Methylmercury-induced alterations in astrocyte functions are attenuated by ebselen

Abstract

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 μM ebselen for 2 hours followed by MeHg (0, 1, 5, and 10 μM) treatments. MeHg-induced changes in astrocytic [ 3 H]-glutamine uptake were assessed along with changes in mitochondrial membrane potential (ΔΨ m ), using the potentiometric dye tetramethylrhodamine ethyl ester (TMRE). Western blot analysis was used to detect MeHginduced 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 μM) 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 μM) (p<0.05); 5 min (1, 5 and 10 μM) (p<0.05)]. MeHg treatment (1 hour) significantly (p<0.05) dissipated the ΔΨ m in astrocytes as evidenced by a decrease in mitochondrial TMRE fluorescence. Ebselen fully reversed the effect of 1 μM MeHg treatment for 1 hour on astrocytic ΔΨ m and partially reversed the effect of 5 and 10 μM MeHg treatments for 1 hour on ΔΨ m . In addition, ebselen inhibited MeHg-induced phosphorylation of ERK (p<0.05) and blocked MeHg-induced activation of caspase-3 (p<0.05 to 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.

A brain proteome profile in rats exposed to methylmercury or thimerosal (ethylmercury)

“…Moreover, oxidative stress also plays an important role in degenerative conditions such as metalinduced toxicity. It is well known that ROS mediate MeHg-induced neurotoxicity in several experimental models, and mitochondrial changes may initiate a cascade of events culminating in cell death (apoptosis or necrosis) Bernardi et al, 1998;Kroemer and Reed, 2000;Yin et al, 2011). At present, several investigators reported that apoptosis occurs as result of organic Hg-mediated toxicity (dos Santos et al, 2016;Sokolowski et al, 2011;Ceccatelli et al, 2010), but the molecular mechanisms are not fully elucidated.…”

Biological responses related to agonistic, antagonistic and synergistic interactions of chemical species

“…After that, other experiments confirmed this finding in tuna fish [60] and other animals. Thus, in general, the simultaneous administration of selenite counteracts the negative impacts of exposure to inorganic mercury, particularly in relation to neurotoxicity, fetotoxicity [61][62][63][64][65] and cardiovascular diseases [66]. However, some authors have suggested that further studies of the potential interplay of these elements in cardiovascular diseases are warranted, especially in relation to fish consumption [67].…”

Methylmercury can induce Parkinson’s-like neurotoxicity similar to 1-methyl-4- phenylpyridinium: a genomic and proteomic analysis on MN9D dopaminergic neuron cells

“…This further confirmed our observation that energy deficit occurred in MN9D cells treated with the two toxicants. MeHg has been shown to inhibit OXPHOS and increase cellular reactive oxygen species (ROS) (Mazzio and Soliman, 2012), and treatment with glutathione peroxidase mimetic (ebselen) reverses MeHg-induced neurotoxicity (Yin et al, 2011). In addition to the disruption of the OXPHOS pathway, we also showed that MeHg changed 5 proteins (GSR, G6PDX, IDH1, GCLM and HNRPLL) involved in glutathione metabolism.…”