Dimethyl Fumarate Improves Diabetic Erectile Dysfunction in Rats via Nrf2-Mediated Suppression of Penile Endothelial Oxidative Stress.

Abstract

Diabetic erectile dysfunction (DMED) is a prevelant urological complication in diabetic men. Increased oxidative stress accompanied with diminished Nrf2 antioxidant pathway has been shown to impair NO/cGMP signaling and distrupt the penile vascular endothelial function in DMED. The present study aimed to investigate the therapeutic effect of dimethyl fumarate (DMF), a clinically approved Nrf2 activator used for psoriasis and multiple sclerosis, in a rat model of streptozotocin (STZ)-induced DMED. Male Sprague Dawley rats were injected with a single intraperitoneal dose of STZ (60 mg/kg) to induce DMED. At week 8, both diabetic and nondiabetic rats were treated orally with DMF (25 or 100 mg/kg) or vehicle for 4 weeks. At week 12, erectile function was evaluated by measuring the intracavernosal pressure (ICP) responses to the electrical stimulation of cavernous nerves. Penile tissues were collected for biochemical and molecular analysis. DMED occurred in diabetic rats, evidenced by reduced the maximum ICP/ mean arterial pressure (MAP) and total ICP/MAP ratios. The penile tissues of diabetic rats exhibited increased MDA level along with decreased Nrf2 and HO-1 protein levels, SOD and CAT activities, and reduced phosphorylated eNOS at serine 1177 and phosphorylated VASP at serine 239. Treatment with DMF at 100 mg/kg was effectively reversed these functional reponses and tissue biochemical alterations in DMED rats. This study provides the first evidence that DMF improved DMED by alleviating oxidative stress and endothelial dysfunction via the activation of Nrf2 antioxidant pathway, suggesting a potential clinical repurposing of DMF for DMED.