Mitigating testicular dysfunction: Metformin's role in combating valproic acid-induced damage in rats

The male reproductive system is significantly affected by valproic acid (VPA), an anti-epileptic medication recognized for its detrimental effects on testicular function. This study evaluates the protective role of metformin, a hypoglycemic agent, against VPA-induced testicular dysfunction in rats. Male Sprague-Dawley rats were randomly assigned into four groups (6 rats per group): a control group, a metformin group (50 mg/kg/day), a VPA group (500 mg/kg/day), and a co-treatment group receiving both VPA and metformin. The treatments were administered for 42 days. Parameters evaluated included sperm characteristics, hormone levels, oxidative stress markers, inflammatory mediators, and apoptotic indicators. VPA exposure led to a pronounced decline in sperm motility and count, coupled with increased sperm abnormalities and decreased testosterone, follicle stimulating hormone (FSH), and luteinizing hormone (LH) levels. Additionally, VPA induced oxidative stress, evidenced by elevated malondialdehyde (MDA) and diminished reduced glutathione, alongside the suppression of Nrf2, HO-1, and NQO1 expressions. The inflammatory response was marked by heightened expression of IL-1β, TNF-α, and TGF-β proteins. VPA also upregulated Caspase-3 and downregulated PCNA, signalling increased apoptosis. Metformin co-administration effectively counteracted these alterations, restoring oxidative balance, mitigating inflammation, and reducing apoptosis to near-normal levels. Metformin significantly alleviates VPA-induced testicular damage by enhancing antioxidant defences via the Nrf2/HO-1/NQO-1 pathway and suppressing inflammatory and apoptotic cascades (TGF-β/TNF-α/IL-1β and Caspase-3/PCNA).