MP38-03: Combination treatment with a JNK inhibitor and hepatocyte growth factor for restoration of erectile function in a rat model of cavernosal nerve injury: Comparison with a JNK inhibitor alone or hepatocyte growth factor alone

Junghoon Lee*, Sangjun Yoo, Min Soo Choo, Hwancheol Son, Hyeon Jeong, Soo Woong Kim, Min Chul Cho, Seoul, Korea, Republic of

Introduction: The structural derangements of the corpus cavernosum are known to be potential causes of intractable impotence or to limit efficacy of PDE5 inhibitors by inducing cavernosal venoocclusive dysfunction, a key pathophysiology of postprostatectomy erectile dysfunction. The aim of this study was to determine if combined administration of a JNK inhibitor and HGF (hepatocyte growth factor) would restore erectile function through both antiapoptotic and regenerative effects in a rat model of erectile dysfunction induced by cavernous nerve crush injury (CNCI), and to compare it with administration of a JNK inhibitor alone or HGF alone.

Methods: We randomized 70 rats into five experimental groups for two weeks from the day of CNCI: a sham surgery group (S), a CNCI (I) group, a group treated with once-daily intraperitoneal administration of 10.0 mg/kg of JNK inhibitor (J), a twice-weekly intracavernosal administration of 4.2 µg HGF group (H), and a combined treatment with 10.0 mg/kg JNK inhibitor and 4.2 µg HGF group (J+H). We investigated erectile responses to electrostimulation, histological staining, caspase-3 activity assay, and immunoblotting at two weeks following surgery.

Results: The three treatment groups showed improvements in the erectile responses (ICP/MAP or AUC/MAP ratio) after stimulation at all voltages as compared to the I group. The erectile responses in the J+H group were greater than those in the J or H group. The erectile responses in the J+H group were not generally different from those in the S-group. Regarding the cavernosal apoptosis, the caspase-3 activity and c-Jun phosphorylation in the J and J+H groups were improved as compared to the I group, whereas the caspase-3 activity in the H group partially improved. Regarding the endothelial status and smooth muscle (SM) content, the protein expression of PECAM-1, eNOS phosphorylation, and a-SM actin content in the J+H group were normalized, although those in the J or H group were partially restored. Phosphorylation of cMet was normalized in the H and J+H groups.

Conclusions: Our data indicates that combination therapy with a JNK inhibitor and HGF can generally normalize erectile function through antiapoptosis and the preservation of cavernosal endothelium or SM in a rat CN injury model. The combined treatment with these two kinds of agents also appears to be superior to the respective agent alone in terms of the therapeutic effects.

Source of Funding: This research was supported by the National Research Foundation of Korea, grant 2018R1D1A1A09083833, and by the JEIL Pharmaceutical Co., LTD, grant 01-2018-33