Nerve Growth Factor (NGF) controls the development and survival of cell of the nervous system. Its levels in urine are decreased in elderly people diagnosed with overactive bladders (OAB). High activity of the enzyme matrix metalloproteinase-9 (MMP-9), the main protease that degrades NGF into inactive peptides explained these results. Interestingly, type 1 and type 2 diabetic animal models with bladder dysfunction display the same characteristics. Chronic treatment of these rodents with THX-B, an antagonist of the proinflammatory receptor p75NTR, improves bladder parameters, restore urinary NGF levels and decrease MMP-9 activity. We here aim to determine the functional benefit of p75NTR antagonism on the bladder in a model of aging mice.

Male and female C57BL/6J mice aged 6- and 12-months were injected once weekly for four weeks with either PBS (control) or THX-B (5 microg/mouse). Voiding spot assay was used to measure urination behaviours and patterns, including volume of urine, volume per miction and frequency of urination (spot number). Organ baths assessed bladder contractility characteristics with regards to different stimuli including KCl, Electrical Field stimulation and Carbachol. NGF and proNGF levels in collected urine of these aging mice were measured using ELISA kits. MMP-9, Vacht and pgp9.5 were semi-quantifies by immunoblotting in bladder extracts.

Compared to controls treated with PBS, voiding behaviour and bladder contractility were improved only in the 12-month old mice after chronic treatment with THX-B. Specifically, total urine volume, volume per micturition and voiding frequency were reduced. In vitro, bladder contractility stimulated by KCl (15 mM), Electrical Field stimulation (1 to 32 Hz) or Carbachol at (3 µM and 100 µM) was reduced in strips from mice after THX-B treatment compared to controls. On the other hand, THX-B increased NGF urine levels, as well as the ration NGF/proNGF, in 12-month-old mice (male and female) while MMP-9 activity was decreased only in female mice. Levels of Vacht and pgp9.5 in 12-month old mice were unaffected by treatment with THX-B.

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.

These findings suggest that THX-B presents an age-specific efficiency, involving enhanced NGF expression through decrease in MMP-9, at least in female mice. THX-B might be a new therapeutic tool to improve OAB.