Neuroprotective effects of zinc oxide nanoparticles of epigallocatechin-3-gallate on rotenone-induced cerebellar neurotoxicity and histological alterations in rats

Abstract

Rotenone, an environmental neurotoxicant, induces neurotoxicity by promoting mitochondrial function impairment, redox inflammation, and neurodegeneration. The study examined the neuroprotective efficacy of zinc oxide nanoparticles of epigallocatechin-3-gallate (ZnONP-EGCG) in cerebellar neurotoxicity mediated by rotenone in rats. A total of fifty-four male adult Wistar rats (180 – 220 g) were randomized to nine groups: Control, RTN (2.5 mg/kg, rotenone); RTN + Sinemet®, and groups treated with ZnONP-EGCG at doses of 10, 20, or 40 mg/kg, administered either alone or alongside rotenone once daily for 14 days. Post-treatment analyses of cerebellar homogenate were performed to assess biomarkers of oxidative stress, inflammation, neurotransmission, and cellular integrity, as well as histopathological examination. Rotenone administration significantly altered cerebellar redox homeostasis as it decreased the endogenous antioxidant enzyme activity (glutathione-S-transferase, glutathione peroxidase, catalase, and superoxide dismutase), with a concomitant increase in lipid peroxidation. It also markedly decreased neurotransmitter (dopamine and γ-aminobutyric acid) levels, intensified inflammatory signaling by elevating inflammatory cytokines (interleukin-6 and tumor necrosis factor-α) levels, and mediators (C-reactive protein, cyclooxygenase-2, and nitric oxide levels, as well as the activity of myeloperoxidase); whereas it increased DNA fragmentation, decreased glucose and total protein levels, and caused histopathological alterations in the cerebellar neuron architecture. Conversely, treatment with ZnONPs-EGCG restored antioxidant enzyme activities, suppressed lipid peroxidation and the inflammatory cascade, preserved dopaminergic and GABAergic neurotransmission, normalized cerebellar metabolic alterations, maintained cellular integrity, and minimized DNA damage and cerebellar histopathological alterations. Overall, these findings support ZnONPs-EGCG as a promising nanotherapeutic strategy for mitigating cerebellar neurotoxicity associated with environmental exposures.