Evaluation of the modulatory potential of berberine against chlorpyrifos induced developmental neurotoxicity by exploring mTOR autophagic pathway in F1 generation of rats

Abstract

Chlorpyrifos (CPF), an organophosphate insecticide commonly used in agriculture and household applications, is a developmental neurotoxicant. This study aimed to investigate the neuroprotective potential of berberine (BBR) against CPF-induced autophagy dysfunction and apoptotic neuronal death in the developing hippocampus, cerebellum, and cerebrum of the F1 generation of rats. Administration of CPF (3mg/kg b.wt.) and BBR (10mg/kg b.wt) in two different exposure regimens, gestational (GD9-12 and GD17-21) and lactational (PND1-20), were given to dams. Our results demonstrated that exposure to CPF caused developmental neurotoxicity, including memory impairment, anxiogenic-despair behavior, oxidant-antioxidant imbalance, DNA damage, specific histological and ultrastructural alterations. The expression of pro-apoptotic genes (Caspase3 and Bax) was upregulated, and that of anti-apoptotic BCl-2 was downregulated. In addition, exposure to CPF also activated autophagy inhibitor (mTOR) transcription and subsequently downregulated the expression of autophagy markers Beclin 1 and LC3-II. In contrast, gestational and lactational co-treatment of BBR significantly upregulated the enzymatic anti-oxidant bar of the three brain regions and attenuated histological alterations. Moreover, BBR co-treatments also reduced the expression of pro-apoptotic markers and ameliorated apoptotic neuronal death by regulating the expression of Caspase3, Bax, and BCl-2 in the F1 generation of pups. Apart from regulating oxidative stress and apoptosis, co-treatment of BBR upregulated the levels of autophagy, confirmed by ultrastructural analysis, decreased gene expression and immunostaining of mTOR and increased gene expression and immunostaining of LC3-II cells. Our results confirm that treatment with BBR induces autophagy, which plays a neuroprotective role in CPF-induced developmental neuronal apoptosis in the F1 generation of Wistar rats by regulating the balance between autophagy and apoptosis. newline