Introduction: Radical prostatectomy (RP) is the most common treatment for localized prostate cancer. Unfortunately, the procedure carries high risk for the development of lower urinary tract symptoms (LUTS). These urogenital complications are highly detrimental to the post-surgical well-being of men, for whom there are presently poor treatment options. We recently demonstrated in a rat model of nerve injury associated with RP, that Fidgetin-Like 2 (FL2) depletion through application of FL2-siRNA at the site and time of cavernous nerve injury (CNI), resulted in significantly enhanced functional nerve recovery, as determined by cavernosometry . In the present studies, we determined if the same approach would also improve bladder function outcomes in the rat model of CNI.
Methods: Animals were submitted to bilateral CNI, or to CNI followed by treatment with either FL2-siRNA or control-siRNA at the time and site of injury (the nerve and major pelvic ganglia). Voiding function was evaluated 7-days post-injury using the voided stain on paper (VSOP) method. Changes in i) micturition frequency and ii) voided volume per micturition were compared to those of naïve (unoperated) rats. The decrease in micturition frequency and increase in voiding volume in the CNI, and CNI treatment groups (FL2-siRNA or control-siRNA groups) were compared to the naïve cohort. 6 rats were analyzed per group and significance determined by Student’s t-test.
Results: Voiding function was significantly altered following CNI injury; at 7-days post-CNI, when compared to naïve (unoperated) age-matched controls, CNI animals displayed significantly lower micturition frequency (0.4 versus 0.55 voids per hour, P=0.02), and more than 2-fold greater voided volume per micturition (P=0.055). Remarkably, FL2-siRNA treatment at the time and site of injury mitigated these side-effects of CNI on voiding function, whereas treatment with control-siRNA was ineffective.
Conclusions: These findings indicate that in addition to promoting recovery of erectile function following CNI rats , FL2 depletion at the site and time of injury also leads to improved bladder function outcomes. However, given that our studies on the role of FL2 depletion in mitigating LUTS were conducted at 7-days rather than 2-weeks after injury (a time point too short for visible nerve regeneration), the primary mechanisms by which FL2 depletion improves these different urogenital conditions are likely to be different and are currently being investigated.
1] Baker, L., Tar, M., Villegas, G., Charafeddine, R.A., Kramer, A., Vafaeva, O., Nacharaju, P., Friedman, J., Davies, K.P., and Sharp, D.J. (2021) Fidgetin-like 2 is a novel negative regulator of axonal growth and can be targeted to promote functional nerve regeneration after injury. JCI Insight. 2021 May 10;6(9):138484. PMID: 33872220