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Effects of dutasteride in a rat model of chemically induced prostatic inflammation-Potential role of estrogen receptor β.

ABSTRACT:

Background

Dutasteride administration reportedly improves lower urinary tract symptoms in patient with chronic, histologically-identified prostatic inflammation, potentially through estrogen receptor β (ERβ), activation of which has anti-inflammatory effects in the prostate tissue. Therefore, we investigated the effect of dutasteride on intraprostatic inflammatory responses and bladder activity using a rat model of chemically induced prostatic inflammation.

Methods

Male Sprague-Dawley rats at 10 weeks old were used. Prostatic inflammation was induced by 5% formalin injection into ventral lobes of the prostate and saline was injected in the control group (control, n = 5). Rats with prostatic inflammation were divided into dutasteride therapy (dutasteride, n = 5) and placebo groups (placebo, n = 5). Dutasteride was administrated at a dose of 0.5 mg/kg daily from 2 days before induction of prostatic inflammation whereas placebo rats received vehicle only. Twenty-eight days later, cystometry was performed in a conscious condition to measure non-voiding contractions (NVCs), intercontraction intervals (ICI) and postvoid residual volume (RV). After cystometry, the prostate was excised for analysis of messenger RNA (mRNA) expression levels of ERα, ERβ, interleukin-1β (IL-1β), and IL-18 by quantitative polymerase chain reaction.

Results

The mean number of NVCs was significantly greater in placebo group than that of control group without prostatic inflammation (p < .05), and ICI were significantly decreased in placebo group compared with control group (p < .05). On the contrary, there was no significant change in NVCs or ICI between control and dutasteride groups. RV was not significantly different among three groups. Gene expression levels of ERα, IL-1β, and IL-18 was significantly increased in placebo rats compared with control rats (p < .05), but not significantly different between control and dutasteride rats. On the other hand, the mRNA expression level of ERβ was significantly decreased in placebo rats (p < .05), but not in dutasteride rats, compared with control rats.

Conclusion

Dutasteride treatment improved not only prostatic inflammation evident as increased gene expression levels in IL-1β and IL-18, but also bladder overactivity shown by increased NVCs during bladder filling. These therapeutic effects were associated with the restored expression of anti-inflammatory ERβ. Therefore, dutasteride might be effective via ERβ modulation for the treatment of prostatic inflammation in addition to its previously known, anti-androgenic effects on benign prostatic hyperplasia.

SUBMITTER: Mizoguchi S

PROVIDER: S-EPMC7685523 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:There is increasing evidence showing that chronic non-bacterial prostatic inflammation is involved in the pathogenesis of benign prostatic hyperplasia (BPH) and male lower urinary tract symptoms (LUTS). It has also been reported that estrogen receptor ? (ER?) could have an immunoprotective role in prostatic tissue. Therefore, we investigated the effect of ER?-activation on not only prostatic inflammation, but also bladder overactive conditions in a rat model with nonbacterial prostatic inflammation.Male Sprague-Dawley rats (8 weeks, n?=?15) were divided into three groups: sham-saline group (n?=?5), formalin-vehicle group (n?=?5), and formalin-treatment group (n?=?5). The sham-saline group had sham operation and 50??l normal saline injected into each ventral lobe of the prostate. The formalin-vehicle group had 50??l 5% formalin injection into bilateral ventral lobes of the prostate. The formalin-treatment group was treated with 3?-Adiol (a selective ER? agonist precursor) at a dose of 3?mg/kg daily from 2 days before induction of prostatic inflammation, whereas formalin-vehicle rats received vehicle (olive oil). In each group, conscious cystometry was performed on day 28 after intraprostatic formalin injection or sham treatment. After cystometry, the bladder and prostate were harvested for evaluation of mRNA expression and histological analysis.In cystometric investigation, the mean number of non-voiding contractions was significantly greater and voiding intervals were significantly shorter in formalin-vehicle rats than those in sham-saline rats (P?<?0.05). In RT-qPCR analysis, mRNA expression of NGF, P2X2, and TRPA1 receptors was significantly increased in the bladder mucosa, and mRNA expression of TNF-?, iNOS and COX2 in the ventral lobes of prostate was significantly increased in formalin-vehicle rats compared with sham-saline rats (P?<?0.05). In addition, relative mRNA expression ratio of ER? to ER? (ER?/ER?) in the ventral lobes of prostate was significantly decreased in formalin-vehicle rats compared with sham-saline rats (P?<?0.05). These changes were ameliorated by 3?-Adiol administration in formalin-treatment rats.These results indicate that ER? activation by 3?-Adiol administration, which normalized the ER?/ER? expression ratio in the prostate, can improve not only prostatic inflammation, but also bladder overactivity. Therefore, ER? agonists might be useful for treating irritative bladder symptoms in patients with symptomatic BPH associated with prostatic inflammation. Prostate 77:803-811, 2017. © 2017 Wiley Periodicals, Inc.