Exploring the cardioprotective effects of canagliflozin against cisplatin‐induced cardiotoxicity: Role of iNOS/NF‐κB, Nrf2, and Bax/cytochrome C/Bcl‐2 signals

Abstract

AbstractCardiotoxicity is a severe considerable side effect of cisplatin (CDDP) that requires much medical attention. The current study investigates the cardioprotective effects of canagliflozin (CA) against CDDP‐induced heart toxicity. Rats were allocated to the control group; the CA group was administered CA 10 mg/kg/day orally for 10 days; the CDDP group was injected with 7 mg/kg, intraperitoneal as a single dose on the 5th day, and the CDDP + CA group. Compared to the CDDP‐treated group, CA effectively attenuated CDDP‐induced heart injury as evidenced by a decrease of serum aspartate aminotransferase, alkaline phosphatase, creatine kinase‐MB, and lactate dehydrogenase enzymes and supported by the alleviation of histopathological changes in cardiac tissues. Biochemically, CA attenuated cardiac oxidative injury through upregulation of the nuclear factor‐erythroid 2 related factor 2 (Nrf2) signal. CA suppressed inflammation by decreasing cardiac NO2−, MPO, iNOS, nuclear factor kappa B (NF‐κB), tumor necrosis factor‐alpha, and interleukin 1‐beta levels. Besides, CA significantly upregulated cardiac levels of phosphoinositide 3‐kinase (PI3K), protein kinase B (AKT), and p‐AKT proteins. Moreover, CA remarkably mitigated CDDP‐induced apoptosis via modulation of Bax, cytochrome C, and Bcl‐2 protein levels. Together, the present study revealed that CA could be a good candidate for preventing CDDP‐induced cardiac injury by modulating iNOS/NF‐κB, Nrf2, PI3K/AKT, and Bax/cytochrome C/Bcl‐2 signals.