MP38-04: Tumor Necrosis Factor Alpha (TNF- &[alpha]) and Rho-kinase 2 (ROCK2) Inhibitors Improve Erectile Function in a Bilateral Cavernous Nerve Injury Rat Model

James Liu*, Kara Lombardo, Alok Singh, Monali Praharaj, Serkan Karakus, Arthur Burnett, Baltimore, MD, Trinity Bivalacqua, Philadelphia, PA

Introduction: Prior studies suggest Rho-kinase (ROCK) upregulation and pro-inflammatory cytokines such as Tumor Necrosis Factor-a act as causative factors of axonal degeneration, neuropathy, and penile fibrosis following peripheral cavernous nerve (CN) injury. We hypothesize the combination therapy using inhibitors/antagonists of ROCK and TNFa  may prevent end-organ damage and neuroinflammation in the penis.  The current study was designed to investigate selective inhibition of ROCK2 (SAR407899) and TNF- a (Infliximab) in a pre-clinical model of post-radical prostatectomy ED to prevent penile neuroinflammation, fibrosis, and preserve penile hemodynamics. This study investigates the effect of FDA approved TNF- a inhibitor (Infliximab) in combination with ROCK2 selective inhibitor (SAR407899) on erectile function restoration in the bilateral crush nerve injury (BCNI) rat model.

Methods: Sprague Dawley rats were randomized to undergo either sham (8) or BCNI (34). The BCNI rats were further randomly stratified to receive saline (8), Infliximab (5 mg/kg IP weekly) (8), low dose of SAR407899 (1.5 mg/kg IP daily) (5), high dose of SAR407899 (3 mg/kg IP daily) (5), or combination treatment SAR407899 (1.5 mg/kg IP daily) + Infliximab (5 mg/kg IP weekly) (8). 14 days after injury rats underwent cavernous nerve stimulation to determine erectile function. Penes were collected for histology, IHC, and immune infiltrate analysis using flow cytometry.

Results: On histology combination therapy showed improvement of smooth muscle compared to single agent alone. Erectile response studies demonstrated that rodents treated with combination of Infliximab and SAR407899 had significantly improved (p < 0.05) erectile function (ICP/MAP) at all voltages compared to BCNI alone (2V: 0.243 vs 0.051, 4V: 0.321 vs 0.0782, 6V: 0.456 vs 0.091, p <0.05). Peak ICP and total ICP were also significantly (p < 0.05) improved compared to BCNI rats. Combination therapy, however, did not show a significant change compared to each treatment alone. Flow cytometry showed that Infliximab and SAR407899 significantly (p < 0.05) decreased % of CD11b+ CD45 monocytes in the penis.  While combination therapy had no effect.  The percent of CD11b+ RT1D+ CD45 macrophages were increased (p < 0.05) in the penes of rats treated with Infliximab and SAR407899 while combination therapy decreased penile macrophage population.

Conclusions: Our study suggests that treatment with commercially available TNF- a and ROCK2 inhibitors result in mitigation of erectile dysfunction in a BCNI rat model when administered at the time of nerve injury.  Despite histologic findings that suggest synergistic benefit from combination therapy, erectile parameters did not.  Our immune infiltrate data also showed disparate finding with combination treatment compared to single agents alone which may allude to conflicting mechanisms of action

Source of Funding: None