Lower urinary tract pathology such as overactive bladder syndrome was recently linked to low urinary levels of the neurotrophin Nerve Growth Factor (NGF) in the urine of aging female patients (1). NGF provides important homeostatic functions and promotes tissue health. The decrease in urinary NGF was linked to high activity of the proteolytic enzyme Matrix Metalloproteinase-9 (MMP-9) (1). We previously found that THX-B, an antagonist of the proinflammatory receptor p75NTR, increased NGF levels by decreasing MMP-9 activity in urothelial cell culture. Here, aging mice were treated with THX-B to evaluate in vivo the functional benefit of p75NTR antagonism on the aging bladder. We aimed to assess bladder behaviour and voiding parameters as well as measure the contractile response of the bladder. We hypothesized that treating bladders of aging mice with THX-B would improve bladder behaviour and function.

Male C57BL/6J mice of 6-, 12- and 18-months were injected intraperitoneal with either PBS (control) or THX-B (50 µg) once weekly for four weeks. Mice were separated based on age and expression of urinary p75NTR extracellular domain. Voiding behaviours and patterns, notably, total urine volume, volume of urine, and frequency of urination were assessed using voiding spot assay biweekly. Once the mice were sacrificed after the 4 weeks of treatment, bladders were collected for organ bath, which evaluated bladder contractility using electrical field stimulation (EFS), KCl and carbachol.

Compared to controls, voiding behaviour and bladder contractility was improved only in the 12-month-old mice treated with THX-B. Specifically, total urine volume and volume per micturition were reduced following four weeks of treatment whereas voiding frequency was reduced following two and four weeks of treatment. Bladder contractility in response to EFS, KCl and carbachol was reduced in the same mice following four weeks of treatment.

Given that only the 12-month-old treated mice responded to treatment with THX-B, our results suggest that there is temporal heterogeneity in voiding pathology related to p75NTR expression or function that alters response to therapy. Nonetheless, p75NTR antagonism with THX-B shows important benefits in age related bladder function since urine volume, volume per micturition and voiding frequency were reduced. THX-B reduced contractility of bladders from 12-month-old treated mice, suggesting a positive impact of p75NTR antagonism possibly linked to changes in voiding behaviour.

Our study is the first to identify the role of p75NTR antagonism on bladder behaviour in aging mice with voiding dysfunction. Our results illustrate an age-specific effect of THX-B. Improvements in bladder behaviour and activity were observed only in 12-month-old treated mice. These results are in accordance with our previous studies and suggest that THX-B could be a new pharmacological tool for improving bladder dysfunction. Future studies aimed at understanding the expression of p75NTR in relation to the aging bladder will help understand the mechanism of p75NTR antagonism in the aging bladder.

Mossa AH, Cammisotto PG, Shamout S, Campeau L. Imbalance of nerve growth factor metabolism in aging women with overactive bladder syndrome. World J Urol. 202Jun;39(6):2055-206doi: 10.1007/s00345-020-03422-Epub 202Sep PMID: 32870355.