Combination of LIM-kinase 2 and Jun Amino-terminal Kinase Inhibitors Improves Erectile Function in a Rat Model of Cavernous Nerve Injury

Abstract

ObjectiveTo determine if combined administration of LIMK2 and JNK inhibitors in a rat model of erectile dysfunction induced by cavernosal nerve (CN) injury could restore erectile function by suppressing both cavernosal apoptosis and fibrosis via rectification of molecular pathways related to the structural alterations. MethodsSixty 12-week-old male Sprague-Dawley rats were categorized into 4 groups: (1) Sham-surgery (Sham) group, (2) CN-crush-injury (CNCI), (3) CNCI group (CNCI+L+1.0J) treated with a combination of 10.0 mg/kg LIMK2-inhibitors and low-dose (1.0 mg/kg) JNK-inhibitors, and (4) CNCI group (CNCI+L+10.0J) treated with a combination of 10.0 mg/kg LIMK2-inhibitors and a high dose (10.0 mg/kg) of JNK-inhibitors. Ten days after surgery, erectile response, histological-studies, and Western-blot was investigated. ResultsThe CNCI group showed a reduced maximal ICP/MAP or AUC/MAP, decreased immunohistochemical-staining of α-SMA, decreased SM/collagen ratio, increased phospho-cJun-positive apoptotic cells, increased phospho-LIMK2-positive fibroblasts, increased cJun-phosphorylation, increased LIMK2/Cofilin-phosphorylation, decreased Bcl-2/Bax ratio, and increased protein-expression of fibronectin, compared to the Sham group. Both the CNCI+L+1.0J and CNCI+L+10.0J groups showed improvements in erectile-responses, content of cavernosal α-SMA, number of phospho-cJun-positive apoptotic cells, Bcl-2/Bax ratio and cJun phosphorylation. Their improvements in the CNCI+L+10.0J group showed a tendency to be greater than those in the CNCI+L+1.0J group. Also, in the 2 treatment groups, rectification of SM/collagen ratio, number of phospho-LIMK2-positive fibroblasts, LIMK2/Cofilin-phosphorylation, and protein-expression of fibronectin was observed. ConclusionThis study suggests that combined inhibition of JNK and LIMK2 may improve erectile function by suppressing cavernosal apoptosis and fibrosis via restoration of cJun/Bcl-2/Bax and LIMK2/Cofilin pathways at 10 days after CN injury.