4.5 Article

Restoration of Cavernous Veno-Occlusive Function through Chronic Administration of a Jun-Amino Terminal Kinase Inhibitor and a LIM-Kinase 2 Inhibitor by Suppressing Cavernous Apoptosis and Fibrosis in a Rat Model of Cavernous Nerve Injury: A Comparison with a Phosphodiesterase Type 5 Inhibitor

期刊

WORLD JOURNAL OF MENS HEALTH
卷 39, 期 3, 页码 541-549

出版社

KOREAN SOC SEXUAL MEDICINE & ANDROLOGY
DOI: 10.5534/wjmh.200085

关键词

Apoptosis; Erectile dysfunction; Fibrosis; Prostatectomy

资金

  1. SNUH Research Fund [04-2017-062-0]
  2. Basic Science Research Program through the National Research Foundation of Korea (NRF) - Ministry of Education [NRF-2015R1D1A1A01060003]

向作者/读者索取更多资源

The study showed that chronic inhibition of JNK and LIMK2 can restore cavernous veno-occlusive function by reducing cavernous apoptosis and fibrosis, similar to the results found with PDE5 inhibitors.
Purpose: To determine if chronic administration of Jun-amino terminal kinase (JNK)-inhibitors and LIM-kinase 2 (LIMK2)-inhibitors from the immediate post-injury period in a rat model of cavernous-nerve-crush-injury could normalize cavernousveno-occlusive-function, and to compare it with phosphodiesterase type 5 (PDE5)-inhibitors. Materials and Methods: A total of 75 12-week-old male Sprague-Dawley-rats were randomized into five groups: sham-surgery (S), cavernous-nerve-crush-injury (I), cavernous-nerve-crush-injury treated with 10.0 mg/kg LIMK2-inhibitor (L) or 10.0 mg/kg JNK-inhibitor and 10.0 mg/kg LIMK2-inhibitor (J+L) or 20.0 mg/kg udenafil (P) for five-weeks. Five-weeks after surgery, dynamic-infusion-cavernosometry, histological-studies, caspase-3-activity-assay, and Western-blot were investigated. Results: Group-I had lower papaverine-response, higher maintenance-rate and higher drop-rate, compared to Group-S. Group-L, Group-J+L and Group-P showed improvement in the three dynamic-infusion-cavernosometry parameters. The papaverine-response and drop-rate in Group-J+L and Group-P recovered to sham-control level, but those in Group-L did not. Regarding apoptosis, Group-I had decreased content of alpha-smooth-muscle-actin, increased caspase-3 activity and increased cJun-phosphorylation. The cJun-phosphorylation improved only in Group-J+L. The alpha-smooth-muscle-actin content and caspase-3-activity in Group-J+L and Group-P improved, but those in Group-L were not. Regarding fibrosis, Group-I had decreased smooth muscle (SM)/collagen-ratio, increased protein-expression of fibronectin, and increased Cofilin-phosphorylation. Cofilin-phosphorylation was normalized in Group-L and Group-J+L, but not in Group-P. SM/collagen-ratio and protein-expression of fibronectin in Group-L, Group-J+L and Group-P improved. Conclusions: Our data indicate that chronic inhibition of JNK and LIMK2 can restore cavernous-veno-occlusive-function by suppressing cavernous-apoptosis and cavernous-fibrosis, comparable to the results by PDE5-inhibitors. Chronic inhibition of JNK and LIMK2 might be a potential mechanism-specific targeted therapy for cavernous-veno-occlusive-dysfunction induced by cavernous nerve-injury.

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