The present study evaluated the efficacy of alpha-lipoic acid, melatonin, and their co-administration in preventing liver injury caused by an acetaminophen overdose in a rat model. Methods: Forty-two rats were allocated into six groups: normal control (0.75% carboxymethyl cellulose, CMC), negative control (acetaminophen 3 g/kg), positive control (N-acetylcysteine 100 mg/kg), alpha-lipoic acid (100 mg/kg), melatonin (10 mg/kg), and a combination of alpha-lipoic acid and melatonin (100 mg/kg + 10 mg/kg, respectively). Treatments were administered once daily for 14 days before a single oral hepatotoxic dose of acetaminophen (3 g/kg). Liver biochemical parameters (alanine aminotransferase, aspartate aminotransferase, alkaline phosphatase, total bilirubin, and total protein), oxidative stress indicators (hepatic and serum reduced glutathione, GSH), inflammatory cytokines (interleukin-6 and interleukin-10), and liver histopathology were assessed 48 hours post-toxication. Results: Acetaminophen overdose caused elevated serum levels of ALT, AST, ALP, and total bilirubin; decreased total protein and GSH; increased IL-6 and IL-10; and marked histopathological alterations. Alpha-lipoic acid reversed these changes. Melatonin improved most parameters, particularly hepatic GSH levels, but had limited effects on ALP and total protein. The combination therapy produced the most complete histological preservation. Conclusions: Alpha-lipoic acid provides comprehensive hepatoprotective activity against acetaminophen-induced toxicity, both alone and in combination with melatonin. While melatonin contributed localized antioxidant benefits, particularly in hepatic tissue, the combination therapy offered the most pronounced structural protection, supporting the therapeutic potential of dual antioxidant strategies.

The present study evaluated the efficacy of alpha-lipoic acid, melatonin, and their co-administration in preventing liver injury caused by an acetaminophen overdose in a rat model. Methods: Forty-two rats were allocated into six groups: normal control (0.75% carboxymethyl cellulose, CMC), negative control (acetaminophen 3 g/kg), positive control (N-acetylcysteine 100 mg/kg), alpha-lipoic acid (100 mg/kg), melatonin (10 mg/kg), and a combination of alpha-lipoic acid and melatonin (100 mg/kg + 10 mg/kg, respectively). Treatments were administered once daily for 14 days before a single oral hepatotoxic dose of acetaminophen (3 g/kg). Liver biochemical parameters (alanine aminotransferase, aspartate aminotransferase, alkaline phosphatase, total bilirubin, and total protein), oxidative stress indicators (hepatic and serum reduced glutathione, GSH), inflammatory cytokines (interleukin-6 and interleukin-10), and liver histopathology were assessed 48 hours post-toxication. Results: Acetaminophen overdose caused elevated serum levels of ALT, AST, ALP, and total bilirubin; decreased total protein and GSH; increased IL-6 and IL-10; and marked histopathological alterations. Alpha-lipoic acid reversed these changes. Melatonin improved most parameters, particularly hepatic GSH levels, but had limited effects on ALP and total protein. The combination therapy produced the most complete histological preservation. Conclusions: Alpha-lipoic acid provides comprehensive hepatoprotective activity against acetaminophen-induced toxicity, both alone and in combination with melatonin. While melatonin contributed localized antioxidant benefits, particularly in hepatic tissue, the combination therapy offered the most pronounced structural protection, supporting the therapeutic potential of dual antioxidant strategies.