Effects of oral administration of nonselective Trk inhibitor on bladder overactivity in rodent models of prostatic inflammation

Abstract

Background: Our research focused on the assessment of the impact of systemic inhibition of Trk receptors, which bind to nerve growth factor (NGF) and brain-derived neurotrophic factor (BDNF), on bladder hypersensitivity in two distinct rodent models of prostatic inflammation (PI).

Methods: Male Sprague-Dawley rats were divided into three groups (n = 6 each): the control group (no PI, vehicle administration), the untreated group (PI, vehicle administration), and the treated group (PI, nonselective Trk inhibitor, GNF 5837, administration). PI in rats was induced by a intraprostatic injection of 5% formalin. Posttreatment, we carried out conscious cystometry and a range of histological and molecular analyses. Moreover, the study additionally evaluated the effects of a nonselective Trk inhibitor on bladder overactivity in a mouse model of PI, which was induced by prostate epithelium-specific conditional deletion of E-cadherin.

Results: The rat model of PI showed upregulations of NGF and BDNF in both bladder and prostate tissues in association with bladder overactivity and inflammation in the ventral lobes of the prostate. GNF 5837 treatment effectively mitigated these PI-induced changes, along with reductions in TrkA, TrkB, TrkC, and TRPV1 mRNA expressions in L6-S1 dorsal root ganglia. Also, in the mouse PI model, GNF 5837 treatment similarly improved bladder overactivity.

Conclusions: The findings of our study suggest that Trk receptor inhibition, which reduced bladder hypersensitivity and inflammatory responses in the prostate, along with a decrease in overexpression of Trk and TRPV1 receptors in sensory pathways, could be an effective treatment strategy for male lower urinary tract symptoms associated with PI and bladder overactivity.

Keywords: BDNF; NGF; Trk receptors; bladder overactivity; prostatic inflammation.

FIGURE 1

Effects of oral administration of a nonselective Trk inhibitor (GNF 5837) on bladder activity in a rat model of PI induced by intraprostatic formalin injection. (A) Representative traces of CMG under an awake condition in Control, Untreated, and Treated le treatment. (B) Comparison of non-voiding contractions (NVC) among Control, Untreated and Treated groups (n = 6 per group). ns, not significant; between Control and Treated groups. *p < 0.05, between Untreated and Control group, or Untreated and Treated groups. [Color figure can be viewed at wileyonlinelibrary.com]

FIGURE 2

Photomicrographs of the prostate and the bladder. Hematoxylin-eosin staining transverse sections of prostate ventral lobes (A–C) and bladder (D–F) from Control, Untreated and Treated groups of rats on Day 28 (n = 6 in each group) after performing CMG. The prostatic ventral lobe of Untreated rat shows inflammatory cells infiltration in the stroma (B, red arrow). Scale bars; 200 μm (A–F). [Color figure can be viewed at wileyonlinelibrary.com]

FIGURE 3

Protein expression levels of NGF (A) and BDNF (B) in the bladder mucosa and the prostatic ventral lobes from Control, Untreated, and Treated groups of rats (n = 6 in each group). ns; nonsignificant, between Control and Treated groups. **p < 0.01, ***p < 0.001, ****p < 0.0001, between Untreated and Control groups, or Untreated and Treated groups. BDNF, brain-derived neurotrophic factor; NGF, nerve growth factor. [Color figure can be viewed at wileyonlinelibrary.com]

FIGURE 4

mRNA expression levels of TrkA (A), TrkB (B), and TrkC (C) in L6-S1 dorsal root ganglia (DRG) from Control, Untreated and Treated rats on Day 28 (n = 6 in each group) after performing CMG. ns; nonsignificant, between Control and Treated groups. *p < 0.05, **p < 0.01, ***p < 0.001, ****p < 0.0001 between Untreated and Control group, or Untreated and Treated groups.

FIGURE 5

mRNA expression levels of TRPV1 in L6-S1 dorsal root ganglia (DRG) from Control, Untreated and Treated rats on Day 28 (n = 6 in each group) after performing CMG. †p < 0.05, between Control and Treated groups. **p < 0.01, ****p < 0.0001 between Untreated and Control group, or Untreated and Treated groups.

FIGURE 6

mRNA expression levels of interleukin (IL)-1β and IL-8 in the prostatic ventral lobes from Control, Untreated and Treated rats on Day 28 (n = 6 in each group) after performing CMG. ns; not significant, between Control and Treated groups. ****p < 0.0001 between Untreated and Control group, or Untreated and Treated groups.

FIGURE 7

Effects of oral administration of a nonselective Trk inhibitor (GNF 5837) on bladder activity in a mouse model of PI induced by prostate epithelial cell-specific deletion of the Cdh1 gene. (A) Representative traces of CMG under an awake condition in Control, Untreated and Treated mice after 10 days of GNF 5837 or vehicle treatment. (B) Comparison of non-voiding contractions (NVC) among Control (n = 6), Untreated (n = 5) and Treated groups (n = 5). ns, not significant; between Control and Treated groups. *p < 0.05, between Untreated and Control group, or Untreated and Treated groups. [Color figure can be viewed at wileyonlinelibrary.com]