Protective Effects of Metformin in Non-Diabetic Rats With Experimentally Induced Lower Extremity Ischemia-Reperfusion Injury

Abstract

Aim: Lower extremity ischemia-reperfusion (IR) injury can lead to substantial skeletal muscle damage and systemic complications, primarily driven by oxidative stress and inflammation. In addition to its well-known glucose-lowering effects, metformin possesses antioxidant and anti-inflammatory properties that may confer protection against tissue damage caused by IR. This study aims to evaluate the potential protective effects of metformin on skeletal muscle injury using a rat model of lower extremity IR. Material and Methods: A total of twenty-four male Wistar albino rats were randomly divided into four experimental groups: Control (C), Ischemia-Reperfusion (IR), IR with metformin at 4 mg/kg (IR+M4), and IR with metformin at 8 mg/kg (IR+M8). Ischemia was induced by clamping the infrarenal aorta for 45 minutes, followed by a reperfusion period of 120 minutes. In the treatment groups, metformin was administered intraperitoneally at the onset of ischemia. Gastrocnemius muscle tissues were harvested for subsequent histopathological and biochemical evaluations, including measurements of Total Antioxidant Status (TAS), Total Oxidant Status (TOS), and Oxidative Stress Index (OSI). Results: Histopathological analysis demonstrated a significant reduction in muscle atrophy, degeneration, leukocyte infiltration, and fiber fragmentation in the IR+M8 group compared to the IR group. Biochemical assessments showed that TAS levels were considerably elevated, whereas TOS and OSI levels were markedly reduced in the metformin-treated groups, with the most prominent effects observed at the higher dosage of 8 mg/kg. Conclusion: The findings indicate that metformin exerts a dose-dependent protective effect against skeletal muscle injury resulting from lower extremity ischemia-reperfusion in rats. These protective properties are likely due to metformin’s antioxidant and anti-inflammatory mechanisms, highlighting its potential therapeutic value in mitigating IR-induced tissue damage. © 2025, Turkish National Vascular and Endovascular Surgery Society. All rights reserved.