Urine storage and release by the bladder are controlled by the peripheral and central nervous systems. [1] Neurotrophins are a class of growth factors that were originally found in the nervous system where they promote growth and survival of neurons [2].  Nerve ending activity is regulated by neurotrophins, among other brain-derived neurotrophic factor (BDNF). The latter is essential in neuroregeneration and its dysregulation contributes to pathologies of the urinary tract. [3] BDNF has been proposed to be a marker for overactive bladder syndrome (OAB). The aim of this study is to examine the levels of proBDNF, BDNF and associated proteins in the urine of a female aging population. We hypothesized that urinary proBDNF/BDNF ratio is unbalanced in aging women with OAB compared to control subjects from the same age group.

In this cohort study, we analyzed urine samples from control and OAB patients to compare the relative amounts of BDNF and proBDNF, along with the proteases involved in the maturation and degradation of BDNF. Urine and blood samples from 20 controls and 20 OAB female patients between the ages of 50 to 80 years were obtained with validated questionnaires. ProBDNF and BDNF were measured using specific ELISA kits (Biosensis). MicroRNAs involved in the control of proBDNF synthesis were measured by RT-qPCR after polyadenylation. Activity of matrix metallopeptidase-9 (MMP-9) was measured using an enzymatic kit. Sortilin and Cortisol were also measured using specific ELISA kits. Results were adjusted with creatinine levels. Data were further adjusted for age, renal function and insulin resistance.

BDNF/creatinine levels were not different in the urine of controls versus OAB patients. ProBDNF/creatinine measures were lower in the OAB population. The ratio BDNF/proBDNF was therefore higher (0.051 ± 0.0078 vs 0.135 ± 0.027) in the OAB population (P<0.005). (Figure 1) MicroRNAs known to control the translation of proBDNF mRNA by binding its 3’UTR sequence, namely MiR-26b-5p, Mir-26-1a-5p, MiR-10a-5p and MiR-103a-3p were not expressed differently between control and OAB patients. Other miRNAs, MiR-15b-5p, MiR-142-3p and MiR-103a-3p that control proBDNF expression through downstream or upstream pathways were not affected as well. On the other hand, enzymatic activity of MMP-9, one of the main enzyme converting proBDNF to BDNF was higher in the OAB group. The microRNA MiR-491-5p, that negatively controls MMP-9 expression was in accordance potently decreased in the OAB group. There was no statistical significance between the levels of sortilin or cortisol measurements found in the urine of controls when compared to OAB patients (P>0.005).

These results suggest that the ratio BDNF/proBDNF might be a better indicator, or potential biomarker of OAB, than BDNF alone. The decrease in proBDNF levels could be the result of the enhanced activity of MMP-9 activity rather than transcription or translation control, highlighting the role or proteases in a bladder pathology such as OAB.

OAB related to aging can be clinically correlated to the BDNF proteolysis imbalance, rendering it as a potential biomarker and therapeutic target. Albeit, concomitant age-related factors, such as polypharmacy and presence of chronic disease, may contribute to the relationship between BDNF and aging-related OAB phenotype.

Yoshimura N, Ogawa T, Miyazato M, Kitta T, Furuta A, Chan- cellor MB, Tyagi P (2014) Neural mechanisms underlying lower urinary tract dysfunction. Korean J Urol 55(2):81–90
Gibon J, Barker PA. Neurotrophins and proneurotrophins. Neuroscientist, 2017.
Mossa AH, Cammisotto PG, Shamout S, Campeau L. Imbalance of nerve growth factor metabolism in aging women with OAB syndrome. World Journal of urology 2020.

Continence 2S2 (2022) 100257
DOI: 10.1016/j.cont.2022.100257