Rectification of cavernosal fibrosis and veno‐occlusive dysfunction by administration of suberoylanilide hydroxamic acid in a rat model of cavernosal nerve injury: Comparison with a PDE5 inhibitor

Abstract

Background Cavernosal fibrosis, which is induced by cavernosal nerve (CN) injury and progresses with time, is the main cause of cavernosal veno‐occlusive dysfunction (CVOD) after radical prostatectomy. Objectives To determine whether daily oral administration of suberoylanilide hydroxamic acid (SAHA; vorinostat) for 5‐weeks from the immediate post‐injury period after CN injury would rectify CVOD by suppressing cavernosal fibrosis and normalizing HDAC pathway in a rat model of CN crush injury (CNCI) and to compare the results with those obtained using chronic administration of PDE5‐inhibitors (a positive control). Methods Fifty‐six 12‐week‐old rats were randomized into the four groups: sham surgery (S), CNCI (I), and CNCI treated with daily administration of 25.0 mg/kg SAHA (V) or 20.0 mg/kg udenafil (P). Group‐V and Group‐P received the respective treatment for 5‐weeks from the following day after CNCI. At 5 weeks after surgery, dynamic infusion cavernosometry (DIC), histological staining, and Western blot analysis were performed. Results Group‐I had a significantly decreased papaverine response, higher maintenance rate or drop rate, lower smooth muscle (SM)/collagen ratio, decreased SM content, and increased protein expression of HDAC2, HDAC3, TGF‐β1, and collagen‐1, compared with Group‐S. The three DIC parameters in Group‐V and Group‐P significantly improved compared to those in Group‐I. Except for the maintenance rate, the improvement in papaverine response and drop rate in Group‐V was not significantly different from that in Group‐P. Group‐V and Group‐P showed the rectification of SM/collagen ratio and protein expression of TGF‐β1 or collagen‐1. SM content was improved in Group‐P, but not in Group‐V. Group‐V showed the normalization of protein expression of both HDAC2 and HDAC3, whereas protein expression of only HDAC2 was partially restored in Group‐P. Discussion Treatment strategies targeting the HDAC pathway might be helpful to alleviate CVOD induced by CN injury. Conclusions According to our data, chronic administration of SAHA improves post‐injury CVOD by suppressing cavernosal fibrosis via rectifying the HDAC/TGF‐β1 pathway in nerve‐injured rats, comparable to that with PDE5 inhibitors.

Sodium butyrate ameliorates erectile dysfunction through fibrosis in a rat model of partial bladder outlet obstruction

“…There are no previous data regarding the effects of an HDAC inhibitor, NaBu on the erectile function in obstructed rats. However, chronic administration of other HDAC inhibitors improved the erectile function by suppressing cavernosal fibrosis in a rat model of cavernosal nerve injury 27,28 . Penile erection is mediated by nitric oxide (NO) produced by eNOS and nNOS 29 .…”

“…However, chronic administration of other HDAC inhibitors improved the erectile function by suppressing cavernosal fibrosis in a rat model of cavernosal nerve injury. 27,28 Penile erection is mediated by nitric oxide (NO) produced by eNOS and nNOS. 29 We found that decreased nNOS protein expression in the PBOO group was ameliorated by NaBu treatment.…”

Restoring erectile function by combined treatment with JNK inhibitor and HDAC inhibitor in a rat model of cavernous nerve injury

“…In a recent study, we showed that the administration of HDACi significantly improved CVOD in a rat model of CNCI. 17 HDAC11), but the differences in their roles have not been clearly identified. SAHA, the HDACi we used in this study, inhibits both class I and II of HDAC.…”

“…For CN crush injuries (mechanical compressions), a microsurgical vascular clamp was applied to the CN 4 ‐ 5 mm distal to the bilateral major pelvic ganglions (MPGs) for 80 s, removed for 30 s, then reapplied for an additional 80 s. In the J group, 10 mg/kg of JNKi (SP600125, Selleckchem, USA) was injected intraperitoneally once a day, and saline vehicle was orally administered 15 . The H group received oral administration of 25 mg/kg of HDACi (SAHA, Vorinostat, Selleckchem, USA) once daily and daily intraperitoneal injection of saline vehicle 17 . The J+H group was administered a combination of 10 mg/kg JNKi and 25 mg/kg HDACi.…”

“…15 The H group received oral administration of 25 mg/kg of HDACi (SAHA, Vorinostat, Selleckchem, USA) once daily and daily intraperitoneal injection of saline vehicle. 17 The J+H group was administered a combination of 10 mg/kg JNKi and 25 mg/kg HDACi.…”