Neuroprotective efficacy of berberine following developmental exposure to chlorpyrifos in F1 generation of Wistar rats: Apoptosis-autophagy interplay

Chlorpyrifos (CPF), an organophosphate insecticide commonly used in agriculture and household applications, is con-sidered a developmental neurotoxicant. This study aimed to explain the neuroprotective role of Berberine (BBR) against CPF-induced autophagy dysfunction and apoptotic neurodegeneration in the developing hippocampus. F1 gen-eration of Wistar rats was exposed to CPF (3 mg/kg b.wt.) and co-treated with BBR (10 mg/kg b.wt) in two different exposure regimens, gestational (GD9-12 and GD17-21) and lactational (PND1-20). Our results demonstrated that CPF intoxication instigated cognitive and neurobehavioral impairment, oxidant-antioxidant imbalance, and histomorphological alterations in CA1, CA3, and DG regions of the offsprings. Furthermore, mRNA expression of pro-apoptotic genes (caspase3 and Bax) was upregulated, and that of anti-apoptotic BCl2 was downregulated. In addi-tion, exposure to CPF also activated the autophagy inhibitor (mTOR) transcription and subsequently downregulated the expression of autophagy markers beclin1 and LC3-II. In contrast, gestational and lactational co-treatment of BBR significantly upregulated the enzymatic anti-oxidant bar of the hippocampus and attenuated histological alterations. Moreover, BBR co-treatments reduced apoptotic neurodegeneration in the hippocampal region by regulating the ex-pression of apoptotic genes and upregulated the levels of autophagy, confirmed by ultrastructural studies, decreased gene expression and immunostaining of mTOR and increased, and increased expression gene expression and immuno-staining of LC3-II positive cells. Our results confirm that treatment with BBR induces autophagy, which plays a neuro-protective role in CPF-induced developmental neuronal apoptosis in the F1 generation of Wistar rats by regulating the balance between autophagy and apoptosis.