Asiatic Acid Augments N-Acetylcysteine Hepatoprotection Against Acetaminophen-Induced Liver Injury in C57BL/6 Mice

Background: Acetaminophen (APAP) is one of the most commonly used analgesics and antipyretic drugs, but overdose often results in severe hepatotoxicity. This toxicity is mediated by the reactive metabolite N-acetyl-p-benzoquinone imine (NAPQI), which induces oxidative stress and inflammation. Although N-acetylcysteine (NAC) is used as a standard therapeutic agent for APAP-induced liver injury, its efficacy is limited by a narrow therapeutic window, warranting adjunct therapy. Asiatic acid (AA), a triterpenoid from Centella asiatica , which is one of the most commonly used herb in Ayurvedic and Chinese medicine that has been shown to exhibits potent antioxidative and anti-inflammatory properties. However, its role as an adjunct to NAC in APAP hepatotoxicity remains unclear. Methods: Hepatotoxicity was induced in C57BL/6 mice by intraperitoneal administration of APAP (300 mg/kg body weight, bw). Three hours later, animals received oral treatment with NAC (150 mg/kg bw), AA (30 mg/kg bw), or a combination of both. Serum biomarkers of liver injury (alanine transaminase [ALT], aspartate transaminase [AST], alkaline phosphatase [ALP]), hepatic histopathology, antioxidant defense markers, such as glutathione, superoxide dismutase, catalase, glutathione peroxidase, and glutathione reductase, and lipid peroxidation levels were assessed. Results: APAP administration significantly elevated ALT, AST, and ALP levels, accompanied by histopathological liver damage. Hepatic glutathione and antioxidant enzyme activities were decreased, while lipid peroxidation increased. NAC or AA alone partially mitigated these effects, whereas their co-administration produced a synergistic hepatoprotective effect, restoring antioxidant defenses, reducing oxidative stress, and improving histopathological outcomes. Conclusions: Asiatic acid augments the hepatoprotective efficacy of N-acetylcysteine against APAP-induced oxidative stress and liver injury, supporting its potential use as an adjunct therapeutic agent for acetaminophen overdose.