Resveratrol attenuates cyclophosphamide-induced hepatic apoptosis in association with the inhibition of oxidative stress and inflammation in a rat model of acute liver injury.

Abstract

Cyclophosphamide (CP) is an alkylating chemotherapy agent that induces liver toxicity by cross-linking DNA, causing cell apoptosis. While CP is effective in cancer treatment, its side effects on the liver are significant. Recent studies have indicated that antioxidants, such as resveratrol, may reduce these toxic effects. In this study, we aimed to investigate the role of resveratrol in mitigating CP-induced hepatic apoptosis, oxidative stress, and inflammation in rats. Twenty male mature Sprague-Dawley rats were divided into 4 groups of equal size: control group, Resveratrol group which received resveratrol (20 mg/kg) for 15 consecutive days, CP group which received CP as a single dose (150 mg/kg) on day 16, and CP+Resveratrol group which was similar of the resveratrol and CP groups. Tissue samples were obtained for the histological, immunohistochemical, biochemical, and molecular evaluations. Findings showed that treatment with CP significantly decreased the total liver volume, numerical density of hepatocytes, length density of sinusoidals, and concentrations of antioxidative biomarkers (GSH and SOD). However, the CP+Resveratrol group exhibited notably greater values in these parameters compared to the CP group. Additionally, CP treatment resulted in a significant increase in serum levels of AST and ALT, higher numerical density of Kupffer cells, increased densities of apoptotic cells (increased Bax and caspase-3, and decreased Bcl-2 expression levels), elevated levels of MDA, and upregulated inflammatory genes (IL-1β and TNF-α). In contrast, co-treatment with resveratrol significantly reduced these parameters, suggesting its protective effects against CP-induced liver toxicity. We conclude that giving resveratrol can attenuate apoptosis, oxidative stress, inflammation, and histological alterations in the liver induced by CP toxicity.