Protective Effects of Metformin and Memantine Against Arsenic-Induced Neurotoxicity: Insights from In-Silico and In-Vivo Studies.

Arsenic (As) is an environmental neurotoxicant that induces oxidative stress and cognitive impairment. There are limited therapeutic options to treat As-induced neurotoxicity. This study investigated the potential for repurposing metformin (Met) and memantine (Mem) use alone, and in combination to mitigate As-induced neurotoxicity in male Wistar rats. Fifty rats were randomly divided into five groups of ten each: Group I (control) received normal feed and water, group II- Sodium arsenite (20 mg/kg), group III- Sodium arsenite (20 mg/kg) + Met (75 mg/kg), group IV- Sodium arsenite (20 mg/kg) + Mem (10 mg/kg), and group V- Sodium arsenite (20 mg/kg) + Met (75 mg/kg) + Mem 10 mg/kg), all administered p.o. for 28 days. At the end of drugs treatment, several behavioral, biochemical, and histological evaluations were performed. Results showed that all drug-treated groups demonstrated enhanced spatial and recognition memory as evidenced by increased spontaneous alternation in the Y-maze task and decreased escape latencies in the Morris Water Maze test. In both behaviors, the combination group showed the best results, followed closely by the Mem alone group. All treatment groups, especially the combination, showed the best results by restoring the activity of glutathione peroxidase, catalase, and superoxide dismutase in the cortex and hippocampus. Histological examination to study cellular preservation demonstrated that Mem alone treated group showed better results. Network pharmacology identified 66 intersecting targets; molecular docking indicated that Mem and Met had the strongest affinity for MMP9 and BDNF, respectively. All hub genes showed better binding affinities with Mem as compared to Met. In conclusion, our study demonstrated that Met and Mem improved learning and memory, reduced oxidative stress, and restored cellular density. Further validation to repurpose Met and Mem for their use against As-induced neurotoxicity can be done so that they can be used in human beings in the future.