Comparative study of quercetin and its two glycoside derivatives quercitrin and rutin against methylmercury (MeHg)-induced ROS production in rat brain slices
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The hypothesis that methylmercury (MeHg) potently induces formation of reactive oxygen species (ROS) in the brain is supported by observations on the neuroprotective effects of various classes of antioxidants. Flavonoids have been reported to possess divalent metal chelating properties, antioxidant activities and to readily permeate the blood–brain barrier. They can also provide neuroprotection in a wide array of cellular and animal models of neurological diseases. Paradoxically, in vivo administration of quercetin displays unexpected synergistic neurotoxic effect with MeHg. Considering this controversy and the limited data on the interaction of MeHg with other flavonoids, the potential protective effect of quercetin and two of its glycoside analogs (i.e., rutin and quercitrin) against MeHg toxicity were evaluated in rat cortical brain slices. MeHg (100 μM) caused lipid peroxidation and ROS generation. Quercitrin (10 μg/mL) and quercetin (10 μg/mL) protected mitochondria from MeHg (5 μM)-induced changes. In contrast, rutin did not afford a significant protective effect against MeHg (100 μM)-induced lipid peroxidation and ROS production in cortical brain slices. MeHg-generated ROS in cortical slices was dependent upon an increase in intracellular Ca2+ levels, because the over-production of MeHg-induced H2O2 in mitochondria occurred with a concomitant increase in Ca2+ transient. Here, we have extended the characterization of mechanisms associated with the neuroprotective effects of quercetin against MeHg-induced toxicity in isolated mitochondria, by performing an array of parallel studies in brain slices. We provide novel data establishing that (1) Ca2+ plays a central role in MeHg toxicity and (2) in brain slices MeHg induces mitochondrial oxidative stress both via direct interaction with mitochondria (as previously reported in in vitro studies) as well as via mitochondria-independent (or indirect) mechanisms.
KeywordsMeHg toxicity Quercetin Quercitrin Rutin ROS Mitochondria
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