In a recent study using a mice model of prostate-specific deletion of E-cadherin , the loss of E-cadherin in the prostatic epithelium induced chronic prostatic inflammation and increased epithelial proliferation as well as bladder overactivity [1]. Also, previous research using a rat model of prostatic inflammation has demonstrated that prostatic inflammation induced bladder overactivity is association of overexpressed nerve growth factor (NGF) in the bladder mucosa via prostate-to-bladder cross-organ afferent sensitization through activation of the pelvic nerve [2].  Because tropomyosin receptor kinase A (TrkA) is known as a high affinity receptor of NGF [3], the present study examined the effect of Trk receptor inhibition on bladder overactivity using a mice model of conditional loss of E-cadherin in the prostatic epithelium.

Mice were divided into three groups: (1) Control group (n = 6); wild-type mice without loss of E-cadherin, given oral administration of non-selective Trk inhibitor (GNF 5837), (2) Untreated group (n = 5); mice with prostate epithelium-specific  conditional loss of E-cadherin, without treatment, (3) Treated group (n = 5); mice with prostate epithelium-specific conditional loss of E-cadherin, given oral administration of GNF 5837. Conditional deletion of E-cadherin in the prostatic epithelium was induced by transient administration of tamoxifen when mice reached sexual maturity (7 weeks of age). Vehicle or GNF 5837 at a dose of 50 mg/kg dissolved in methyl cellulose (0.5w/v %, 0.1 ml) and TWEEN 80 (0.5w/v %, 0.1 ml) was then given to Control and Treated groups daily by oral gavage for 10 days.  Thereafter, conscious cystometry (CMG) was preformed, followed by tissue removal for evaluation of mRNA levels of 3 types of Trk receptors (Trk A, B & C), TRPV1 and TRPA1 in L6-S1 dorsal root ganglia (DRG), and inflammation/ischemia markers (TNFα and HIF 1-α) in the prostate by RT-PCR.

In CMG, there was no significant change in intercontraction intervals (ICIs) among three groups; however, Treated group demonstrated a significant decrease in non-voiding contractions (NVC/min) compared to Untreated group, while there were no significant differences between Treated and Control group (Fig. 1). In other CMG parameters, there were no significant differences among three groups. In Untreated group, mRNA levels of all Trk receptor subtypes (Trk A, B, C), TRPV1 and TRPA1 in L6-S1 DRG were significantly increased, compared to Control group (Fig. 2A); however, these changes were normalized in Treated group (Fig. 2A). In addition, mRNA expressions of TNF α and HIF 1-α in the prostate of Untreated group were significantly greater than those of Control group while there were no significant differences between Treated and Control groups (Fig. 2B).

These results indicate that prostate epithelium-specific deletion of E-cadherin induces bladder overactivity shown by increased NVC in association with Trk receptors upregulation in L6-S1 DRG and that inhibition of Trk receptors improved E-cadherin deletion-induced cytokine production in the bladder, bladder overactivity and C-fiber afferent marker (TRPV1 and TRPA1) overexpression in L6-S1 DRG that contain bladder and prostate afferent neurons. Thus, it is assumed that Trk receptors plays a significant role in prostate-to-bladder cross-organ sensitization, which induces bladder overactivity due to enhanced bladder afferent activity, after prostate epithelium-specific E-cadherin deletion.

Blockade of Trk receptors improved not only prostatic inflammation, but also bladder overactivity, shown by increased NVC in the E-cadherin knockout mouse model. Also, improvement of bladder overactivity is associated with reductions of Trk A receptor, TRPV1 and TRPV1 in L6-S1 DRG. Thus, the NGF-Trk receptor mechanism would be a potential target for the treatment of irritative bladder symptoms in patients with chronic prostatitis.

L.E Pascal, et al. Prostate-Specific Deletion of Cdh1 Induces Murine Prostatic Inflammation and Bladder Overactivity. ENDOCRIOLOGY. 2021; 162 (1): 1-15.
Funahashi Y, et al. Bladder overactivity and afferent hyperexcitability induced by prostate-to-bladder cross-sensitization in rats with prostatic inflammation. J Physiol. 2019; 597(7): 2063-78.
Indo Y, et al. Mutations in the TrkA/NGF receptor gene in patients with congenital insensitivity to pain with anhidrosis. Nat. Genet. 1996; 13: 485–88.