Presentation Authors: Junghoon Lee*, Seung-EE Kim, Young Cheol Hwang, Sangjun Yoo, Seoul, Korea, Republic of, Sang Jun Chun, Gwangju, Korea, Republic of, Juhyun Park, Min Chul Cho, Seoul, Korea, Republic of, Jae-Seung Paick, Incheon, Korea, Republic of, Soo Woong Kim, Seoul, Korea, Republic of
Introduction: Cavernosal apoptosis and fibrosis are important pathophysiologies of post-radical prostatectomy erectile dysfunction (ED). Recent studies showed that JNK inhibition alone or LIMK2 inhibition alone improved ED by suppressing cavernosal apoptosis or fibrosis, respectively. Thus, this study aimed to determine if combined administration of LIM-kinase 2 (LIMK2) and Jun-amino terminal kinase (JNK) inhibitors in a rat model of ED induced by cavernosal nerve (CN) injury could restore erectile function by suppressing both apoptosis and fibrosis of corpus cavernosum via rectification of molecular pathways related to the structural alterations.
Methods: Sixty 12-week-old male Sprague-Dawley rats were equally categorized into four groups: (i) Sham surgery (Sham) group, (ii) CN crush injury (CNCI), (iii) CNCI group (CNCI+L+LJ) treated with a combination of 10.0 mg/kg LIMK2 inhibitors and low-dose (1.0 mg/kg) JNK inhibitors, and (iv) CNCI group (CNCI+L+HJ) treated with a combination of 10 mg/kg LIMK2 inhibitors and a high dose (10.0 mg/kg) of JNK inhibitors. Ten days after surgery, erectile response using electrostimulation, histological studies, and Western blot was investigated.
Results: The CNCI group showed a significant reduction of maximal ICP/MAP or AUC/MAP, decreased immunohistochemical staining of Î±-smooth muscle actin (SMA), decreased SM/collagen ratio, increased number of apoptotic cells positive for phospho-cJun, increased number of fibroblasts positive for phospho-LIMK2, increased cJun phosphorylation, increased LIMK2 or Cofilin phosphorylation, decreased Bcl-2/Bax ratio, and increased protein expression of fibronectin, compared to the Sham group. Both the CNCI+L+LJ and CNCI+L+HJ groups showed improvements in erectile responses, the content of cavernosal Î±-SMA, the number of apoptotic cells positive for phospho-cJun, Bcl-2/Bax ratio and cJun phosphorylation in a dose-dependent manner of a JNK inhibitor, together with rectification of SM/collagen ratio, the number of fibroblasts positive for phospho-LIMK2, LIMK2/Cofilin phosphorylation, and protein expression of fibronectin.
Conclusions: This study suggests that combined inhibition of JNK and LIMK2 may improve erectile function by suppression of cavernosal apoptosis and fibrosis via restoration of cJun/Bcl-2/Bax and LIMK2/Cofilin pathways at the acute phase after CN injury. Thus, the combined inhibition may be a potential mechanism-specific targeted therapy for ED induced by CN injury.