IGF-1/AKT signaling attenuates arsenic-induced neuronal apoptosis and DNA fragmentation

Chronic arsenic exposure is a major environmental cause of neurotoxicity, linked to oxidative stress and apoptosis. While its toxicity is established, protective strategies are limited. Insulin-like growth factor-1 (IGF-1) is a key neurotrophic factor, but its potential to counteract arsenic-induced neuronal apoptosis and DNA fragmentation remains largely unexplored. The neuroprotective role of IGF-1 against sodium arsenite (NaAsO₂) was investigated in human SH-SY5Y neuroblastoma cells. Differentiated cells were employed to study IGF-1/AKT signaling, while undifferentiated cells were employed for apoptosis assays. Cells were exposed to NaAsO₂ with or without IGF-1 treatment. AKT phosphorylation status at Thr308 and Ser473 was assessed by Western blot. Apoptosis was evaluated via flow cytometric analysis of the sub-G1 population and by immunoblotting for key apoptotic markers, including cleaved caspase-3, cleaved PARP, p53, and Bcl-2. Arsenic exposure significantly suppressed AKT phosphorylation and induced concentration-dependent apoptosis, evidenced by increased p53, cleaved caspase-3, PARP cleavage, and a compensatory increase in Bcl-2. Treatment with IGF-1 significantly attenuated these effects. IGF-1 restored AKT signaling, reduced pro-apoptotic markers (p53, cleaved caspase-3), diminished PARP cleavage, and significantly decreased apoptotic cell death and DNA fragmentation (sub-G1 population). The observed reduction in Bcl-2 following IGF-1 treatment suggests a restoration of apoptotic equilibrium. The findings present novel evidence that IGF-1 confers protection against arsenic-induced neuroapoptosis and DNA fragmentation by reactivating the PI3K/AKT pathway. This reactivation rebalances apoptotic regulators and suppresses p53-mediated apoptosis. The findings highlight IGF-1 signaling as a promising therapeutic target for arsenic-related neuronal damage, warranting further investigation in vivo.