Mechanisms of Saposhnikovia divaricata in attenuating NaAsO2-induced neural injury via the PI3K/AKT pathway

Saposhnikovia divaricata (S. divaricata) has demonstrated significant efficacy in mitigating arsenic poisoning. However, its protective effects of S. divaricata against NaAsO₂-induced neural injury remain unclear. Based on network pharmacology, through intersection analysis, the common targets of the effective ingredients and targets of S. divaricata were selected from the TCMSP database, and the targets related to neural injury and arsenic toxicity were selected from the GeneCards database. Subsequently, protein-protein interaction (PPI), GO and KEGG enrichment analyses were carried out. We validated the PI3K/AKT pathway in vitro by assessing drug effects by CCK8 assays, flow cytometry, Western blot, and RT-qPCR. The PI3K/AKT pathway was screened by using network pharmacology, and AKT1 was identified as a core target via topological analysis using the degree algorithm among 45 potential targets derived from 72 traditional Chinese medicine targets, 9717 nerve injury targets, and 2224 arsenic toxicity targets. Molecular docking revealed that 9 active components of S. divaricata interacted with AKT1. In vitro experiments revealed that S. divaricata effectively mitigated neural injury by increasing cell viability, antioxidant activity and Bcl2 level while decreasing the apoptosis rate and the levels of Bax, Caspase8, Caspase3 and Cleaved-caspase3 in HT22 cells exposed to NaAsO₂. The ratios of p-PI3K/PI3K and p-AKT/AKT were further increased by S. divaricata as well as Nrf2 expression. Our findings indicated that S. divaricata exerted multicomponent, multitarget and multipathway protection against NaAsO₂-induced neurotoxicity. These effects were related to the antioxidant and antiapoptotic properties of S. divaricata, which might be achieved by activating the PI3K/AKT signaling pathway.