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 proregenerative 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 + twiceweekly 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.

Caveolin-1 scaffolding domain-derived peptide enhances the antiapoptotic progresses of corpus cavernosum smooth muscle cells after cavernous nerve injury

“…By targeting TGF-β1 signaling as CAV1 does, CSD peptide serves as a signi cant functional replacement for CAV1 and may be involved in the control of multiple pathways [15,16]. While TGF-β1, a signi cant contribution to CNI-ED, can activate Smad, c-Jun N-terminal kinase (JNK), and Rho/ROCK so as to provoke corporal apoptosis [4,[11][12][13][14]. It is uninvestigated if CSD peptide can inhibit the aforementioned signaling pathways to limit CCSMCs apoptosis and oxidative stress.…”

“…In addition, it has been reported that CCSMCs from CNI mices and Spinal Cord Injury (SCI) men has higher levels of Smad2 phosphorylation and apoptosis [6,10]. However, targeting TGF-β1 signaling, including Smaddependent and -independent pathways, seems to be highly e cient in avoiding corporal apoptosis, restoring smooth muscle content, and erectile function (EF) in CNI rats [4,[11][12][13][14].…”