Inhibition of Jun N-terminal Kinase Improves Erectile Function by Alleviation of Cavernosal Apoptosis in a Rat Model of Cavernous Nerve Injury

Abstract

To determine whether Jun N-terminal kinase (JNK) inhibition could alleviate erectile dysfunction (ED) through suppressing cavernosal apoptosis in a rat model of carvernosal nerve crush injury (CNCI), thereby providing potential therapeutic strategy for alleviating postradical prostatectomy ED. Fifty-six 11-week-old male Sprague-Dawley rats were categorized equally into the following 4 groups: (1) sham surgery (S), (2) CNCI (I), (3) CNCI treated with low-dose JNK inhibitor (L), and (4) CNCI treated with high-dose JNK inhibitor (H). The L and H groups received daily intraperitoneal injection of JNK inhibitors (1.0 mg/kg for the L group and 10.0 mg/kg for the H group) for 2 weeks starting from the following day after surgery. Erectile response, Western blot, and immunohistochemistry were assessed. At 2 weeks after surgery, intracavernous pressure-mean arterial pressure and area under the curve-mean arterial pressure in group I were significantly decreased compared with those in group S. Erectile responses in group H were significantly improved compared with those in group I. Group I showed decreased smooth muscle (SM) content, increased apoptosis, increased apoptotic or SM cells positive for phosphorylated c-Jun, increased c-Jun phosphorylation, and decreased Bcl2-to-Bax ratio compared with group S. Group H showed significant improvements in histologic alterations and dysregulation of the JNK-driven pathway. Our data suggest that JNK inhibition can improve erectile function by alleviating cavernosal apoptosis through restoring the JNK-related pathway toward normal. Thus, an early therapeutic strategy targeting the JNK pathway might be able to alleviate cavernosal SM apoptosis and postradical prostatectomy ED caused by cavernous nerve injury.