Granisetron ameliorates doxorubicin-evoked nephrotoxicity via modulation of Nrf2 and TLR4/p38 MAPK/NLRP3 signals in rats

Doxorubicin (DOX) is an anthracycline chemotherapy employed in treating malignancies. Unfortunately, the clinical application of DOX is limited due to its nephrotoxicity. Granisetron (GRAN) is a 5-HT3 receptor blocker used widely to manage post-chemotherapy nausea and vomiting with anti-inflammatory, anti-oxidant, and anti-apoptotic bioactivities. We plan to examine the renoprotective effect of GRAN against DOX-associated renal toxicity. In this investigation, twenty-four adult male Wistar rats were allocated to control, DOX (30 mg/kg, i.p), and GRAN (2.5 mg/kg, p.o) + DOX groups. GRAN attenuated renal impairment induced by DOX in rats by decreasing the BUN, creatinine, KIM-1, and Cys-C levels, and such finding is supported by attenuating histological alterations caused by DOX. GRAN combated oxidative stress proved by decreasing MDA content and elevating GSH and CAT levels mediated by Nrf2 activation. GRAN suppressed inflammation evidenced by decreasing IL-6 and TNF-α levels mediated by downregulation of inflammatory sensitive controllers TLR-4, NLRP3, and p38 MAPK. GRAN prevented apoptosis by controlling renal expression of BAX, caspase-3 and Bcl2. Therefore, GRAN holds promise agent against DOX-induced renal toxicity by upregulating Nrf2 and suppressing apoptosis and inflammatory cascadeTLR4/p38 MAPK/ NLRP3.