Department of Urology, Seoul Metropolitan Government Boramae Medical Center, Seoul National University College of Medicine, Seoul 07061, Korea.
Department of Urology, Seoul National University Hospital, Seoul National University College of Medicine, Seoul 03080, Korea.
J Sex Med. 2023 May 26;20(6):749-755. doi: 10.1093/jsxmed/qdad046.
Structural alterations of the penis, including cavernosal apoptosis and fibrosis, induce venous leakage into the corpus cavernosum or cavernosal veno-occlusive dysfunction, a key pathophysiology associated with erectile dysfunction after radical prostatectomy. We hypothesized that the effect of JNK inhibitors on reducing apoptosis and hepatocyte growth factor (HGF) on inducing tissue regeneration could be another treatment mechanism of erectile dysfunction after radical prostatectomy.
To investigate whether JNK inhibition combined with intracavernosal administration of HGF can completely preserve cavernosal veno-occlusive function (CVOF) in a rat model of erectile dysfunction induced via bilateral cavernosal nerve crush injury (CNCI).
A total of 42 male Sprague-Dawley rats were randomly assigned to sham control (group S), CNCI (group I), and CNCI treated with a combination of JNK inhibitor and HGF (group J + H) for 5 weeks after surgery.
Rats in each group were evaluated via dynamic infusion cavernosometry (DIC), caspase-3 activity assay, Masson trichrome staining, immunohistochemical staining of α-smooth muscle actin, and immunoblotting at 5 weeks after surgery.
Regarding CVOF, group I showed decreased papaverine response, increased maintenance, and drop rates of DIC when compared with group S. Group J + H showed significant improvement in the 3 DIC parameters vs group I. No differences in the 3 DIC parameters were found between group J + H and group S. Regarding the structural integrity of the corpus cavernosum, group I showed increased caspase-3 activity, decreased smooth muscle (SM):collagen ratio, decreased SM content, decreased protein expression of PECAM-1, and decreased phosphorylation of c-Jun and c-Met. Group J + H showed significant attenuation in histologic and molecular derangement as compared with group I. There were no differences in caspase-3 activity, SM content, SM:collagen ratio, PECAM-1 protein expression, c-Jun phosphorylation, and c-Met phosphorylation between groups J + H and S.
Our results suggest that antiapoptotic and regenerative therapy for the corpus cavernosum is a potential mechanism of penile rehabilitation after radical prostatectomy.
This study provides evidence that combination treatment of JNK inhibitor and HGF preserves erectile function by restoring corporal SM and endothelium. However, additional human studies are needed to confirm the clinical effect.
Chronic treatment with JNK inhibitor and HGF may preserve CVOF to levels comparable to sham control by preserving the structural integrity of the corpus cavernosum and so represents a potential therapeutic option for preventing the development of cavernosal veno-occlusive dysfunction.
阴茎结构的改变，包括海绵体细胞凋亡和纤维化，导致静脉漏入海绵体或海绵体静脉闭塞功能障碍，这是与根治性前列腺切除术后勃起功能障碍相关的关键病理生理学。我们假设 JNK 抑制剂减少凋亡和肝细胞生长因子（HGF）诱导组织再生的作用可能是根治性前列腺切除术后勃起功能障碍的另一种治疗机制。
研究 JNK 抑制剂联合海绵体内给予 HGF 是否可以完全保留勃起功能障碍大鼠模型中因双侧海绵体神经挤压损伤（CNCI）导致的海绵体静脉闭塞功能（CVOF）。
将 42 只雄性 Sprague-Dawley 大鼠随机分为假手术对照组（S 组）、CNCI 组（I 组）和 CNCI 联合 JNK 抑制剂和 HGF 治疗组（J+H 组），术后 5 周进行评估。
各组大鼠分别通过动态灌注海绵体测压术（DIC）、半胱天冬酶-3 活性测定、Masson 三色染色、α-平滑肌肌动蛋白免疫组化染色和免疫印迹检测。
在 CVOF 方面，与 S 组相比，I 组罂粟碱反应降低，维持和 DIC 下降率增加。与 I 组相比，J+H 组 3 项 DIC 参数均显著改善。与 S 组相比，J+H 组和 I 组 3 项 DIC 参数无差异。在海绵体结构完整性方面，I 组半胱天冬酶-3 活性增加，平滑肌（SM）：胶原比率降低，SM 含量降低，PECAM-1 蛋白表达降低，c-Jun 和 c-Met 磷酸化降低。与 I 组相比，J+H 组组织学和分子紊乱明显减轻。与 S 组相比，J+H 组半胱天冬酶-3 活性、SM 含量、SM：胶原比率、PECAM-1 蛋白表达、c-Jun 磷酸化和 c-Met 磷酸化无差异。
我们的研究结果表明，海绵体的抗凋亡和再生治疗可能是根治性前列腺切除术后阴茎康复的潜在机制。
本研究提供的证据表明，JNK 抑制剂联合 HGF 治疗可通过维持海绵体平滑肌和内皮来维持 CVOF，达到与假手术对照组相当的水平，这代表了预防海绵体静脉闭塞功能障碍发展的一种潜在治疗选择。
