Selenium Ameliorates Modafinil-Induced Male Reproductive Toxicity via Modulation of PI3K/Akt/NF-ҡB Pathway: Experimental Study and Molecular Docking Verification

Modafinil (MOD) is a nootropic nonamphetamine medication of growing therapeutic interest. Despite the drug's rapidly expanding usage, little is known about its toxic effects on male reproduction. The present study aimed to reveal the dose-dependent MOD-induced reproductive toxicity and the potential mitigating effects of selenium (Se) in testis. Adult male rats were administered MOD300 or 600 mg/kg/day alone for 14 days or co-treated with Se either 0.1 or 0.2 mg/kg/day for 21 days. Functional, biochemical (Testosterone, Follicle-stimulating hormone, Luteinizing hormone, Nitric oxide, Malondialdehyde, Superoxide Dismutase, and Total Antioxidant Capacity), molecular, histopathological, and Transmission electron microscopy examinations were studied. Results revealed that MOD doses significantly induced deterioration of erectile function and sperm quality accompanied by a significant alteration in reproductive hormonal levels (Total and Free testosterone, LH, and FSH). MOD doses also evoked a significant increase in MDA, and NO, with a significant decrease in SOD and TAC. Furthermore, upregulation of the PI3K/Akt/NF-ҡB pathway and the increased expression of the inflammatory gene (iNOS) were demonstrated with both MOD doses. Molecular docking highlighted the virtual mechanism of binding of MOD towards the tested proteins. The observed toxicity was further confirmed by the histopathological and ultrastructural changes. The results demonstrated a significant improvement in the parameters when a Se dose of 0.2 mg/kg/day was co-administered. In conclusion, MOD interferes with male reproductive function in a dose-dependent manner, and Se may be a potentially helpful new approach for abating such toxicity.