Abstract
We determined if combined administration of JNK-inhibitors and HGF (hepatocyte-growth-factor) would restore erectile-function through both antiapoptotic and regenerative effects in a rat model of cavernous-nerve-crush-injury (CNCI), and compared the results with administration of JNK-inhibitor alone or HGF alone. We randomized 70 rats into 5 groups: sham-surgery-group (S), CNCI (I) group, a group treated with once-daily intraperitoneal-administration of 10.0-mg/kg of JNK-inhibitors (J), a twice-weekly intracavernosal-administration of 4.2-μg HGF group (H), and a combined-treatment with 10.0-mg/kg JNK-inhibitors 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 postoperatively. The three treatment groups showed improvements in erectile-responses (ICP/MAP and AUC/MAP ratios) compared to Group-I. The erectile-responses in Group-J+H were greater than those in Group-J or Group-H. The erectile-responses in Group-J+H were generally normalized. Caspase-3-activity and cJun-phosphorylation in Group-J and Group-J+H improved compared to Group-I, whereas caspase-3-activity in Group-H partially improved. Protein-expression of PECAM-1, eNOS-phosphorylation, and smooth-muscle content in Group-J+H were normalized, although those in Group-J or Group-H were partially restored. Combination therapy with JNK-inhibitors and HGF can generally normalize erectile-function through anti-apoptosis and preservation of endothelium or SM in rat CNCI model. The combined treatment appears to be superior to the respective agent alone in terms of therapeutic effects.
Highlights
A considerable number of men who undergo radical prostatectomy (RP) due to localized prostate cancer suffers badly from erectile dysfunction following surgery, despite their excellent oncological outcomes [1,2,3]
Our recent study tested whether the combination of anti-apoptotic effects induced by Jun N-terminal kinase (JNK) inhibition and anti-fibrotic effects of LIM-kinase 2 (LIMK2) inhibition could restore erectile function by rectifying the JNK-driven and LIMK2-driven pathways related to apoptosis and fibrosis in a rat cavernous nerves (CNs) crush injury model (CNCI) [14,15]
Our previous studies reported that JNK pathway inhibition, which was known to play a critical role in apoptosis through both nucleus- targeted and mitochondria-targeted signaling, improved erectile function in a CNCI rat model [11,14,15,28]
Summary
A considerable number of men who undergo radical prostatectomy (RP) due to localized prostate cancer suffers badly from erectile dysfunction following surgery, despite their excellent oncological outcomes [1,2,3]. The derangement of penile integrity, including apoptosis of endothelial cells or smooth muscle (SM) cells and progressive fibrosis of the corpus cavernosum, develops in the early period following CN injury [5,6]. These structural derangements of the corpus cavernosum are known to be potential causes of intractable impotence or for poor efficacy of phosphodiesterase type 5 inhibitors (PDE5Is) by inducing cavernosal venoocclusive dysfunction, a key pathophysiology of post-RP ED [2,5]. It would be reasonable to focus on the inhibition of apoptosis rather than fibrosis for the prevention of structural derangements
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