Resveratrol Ameliorates Brain Functions During Gestation in Mancozeb-Low-Dose-Induced Brain Disorders via Mitigating Inflammation, Lipid Peroxidation, Mitochondrial Dysfunction, DNA Damage, Cell Death, and Histopathological Alterations.

Worldwide, many old and young people suffer from neurodegenerative brain disorders. Continuous exposure to mancozeb (MNZ), a fungicide extensively used worldwide on a wide range of crops, is a serious threat to public health because of inducing neuroinflammation and oxidative stress. Resveratrol (RES) is a natural polyphenol with antioxidant and anti-inflammatory effects. This study evaluated the neuroprotective potential of RES against MNZ low-dose-induced brain damage during gestation and elucidated its underlying mechanisms. Thirty-two pregnant Wistar rats were randomly allocated into four groups (n = 8): control, RES-treated rats (100 mg/kg/day, intraperitoneal injection), MNZ-treated rats (100 mg/kg/day, oral), and RES + MNZ-treated rats (100 mg/kg/day intraperitoneal before 100 mg/kg/day MNZ oral). Treatments were administered daily from gestational day (GD) 1 to GD 20. On GD 20, brain samples were collected for biochemical, DNA integrity, morphometric, histopathological, and immunohistochemical assays. Gestational MNZ exposure induced neuroinflammation, lipid peroxidation, reduced CAT activity, and triggered GFAP accumulation, resulting in astrogliosis in the cerebrum and hippocampus. Furthermore, MNZ disrupted mitochondrial apoptosis regulatory proteins, increased DNA damage in maternal and fetal brain cells, induced cerebral and hippocampal neurodegeneration, and reduced cortical thickness while increasing the hippocampal stratum lucidum thickness. Remarkably, pretreatment with RES protected the maternal and fetal brains, preserving cerebral and hippocampal-dependent brain functions through suppressing lipid peroxidation, inflammation, mitochondrial-mediated apoptosis, DNA damage, and histopathological changes. In conclusion, RES demonstrates a potent prophylactic neuroprotective efficacy during gestation against MNZ-induced neurotoxicity, suggesting its potential value as a preventive dietary agent against environmental toxin-mediated brain disorders.