TNF-α, Erectile Dysfunction, and NADPH Oxidase-Mediated ROS Generation in Corpus Cavernosum in High-Fat Diet/Streptozotocin-Induced Diabetic Rats

Introduction. Patients with diabetes-associated erectile dysfunction (ED) are characterized by an increase in circulating tumor necrosis factor-alpha (TNF-a). However, no study has indicated whether and how TNF-a plays a role in the pathogenesis of ED associated with diabetes. Aim. We examined the effects and potential mechanism of infliximab (INF), a chimeric monoclonal antibody to TNF-a, on reactive oxygen species (ROS) generation in corpus cavernosum and ED in diabetic rats. Methods. Four groups of male rats were used: age-matched normal controls; diabetic rats induced by a high-fat diet (HFD) combined with a single streptozotocin (STZ) injection (35 mg/kg body weight, intraperitoneal [i.p.]); nondiabetic rats receiving INF (5 mg/kg body weight/week, i.p.), and diabetic rats receiving INF. Erectile function was assessed with electrical stimulation of the cavernous nerve after 8 weeks. The blood and penile tissues were harvested for plasma biochemical determinations, serum TNF-a measurement, penile ROS detection, and molecular assays of nicotinamide adenine dinucleotide phosphate (NADPH) oxidase subunits, endothelial nitric oxide synthase (eNOS), phospho-eNOS, and neural nitric oxide synthase (nNOS) in the penis. Main Outcome Measures. The effect of INF on HFD/STZ-induced diabetic ED and NADPH oxidase-mediated ROS generation was studied in diabetic corpus cavernosum. Results. Untreated diabetic rats displayed significantly decreased erectile parameters, and increased plasma TNF-a levels, penile ROS production, p47phox and gp91phox expression compared with nondiabetic controls. INF neutralized TNF-a and significantly reduced ED in diabetic rats, in which marked decreases in p47phox and gp91phox expression and ROS generation in corpus cavernosum were noted. The ratio of phospho-eNOS to eNOS and expression of nNOS in the penis were significantly increased in INF-treated vs. untreated diabetic rats. Conclusions. Increased TNF-a expression associated with diabetes contributes to ED by promoting NAPDH oxidase-mediated ROS generation in corpus cavernosum. INF protects against diabetic ED by neutralizing TNF-a. Long T, Liu G, Wang Y, Chen Y, Zhang Y, and Qin D. TNF-a, erectile dysfunction, and NADPH oxidase-mediated ROS generation in corpus cavernosum in high-fat diet/streptozotocin-induced diabetic rats. J Sex Med 2012;9:18181831.