 ppm）和醋酸铅（0.2%），联合暴露为（As = 25 ppm + Pb = 0.1%），通过饮用水给予。在出生后第18天的幼崽（即出生后第18天至出生后第20天）连续三天给予MiADMSA（50 mg/kg，经口灌胃）。暴露于金属混合物导致抗氧化酶如锰超氧化物歧化酶（Mn-SOD）、铜/锌超氧化物歧化酶（Cu/Zn-SOD）、过氧化氢酶（CAT）和谷胱甘肽过氧化物酶（GPx）的活性水平显著降低，而丙二醛（MDA）水平以及半胱天冬酶-3和半胱天冬酶-9的mRNA表达水平在所有三个脑区均显著升高。与单独暴露于金属（As或Pb）相比，暴露于金属混合物时观察到的改变更大，且这些变化在出生后第28天更为明显，在大脑皮层比海马体和小脑更显著。有趣的是，用MiADMSA进行螯合治疗显示抗氧化酶、脂质过氧化以及半胱天冬酶-3和半胱天冬酶-9的基因表达水平有显著恢复。从这些发现可以得出结论，与单独暴露于金属相比，联合暴露于As和Pb对抗氧化酶具有相加作用，并且用MiADMSA进行螯合治疗显著逆转了As和Pb诱导的细胞凋亡和氧化应激，而氧化应激是神经毒性的一个主要促成因素。
