Preclinical mechanistic study of rotundic acid against cyclophosphamide-induced nephrotoxicity in Swiss albino mice through modulation of oxidative stress, inflammation, apoptosis, and fibrosis via NF-κB/Caspase-3/TGF-β1 Pathways.

Abstract

Cyclophosphamide (CP) is a widely used chemotherapeutic agent; however, its clinical utility is limited by severe adverse effects, including nephrotoxicity. Therefore, the present study investigated the nephroprotective potential of rotundic acid (RA) against CP-induced renal toxicity in mice. RA is a natural pentacyclic triterpene reported to possess anticancer, antioxidant, anti-inflammatory, and antidiabetic activity. A molecular docking analysis has demonstrated that RA exhibits a substantial affinity for the pocket domain of TGF-β1, thereby indicating the nephroprotective potential of RA. Animal were randomly assigned to 7 groups. Control; CP 200; RA 10 + CP 200; RA 20 + CP 200; RA 40 + CP 200; NER 400 + CP 200 and RA 40 per se. RA was given orally for 14 days, and CP 200 mg/kg, i.p., once on the 7th day. On the 15th day animals were sacrificed, and kidney were isolated for study. CP 200 group significant nephrotoxicity in term of oxidative stress, inflammation, fibrosis and apoptosis as demonstrated by decreased levels of SOD, GSH, catalase, IL-10 and increased TBARS, nitrite, TNF-α, IL-6, IL-1β, urea, uric acid, creatinine, and BUN. NF-κB, cleaved caspase-3 and TGF-β1 expression was also increased and histopathological tissue architecture change. RA 20, 40 mg/kg effectively normalized these damages and confirmed nephroprotective effect. The findings indicate that RA may effectively mitigate CP-induced nephrotoxicity and could be considered a potential adjuvant to CP in cancer therapy. However, further studies using appropriate cancer models are essential to confirm and validate its therapeutic potential.