Asiatic Acid Ameliorates Doxorubicin-Induced Cardiac and Hepato-Renal Toxicities with Nrf2 Transcriptional Factor Activation in Rats

Abstract

Asiatic acid (AA), a pentacyclic triterpenoid, is a key phytoconstituent of Centella asiatica. AA is a patented as a cytotoxic substance, and it exerts cytotoxicity against Hep3B, Hela and MCF-7 cell lines. However, pentacyclic triterpenoids also modulate the expression and transcriptional activities of Nrf2 and exert cytoprotective effects. In this study, we investigated the effects of AA on the doxorubicin (DXR)-induced organ toxicities and expression of the Nrf2. DXR toxicity was induced by a single intravenous injection of 65.75 mg/kg of DXR. Seven days pretreatment with AA at the doses of 5, 10 and 20 mg/kg, p.o. significantly reverted the DXR-induced oxidative stress in heart, liver and kidney. The biochemical indicators of DXR toxicity including increased activities of serum creatinine kinase isoenzyme, transaminases and lactate dehydrogenase along with increased serum creatinine and serum blood urea nitrogen were normalised by AA. AA was also protected against the DXR-induced histological alterations including necrosis, hyaline degeneration and congestion in the heart; leukocytic inflammation, centrilobular necrosis, apoptosis and fatty changes in the liver; and necrosis and inflammation in the kidney. The protective effects of AA were dose dependent, and the 20 mg/kg dose exerted protection against the DXR toxicity by increasing Nrf2 protein expression.

Keywords: Asiatic acid; Cytoprotection; Doxorubicin-induced organ toxicity; Injury biomarkers; Nrf2 protein expression; Nrf2 transcriptional factor.