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The selenoprotein glutathione peroxidase is a primary molecular target of methylmercury-induced neurotoxicity: insights on potential therapeutic strategies

AuthorsFarina, Marcelo ; Campos, Francisco ; Vendrell, Iolanda ; Suñol, Cristina
Issue Date2008
AbstractMethylmercury (MeHg) is an environmental neurotoxicant whose molecular mechanisms underlying toxicity remain elusive. Here we investigated potential primary molecular events involved with the neurotoxicity induced by low-dose MeHg exposure in cultured cerebellar granule cells (CGCs), as well as potential protective strategies for such toxicity. We found that MeHg induced a time- and dose-dependent neuronal death. This phenomenon was preceded by a decrease in glutathione peroxidase (GPx) activity, but no changes in glutathione levels, intracellular calcium homeostasis and glutamate uptake were observed prior to cell death. In agreement with the decreased GPx activity, MeHg-induced neurotoxicity was related to an enhanced susceptibility to hydrogen- and tert-butyl-peroxides, as well as to increased lipid peroxidation. The antioxidants ascorbic acid and trolox displayed a transitory protective effect against MeHg-induced cell death. Conversely, probucol, a lipid-lowering agent with antioxidant properties, displayed a complete and long-lasting protection against MeHg-induced neurotoxicity, which was correlated to increased GPx activity and inhibition of MeHg-induced lipid peroxidation. These data indicate that GPx is a primary molecular target involved with MeHg-induced neurotoxicity, pointing to a direct inhibitory effect of MeHg toward this selenoenzyme, which leads to increase sensitivity to peroxides, increased lipid peroxidation and cell death. The data also show that probucol, a lipid-lowering agent currently used in the clinic, induces an enduring protection against MeHg-induced neurotoxicity by increasing GPx activity due to direct activating effects. Taken together, the results presented herein bring out new insights on the mechanisms of MeHg neurotoxicity and potential therapeutic strategies for poisonings to this environmental pollutant.
Appears in Collections:(IIBB) Comunicaciones congresos
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