期刊
NEUROTOXICOLOGY
卷 32, 期 3, 页码 291-299出版社
ELSEVIER SCIENCE BV
DOI: 10.1016/j.neuro.2011.01.004
关键词
Ebselen; Methylmercury neurotoxicity; Mitochondrial membrane potential; Oxidative stress
资金
- NIH Public Health Service [ES07331, ES P30 000267]
Methylmercury (MeHg) preferentially accumulates in glia of the central nervous system (CNS), but its toxic mechanisms have yet to be fully recognized. In the present study, we tested the hypothesis that MeHg induces neurotoxicity via oxidative stress mechanisms, and that these effects are attenuated by the antioxidant, ebselen. Rat neonatal primary cortical astrocytes were pretreated with or without 10 mu M ebselen for 2 h followed by MeHg (0, 1, 5, and 10 mu M) treatments. MeHg-induced changes in astrocytic [(3)H]-glutamine uptake were assessed along with changes in mitochondrial membrane potential (Delta Psi(m)), using the potentiometric dye tetramethylrhodamine ethyl ester (TMRE). Western blot analysis was used to detect MeHg-induced ERK (extracellular-signal related kinase) phosphorylation and caspase-3 activation. MeHg treatment significantly decreased (p < 0.05) astrocytic [(3)H]-glutamine uptake at all time points and concentrations. Ebselen fully reversed MeHg's (1 mu M) effect on [(3)H]-glutamine uptake at 1 min. At higher MeHg concentrations, ebselen partially reversed the MeHg-induced astrocytic inhibition of [(3)H]-glutamine uptake [at 1 min (5 and 10 mu M) (p < 0.05); 5 min (1, 5 and 10 mu M) (p < 0.05)]. MeHg treatment (1 h) significantly (p < 0.05) dissipated the Delta Psi(m) in astrocytes as evidenced by a decrease in mitochondrial TMRE fluorescence. Ebselen fully reversed the effect of 1 mu M MeHg treatment for 1 h on astrocytic Delta Psi(m) and partially reversed the effect of 5 and 10 mu M MeHg treatments for 1 h on In addition, ebselen inhibited MeHg-induced phosphorylation of ERK (p < 0.05) and blocked MeHg-induced activation of caspase-3 (p < 0.05-0.01). These results are consistent with the hypothesis that MeHg exerts its toxic effects via oxidative stress and that the phosphorylation of ERK and the dissipation of the astrocytic mitochondrial membrane potential are involved in MeHg toxicity. In addition, the protective effects elicited by ebselen reinforce the idea that organic selenocompounds represent promising strategies to counteract MeHg-induced neurotoxicity. (C) 2011 Elsevier Inc. All rights reserved.
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