Potentiation of paraquat toxicity by inhibition of the antioxidant defenses and protective effect of the natural antioxidant, 4-hydroxyisopthalic acid in Drosophila melanogaster

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Exposure to pesticides such as paraquat (PQ) is known to induce oxidative stress-mediated damage, which is implicated in neurodegenerative diseases. The antioxidant enzymes are part of the endogenous defense mechanisms capable of protecting against oxidative damage, and down-regulation of these enzymes results in elevated oxidative stress. In this study, we have evaluated the protective action of 4-hydroxyisophthalic acid (DHA-I), a novel bioactive molecule from the roots of D. hamiltonii, against PQ toxicity and demonstrated the protective role of endogenous antioxidant enzymes under the condition of oxidative stress using Drosophila model. The activity of the major antioxidant enzymes, superoxide dismutase 1 (SOD1) and catalase, was suppressed either by RNAi-mediated post transcriptional gene silencing or chemical inhibition. With the decreased in vivo activity of either SOD1 or catalase, Drosophila exhibited hypersensitivity to PQ toxicity, demonstrating the essential role of antioxidant enzymes in the mechanism of defense against PQ-induced oxidative stress. Dietary supplementation of DHA-I increased the resistance of Drosophila depleted in either SOD1 or catalase to PQ toxicity. Enhanced survival of flies against PQ toxicity indicates the protective role of DHA-I against oxidative stress-mediated damage under the condition of compromised antioxidant defenses.