Cilostazol ameliorates Cisplatin-induced nephrotoxicity via modulation of PI3K/AKT/mTOR signaling pathway and autophagy in rats.

This study aimed to evaluate the nephroprotective effect of Cilostazol on Cisplatin-induced nephrotoxicity. Female Wistar albino rats were divided into four groups: normal, Cis (8 mg/kg), and two Cilostazol treatment groups (30 and 60 mg/kg) with cisplatin. Cisplatin application significantly deteriorated renal function- manifested by increased serum creatinine (261%) and BUN (134%)-and enhanced oxidative stress-characterized by increased MDA (234%) and decreased GSH (64%). Cisplatin also affected autophagy markers, which included a 62% decrease in P62 and a doubling of LC3II. The PI3K/AKT/mTOR signaling pathway was significantly downregulated with reductions in PI3K (72%), mTOR (73%), and p-AKT/AKT ratio. NF-κB p65 was also increased by 1.5-fold. Moreover, an observed pronounced increase in the expression of TNF-α, caspase-3, and beclin-1 of the cisplatin-intoxicated rats. At the same time, Cilostazol (30 or 60 mg/kg) significantly reversed these changes, with a dose-dependent nephroprotective effect. At a higher dose (60 mg/kg), most parameters were comparable to the normal group, demonstrating superiority over the 30 mg/kg dose. These findings underpin that cilostazol modulates oxidative stress, inflammation, and autophagy pathways mainly via the PI3K/AKT/mTOR signaling axis to exert its renoprotective effect. Thus, cilostazol provides a promising potential in preventing cisplatin-induced nephrotoxicity. This outcome paves the way for the possible co-administration of cilostazol in the clinical realm to spare the deleterious effects of cisplatin.