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.

Asiatic acid ameliorates CC l₄-induced liver fibrosis in rats: involvement of Nrf2/ARE, NF-κB/IκBα, and JAK1/STAT3 signaling pathways

“… 10 , 32 , 33 In addition, several studies have reported that AA could activate Nrf2 pathways to exhibit antioxidant and anti-inflammatory activities. 34 , 35 In the current study, AA markedly increased the expression level of nuclear Nrf2 as compared to the model group. Furthermore, the expressions of Nrf2-target proteins HO-1, NQO-1, and GCLC were increased in the AA-treated group.…”

Centella Asiatica Improves Memory and Promotes Antioxidative Signaling in 5XFAD Mice

“…These NRF2 targets, and others, are known to be induced by multiple compounds found in CA. Compounds such as the phenolic ferulic acid [89,90] and the triterpene asiatic acid [2,91], induce Nrf2 and its ARE-regulated targets, exhibiting a neuroprotective effect [92][93][94][95]. Caffeoylquinic acids found in CA [28,96,97], are also known to induce Nrf2 and Ho-1 signaling, and positively impact glutathione levels [98,99].…”

Pharmacological Properties, Molecular Mechanisms, and Pharmaceutical Development of Asiatic Acid: A Pentacyclic Triterpenoid of Therapeutic Promise

“…Increased activities of carbonic anhydrase II is associated with cardiac hypertrophy and heart failure. In another study, AA attenuated doxorubicin-induced oxidative stress and inflammation in the heart, liver, and kidney by upregulating Nrf2 protein expression (Kamble and Patil, 2018 ). Recently, AA showed to inhibit pressure overload or angiotensin II induced hypertrophic responses by suppressing collagen accumulation mediated cardiac fibrosis (Ma et al, 2016 ).…”