Synergistic Protective Effects of Metformin and Curcumin in Experimental Multiorgan Toxicity in Rats: Integrated Toxicological, Pharmacological, and Histopathological Evaluation

Abstract

Background and Objective

Multi-organ toxicity, resulting from exposure to various drugs and chemicals, is a serious condition affecting the liver, kidneys, heart, and other vital organs simultaneously. The main mechanisms of injury include primary pathological mechanisms such as oxidative stress, inflammation, mitochondrial dysfunction, and apoptosis. While several agents have protective effects on organs, accumulating evidence suggests that combination therapies targeting multiple pathological mechanisms are more effective than monotherapy in protecting organs. Metformin is a drug with antioxidant, anti-inflammatory, and cytoprotective effects, independent of its hypoglycemic effect, while curcumin is a natural polyphenol known for its antioxidant, anti-inflammatory, antifibrotic, and anti-apoptotic properties. This study aimed to evaluate the individual and combined protective effects of metformin and curcumin against experimentally induced multi-organ toxicity in rats, using integrated biochemical, toxicological, molecular, and histopathological assessments.

Methods

Seventy adult male Wistar rats were randomly assigned into seven experimental groups. Multiorgan toxicity was induced using a validated experimental toxicant administered for six consecutive weeks. Rats received metformin alone, curcumin alone, or a combination of both following toxicant exposure. Liver function enzymes, renal function parameters, cardiac injury biomarkers, oxidative stress indices, inflammatory cytokines, apoptosis-related proteins, antioxidant signaling molecules, and histopathological alterations of the liver, kidney, heart, and lung tissues were evaluated. Statistical analysis was performed using one-way analysis of variance followed by Tukey's post hoc multiple comparison test.

Results

Toxic effects induced experimental severe damage in hepatic, renal, cardiac and pulmonary tissues along with oxidative damage, oxidative stress, inflammation, mitochondrial dysfunction and activation of apoptotic process. Either metformin or curcumin restored both biochemical and histopathological damages compared to the toxic group. Whereas co-administration of both drugs resulted in more potent effects compared to either drug alone.

They restored the level of liver enzymes, kidney functions, cardiac biomarkers, activities of antioxidant enzymes, inflammatory mediators and levels of apoptotic signal proteins to near normal. The histological findings showed excellent tissue morphology in the tissues studied for treated groups with combined drugs.

Conclusion

Combined metformin and curcumin treatment is more efficient in preventing the experimentally-induced multiorgan toxicity than individual treatment. The synergy in prevention by metformin and curcumin might be associated with the reduction of oxidative stress, inhibition of the inflammatory pathway, activation of the intrinsic antioxidant defense mechanisms, inhibition of apoptosis, and maintenance of the integrity of tissue architecture. Thus, it is plausible that combined therapy by metformin and curcumin might offer benefit to protect against toxic insult-induced multiorgan damage.