Donepezil and quercetin alleviate valproate-induced testicular oxidative stress, inflammation and apoptosis: Imperative roles of AMPK/SIRT1/ PGC-1α and p38-MAPK/NF-κB/ IL-1β signaling cascades.

The mounting evidence of valproate-induced testicular damage in clinical settings is alarming, especially for men taking valproate (VPA) for long-term or at high doses. Both donepezil (DON) and quercetin (QUE) have promising antioxidant, anti-inflammatory, and anti-apoptotic effects. Therefore, this study aimed to determine whether DON, QUE, and their combination could mitigate VPA-induced testicular toxicity and unravel the mechanisms underlying their protective effect. In this study, male albino rats were randomly categorized into six equal groups: control, VPA (500 mg/kg, I.P., for 14 days), DON (3 and 5 mg/kg), QUE (50 mg/kg), and DON 3 + QUE combination groups. The DON and QUE treatments were administered orally for 7 consecutive days before VPA administration and then concomitantly with VPA for 14 days. VPA administration disrupted testicular function by altering testicular architecture, ultrastructure, reducing sperm count, viability, and serum testosterone levels. Additionally, VPA triggered oxidative damage, inflammatory, and apoptotic processes and suppressed the AMPK/SIRT1/PGC-1α signaling cascade. Pretreatment with DON, QUE, and their combination significantly alleviated histological and ultrastructure damage caused by VPA and increased the serum testosterone level, sperm count, and viability. They also suppressed the oxidative stress by reducing testicular MDA content and elevating SOD activity. In addition, they reduced the inflammatory response by suppressing IL-1β level, NF-κB, and the p38-MAPK expression as well as inhibiting apoptosis by diminishing caspase-3 and increasing Bcl-2 expression. These novel protective effects were mediated by upregulating AMPK/SIRT1/PGC-1α signaling cascade. In conclusion, these findings suggest that DON, QUE, and their combination possess potent protective effects against VPA-induced testicular toxicity.