Dimethyl Fumarate Protects Rats against Testicular Ischemia–Reperfusion Injury

Abstract

Ischemia–reperfusion injury (IRI) after testicular torsion is linked to significant damage in testicular tissue. Dimethyl fumarate (DMF) activates the nuclear factor erythroid 2-related factor 2 (Nrf2) signaling pathway, thereby inducing antioxidant and anti-inflammatory effects. We analyzed the usefulness of DMF in preventing IRI following testicular torsion/detorsion in Sprague-Dawley rats ( $n=32$ ). The animals were classified into control (sham), DMF (200 mg/kg/day), IRI, and IRI+DMF (IRI with 200 mg/kg/day DMF) groups. Testicular IRI was induced by detorsion after 1.5 h of torsion. DMF was administered via oral gavage daily from 1 h before testicular detorsion until day 7, when orchiectomy was performed. The testis-to-body weight ratio was calculated. Histopathological evaluation was performed using the Johnsen and Cosentino scores for seminiferous tubules. Malondialdehyde, superoxide dismutase, and total glutathione levels were determined in testicular tissues. Moreover, Nrf2, heme oxygenase 1 (HO-1), NAD(P)H quinone dehydrogenase 1 (NQO1), nuclear factor kappa B (NF-κB), and inflammatory cytokine (interleukin 1b (IL1b), IL6, and tumor necrosis factor alpha (TNF-α)) levels were determined through quantitative polymerase chain reaction. Nuclear Nrf2 and cytoplasmic HO-1 and NQO1 protein levels were also evaluated. DMF significantly improved the testis-to-body weight ratio and reduced histopathological damage in the testes. Moreover, it significantly improved the concentration of malondialdehyde, superoxide dismutase, and total glutathione. Furthermore, it inhibited NF-κB and inflammatory cytokine mRNA expression compared with the findings obtained in untreated rats with IRI (all $p<0.05$ ). Nrf2, HO-1, and NQO1 expressions (mRNA and protein) were markedly elevated following DMF treatment in rats with IRI (all $p<0.05$ ). DMF administration activated the Nrf2 signaling pathway and induced antioxidant and anti-inflammatory effects, thereby improving IRI-induced testicular damage. Thus, DMF may prevent IRI following testicular torsion.