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R-α-Lipoic Acid Attenuates Acetaminophen-Induced Acute Liver Injury by Reducing Oxidative Stress, Inflammation, and
1Department of Pharmacology and Toxicology, College of Pharmacy, Umm Al-Qura University, Makkah, Saudi Arabia.
Background:
Acetaminophen (APAP) overdose is a leading cause of acute liver injury and is frequently associated with oxidative stress, mitochondrial dysfunction, inflammation, and hepatocellular toxicity. R-α-lipoic acid (R-ALA) is a natural antioxidant and mitochondrial cofactor that provides protective effects against APAP-induced hepatic damage.
Objective:
To examine the protective effects of R-ALA against acute APAP-induced liver injury in mice.
Methods:
Adult male mice were randomly divided into five groups: control, APAP, R-ALA, repeated R-ALA pretreatment + APAP, and single R-ALA pretreatment + APAP. APAP was given orally at 500 mg/kg, while R-ALA was administered orally at 100 mg/kg. R-ALA was administered daily for 10 days, with a single dose given 1 hour before APAP. Twenty-four hours after APAP administration, blood and liver samples were collected. Serum levels of alanine aminotransferase (ALT), aspartate aminotransferase (AST), glutamate dehydrogenase (GLDH), high mobility group box-1 (HMGB1), keratin-18 (K18), caspase-cleaved keratin-18 (ccK18), interleukin-6 (IL-6), and tumor necrosis factor-α (TNF-α) were measured. Liver malondialdehyde (MDA), glutathione (GSH), superoxide dismutase (SOD), catalase (CAT), and glutathione peroxidase 3 (GPx3) were also assessed.
Results:
APAP administration increased serum markers of hepatocellular injury, mitochondrial injury, hepatocyte death, and inflammation, including ALT, AST, GLDH, HMGB1, K18, ccK18, IL-6, and TNF-α. APAP also increased hepatic MDA and decreased hepatic GSH, SOD, CAT, and GPx3. R-ALA pretreatment significantly attenuated these APAP-induced changes. APAP increased ALT from 7.49 to 29.46 and AST from 11.10 to 32.49, while R-ALA pretreatment significantly reduced both markers compared with the APAP group.
Conclusion:
R-ALA attenuated APAP-induced liver injury biomarker changes in mice, through antioxidant defenses and reduction of oxidative stress, inflammatory responses, mitochondrial injury markers, and hepatocyte death markers. These protective effects are mediated by antioxidant, anti-inflammatory, and mitochondrial-protective mechanisms. Further histological and pathway-focused molecular studies are needed to confirm the underlying mechanisms and translational relevance.
