Metformin mitigates oxidative stress and prevents apoptosis by modulating the Nrf2/HO-1 signaling pathway in a rat model of testicular ischemia/reperfusion.

Objectives: This study aimed to investigate the effect of metformin on testicular ischemia-reperfusion (I/R) injury in rats. Materials and Methods: Eighteen male SD rats were randomly divided into three groups: Sham group, I/R group, and Metformin (Met) group (n=6 per group). The I/R model was established by rotating the left testis 720° clockwise and fixing it for 1 hr, followed by reperfusion for 4 hr. Rats in the Met group were intraperitoneally injected with 300 mg/kg metformin for 30 min before reperfusion. In contrast, the Sham group underwent a similar surgical procedure without testicular rotation. Histopathological examination, biochemical assays (MDA and SOD), TUNEL assay for germ cell apoptosis, and Western blot analysis for Nrf2, HO-1, and Keap1 protein expressions were performed. Results: Compared with the Sham group, the I/R group exhibited severe testicular tissue damage, including seminiferous tubule atrophy, disordered spermatogenic epithelium, increased MDA levels, decreased SOD activity, elevated germ cell apoptosis index, up-regulated Nrf2 and HO-1 expressions, and down-regulated Keap1 expression. In contrast, pretreatment with metformin in the Met group significantly ameliorated these pathological changes, as evidenced by improved testicular histology, reduced MDA concentration, increased SOD activity, decreased apoptosis, and reversal of the expression of Nrf2, HO-1, and Keap1 compared with the I/R group. Conclusion: These results indicate that metformin exerts a protective effect against testicular I/R injury, which may be associated with its anti-oxidant, anti-apoptotic properties, and regulation of the Nrf2/ HO-1pathway.