Hepatoprotective effect of Betulin against Cisplatin‐induced toxicity via inhibiting apoptotic and Nek7‐independent NLRP3 inflammasome pathways: An in vivo study

Abstract

Background Despite its wide use, cisplatin induces serious multiorgan toxicity via stimulating vicious inflammatory, oxidative stress and apoptotic cascades. Betulin is a naturally occurring triterpene that has been shown to protect against cisplatin-induced nephrotoxicity, yet its protective effect against cisplatin-induced hepato- and cardiotoxicity has not been studied. Aim of the work Here we investigated the potential protective effect of betulin against cisplatin-induced hepatotoxicity in rats and the potential underlying mechanism of this effect. Methods Induction of cisplatin acute hepatotoxicity was achieved by single intraperitoneal injection of 10 mg/kg in the middle of the experimental model timeframe. Betulin treatment (8 mg/kg) was intraperitoneally injected daily for total period of 10 days. Results Treatment with betulin significantly improved biochemical liver functions as indicated by restoring cisplatin disrupted levels of serum Aspartate transaminase (AST), Alanine transaminase (ALT), albumin and total bilirubin. In addition, betulin significantly improved histopathological structural features of liver tissues and significantly reduced hepatic tissue fibrosis turnover. Betulin hepatoprotective effect was mediated via reducing cisplatin-provoked oxidative stress, inflammation and apoptosis. Specifically, betulin increased hepatic total antioxidant capacity and decreased hepatic malondialdehyde levels compared to cisplatin group. In addition, betulin significantly attenuated cisplatin-induced NOD-like receptor pyrin domain-containing protein 3 (NLRP3) inflammasome pathway activation as evident by downregulating hepatic tissue levels of NLRP3, caspase-1 and interleukin-1β (IL-1β). Interestingly, despite of the cisplatin-induced upregulation of the hepatic NLRP3 interacting protein, mitotic kinase NIMA-related kinase 7 (Nek7), betulin did not induce any significant alteration of its levels in liver tissues. Betulin significantly reduced cisplatin-induced apoptosis induction as indicated by significant reduction of the apoptotic proteins P53 and Bax, significant reduction of caspases-8, -9 and -3 and upregulation of the anti-apoptotic protein Bcl2. Conclusion To the best of our knowledge, this is the first study to address the hepatoprotective effect of betulin against cisplatin-induced liver injury through modulation of inflammatory and apoptotic pathways.