Omaveloxolone ameliorates erectile dysfunction in a rat model of bilateral cavernous nerve injury and is associated with activation of the NRF2 pathway

Erectile dysfunction (ED) following bilateral cavernous nerve injury (BCNI) remains a significant clinical challenge with limited effective treatments. Omaveloxolone (OMAV), a nuclear factor erythroid 2-related factor 2 (NRF2) activator recently approved for Friedreich's ataxia, has potent antioxidant and anti-inflammatory properties. To investigate the therapeutic effects of OMAV on BCNI-induced ED and elucidate the underlying mechanisms. Forty-two adult male Sprague–Dawley rats were divided into sham, BCNI+normal saline (NS), and BCNI+OMAV (5, 10, 20, or 50 mg/kg) groups. After 4 weeks of treatment, erectile function was assessed by measuring intracavernous pressure (ICP)/mean arterial pressure (MAP) ratios. Cavernous tissue was analyzed by electron microscopy, western blot, immunofluorescence, and Masson's trichrome staining. OMAV treatment (20 mg/kg) significantly improved the ICP/MAP ratio compared to the BCNI+NS group (51.2±2.7% vs. 25.3±2.1%, P<0.001). OMAV enhanced NRF2 signaling, as evidenced by increased NRF2 phosphorylation, nuclear translocation, and NAD(P)H oxidoreductase 1 (NQO1) expression. Additionally, OMAV reduced apoptosis by decreasing the BAX/BCL2 ratio and cleaved caspase−3 levels, preserved endothelial function (eNOS and vWF), protected nitrergic neurons (nNOS) and Schwann cells (S100β), and maintained smooth muscle content (αSMA). Furthermore, OMAV significantly reduced malondialdehyde (MDA) levels while restoring superoxide dismutase (SOD) activity and glutathione (GSH) levels in cavernous tissue, indicating attenuation of oxidative stress. OMAV improves erectile function in a rat model of BCNI-induced ED. These protective effects are closely associated with NRF2 activation, offering a potential exploratory therapeutic approach for neurogenic ED.