Neuroprotective action of 4-Hydroxyisophthalic acid against paraquat-induced motor impairment involves amelioration of mitochondrial damage and neurodegeneration in Drosophila

•Paraquat causes movement disorder due to neurodegeneration in the brain of Drosophila.•Oxidative stress-mediated mitochondrial damage is implicated in neurodegeneration.•Natural antioxidants are promising neuroprotective agents.•4-Hydroxyisophthalic acid, from Decalepis hamiltonii, protects against paraquat-induced neurodegeneration. Neurodegenerative disorders including Parkinson’s disease (PD) are believed to be caused by oxidative stress and mitochondrial dysfunction. Exposure to environmental agents such as pesticides has been implicated in the etiology of sporadic PD. Paraquat (PQ), a widely used herbicide, induces PD symptoms in laboratory animals including Drosophila. PQ acts as a free radical generator and induces oxidative damage, which is implicated in neuronal cell death. Drosophila model of PQ-induced PD offers a convenient tool for mechanistic studies and, to assess the neuroprotective potential of natural antioxidants. We have investigated the neuroprotective potential of 4-Hydroxyisophthalic acid (DHA-I), a novel bioactive molecule from the roots of Decalepis hamiltonii, against PQ-induced locomotor impairment and neurodegeneration in Drosophila melanogaster. Our study shows that PQ treatment results in movement disorder associated with oxidative stress-mediated mitochondrial damage and neurodegeneration in the brain as evident by ultrastructural observations. Treatment with DHA-I markedly attenuated locomotor deficits, oxidative stress, mitochondrial damage, and neurodegenerative changes induced by PQ in Drosophila. Our results show that DHA-I could be a promising natural antioxidant and a neuroprotective molecule targeting oxidative stress-mediated mitochondrial dysfunction with therapeutic potential for neurodegenerative disorders.