Abstract
We evaluated the potential neuroprotective effect of 1-100 µM of four organoselenium compounds: diphenyl diselenide, 3'3-ditri-fluoromethyldiphenyl diselenide, p-methoxy-diphenyl diselenide, and p-chloro-diphenyl diselenide, against methylmercury-induced mitochondrial dysfunction and oxidative stress in mitochondrial-enriched fractions from adult Swiss mouse brain. Methylmercury (10-100 µM) significantly decreased mitochondrial activity, assessed by MTT reduction assay, in a dose-dependent manner, which occurred in parallel with increased glutathione oxidation, hydroperoxide formation (xylenol orange assay) and lipid peroxidation end-products (thiobarbituric acid reactive substances, TBARS). The co-incubation with diphenyl diselenide (100 µM) completely prevented the disruption of mitochondrial activity as well as the increase in TBARS levels caused by methylmercury. The compound 3'3-ditrifluoromethyldiphenyl diselenide provided a partial but significant protection against methylmercury-induced mitochondrial dysfunction (45.4 ± 5.8% inhibition of the methylmercury effect). Diphenyl diselenide showed a higher thiol peroxidase activity compared to the other three compounds. Catalase blocked methylmercury-induced TBARS, pointing to hydrogen peroxide as a vector during methylmercury toxicity in this model. This result also suggests that thiol peroxidase activity of organoselenium compounds accounts for their protective actions against methylmercury-induced oxidative stress. Our results show that diphenyl diselenide and potentially other organoselenium compounds may represent important molecules in the search for an improved therapy against the deleterious effects of methylmercury as well as other mercury compounds.
Highlights
Reactive oxygen/nitrogen species (ROS/RNS) such as superoxide anion, hydrogen peroxide and nitric oxide induce damage to key biological components and cell membranes
We used isolated brain mitochondria as a model to investigate MeHg toxicity, since this organelle represents a major target for MeHg in cells and plays a pivotal role in the initiation of biochemical cascades that lead to cell death [30,31]
The acute treatment of mitochondrial-enriched fractions from mouse brain with MeHg caused a decrease in mitochondrial activity, in agreement with previously reported results for kidney, brain and striatal mitochondrial fractions [17,24,34]
Summary
Reactive oxygen/nitrogen species (ROS/RNS) such as superoxide anion, hydrogen peroxide and nitric oxide induce damage to key biological components and cell membranes. Seleno-organic compounds such as ebselen and diphenyl diselenide (DD) [3,4] have a catalytic activity similar to that of the enzyme glutathione peroxidase involving the reduction of peroxides at the expense of thiol compounds [2,5] and represent important molecules whose protective and antioxidant properties against experimental oxidative stress conditions have been reported [6,7,8] These studies stimulated the search for new organoselenium compounds with catalytic properties similar to those of ebselen and DD, which could provide antioxidant and protective effects in biological systems.
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