Restoration of erectile function by a combination of antiapoptosis by JNK inhibitor and preservation of smooth muscle or endothelium by hepatocyte growth factor in a rat model of cavernous nerve injury

Abstract Background Because of structural alterations in the corpus cavernosum after radical prostatectomy (RP), post‐RP erectile dysfunction remains a very difficult condition to treat. We aimed to determine if the combined administration of a Jun‐amino terminal kinase (JNK) inhibitor and hepatocyte growth factor (HGF) in the immediate post‐injury period would restore erectile function by antiapoptotic and pro‐regenerative effects through the rectification of molecular pathways related to the structural integrity of the penis in a rat model of bilateral cavernosal nerve crush injury (CNCI). Methods A total of 70 rats were divided into five groups: Sham surgery (S), CNCI (I), and once‐daily intraperitoneal administration of 10.0 mg/kg JNK inhibitor + twice‐weekly intracavernosal administration of low‐dose (2.1 μg), medium‐dose (4.2 μg), or high‐dose (8.4 μg) HGF (I + J + LH or I + J + MH or I + J + HH, respectively) in the immediate post‐injury period. Erectile responses to electrostimulation (1.0, 3.0, and 5.0 V), histological staining, caspase‐3 activity, and Western blotting were evaluated 9 days after surgery. Results Group I showed lower intracavernosal pressure (ICP)/mean arterial pressure (MAP) after stimulation at each voltage, lower area under the curve (AUC)/MAP after stimulation at each voltage, less smooth muscle (SM) content, a lower SM/collagen ratio, higher caspase‐3 activity, increased cJun phosphorylation, decreased protein expression of PECAM‐1, decreased cMet phosphorylation, and decreased endothelial nitric oxide synthase (eNOS) phosphorylation compared to Group S. The SM content, SM/collagen ratio, protein expression of ICP/MAP, or AUC/MAP after stimulation at each voltage in Group I + J + LH were partially restored, despite the normalization of cJun phosphorylation and caspase‐3 activity. The ICP/MAP, AUC/MAP, caspase‐3 activity, SM content, protein expression of PECAM‐1, cJun phosphorylation, cMet phosphorylation, and eNOS phosphorylation in both Groups I + J + MH and I + J + HH were restored to the levels observed in Group S, while the SM/collagen ratio was significantly improved but not completely normalized. Conclusions Our data indicated that the combined administration of a JNK inhibitor and medium or high‐dose HGF to nerve‐injured rats in the immediate post‐injury period after CNCI may restore erectile function to a level comparable to the normal level by suppressing cavernosal apoptosis and preserving the integrity of SM or endothelium via rectification of the cJun and cMet/eNOS pathways.