Ameliorative impact of aprepitant on cisplatin testicular toxicity: Dual regulation of PI3K/AKT pro-survival signaling and Bax/cytochrome c/caspase-3 apoptotic signaling

AIM: Cisplatin is a powerful antineoplastic agent utilized for the management of several cancers. Due to its significant deleterious impact on the testis, manifested as long-term infertility and irreversible azoospermia in 50% of individuals, its clinical application is markedly restricted. Therefore, this study focused on the investigation of aprepitant's potential effectiveness against cisplatin-induced testicular injury due to its previously reported efficacy in modulation of inflammatory, pro-survival, and apoptotic signaling. MAIN METHODS: day-only), aprepitant (10 mg/kg) + cisplatin, and aprepitant (20 mg/kg) + cisplatin, then sacrificed on day 11. Sperm quality and testosterone level were evaluated, along with biochemical, immunohistochemical, and histopathological analysis of the testicular tissue. KEY FINDINGS: Cisplatin administration notably diminished sperm viability, count, morphology, and increased abnormalities, alongside the decline in serum testosterone level. Furthermore, cisplatin upregulated nuclear factor-kappa B p65 (NF-κB p65), while downregulating phosphorylated-phosphatidylinositol-3-kinase (p-PI3K), and phosphorylated protein kinase B (p-AKT) protein expressions in testicular tissue sections. That in turn enhanced the transcription of interleukin-6 (IL-6), interleukin-1β (IL-1β), tumor necrosis factor-α (TNF-α) pro-inflammatory cytokines, aggravated oxidant/antioxidant imbalance, triggered apoptosis via Bax/cytochrome c/caspase-3 intrinsic pathway, while suppressing the antiapoptotic Bcl-2 protein. In contrast, aprepitant treatment guarded against these alterations in a dose-dependent manner. SIGNIFICANCE: Aprepitant exhibits efficient protection against cisplatin-induced testicular toxicity that could be attributed to its inhibitory influence on Bax/cytochrome c/cleaved caspase-3 apoptotic signaling, with simultaneous enhancement of PI3K/AKT pro-survival signaling.