4.7 Article

Combination Therapy with a JNK Inhibitor and Hepatocyte Growth Factor for Restoration of Erectile Function in a Rat Model of Cavernosal Nerve Injury: Comparison with a JNK Inhibitor Alone or Hepatocyte Growth Factor Alone

期刊

出版社

MDPI
DOI: 10.3390/ijms222312698

关键词

erectile dysfunction; apoptosis; endothelium; prostatectomy; hepatocyte growth factor; Jun amino-terminal kinase

资金

  1. Basic Science Research Program through the National Research Foundation of Korea (NRF) - Ministry of Education [NRF-2018R1D1A1A09083833]
  2. JEIL Pharmaceutical Co., Ltd. [01-2018-33]

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The combined treatment with JNK-inhibitors and HGF can effectively restore erectile function in a rat model of CNCI by anti-apoptosis and preservation of endothelium or smooth muscle, showing superior therapeutic effects compared to using each agent alone.
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-mu g HGF group (H), and a combined-treatment with 10.0-mg/kg JNK-inhibitors and 4.2-mu g 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.

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