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

Abstract

Chlorpyrifos (CPF), an organophosphate insecticide commonly used in agriculture and household applications, is considered 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 generation 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 addition, 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 expression 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 immunostaining of LC3-II positive 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.