Botulinum Toxin A for Bladder Pain Syndrome/Interstitial Cystitis

Botulinum neurotoxin A (BoNT-A), derived from Clostridium botulinum, has been used clinically for several diseases or syndrome including chronic migraine, spasticity, focal dystonia and other neuropathic pain. Chronic pelvic or bladder pain is the one of the core symptoms of bladder pain syndrome/interstitial cystitis (BPS/IC). However, in the field of urology, chronic bladder or pelvic pain is often difficult to eradicate by oral medications or bladder instillation therapy. We are looking for new treatment modality to improve bladder pain or associated urinary symptoms such as frequency and urgency for patients with BPS/IC. Recent studies investigating the mechanism of the antinociceptive effects of BoNT A suggest that it can inhibit the release of peripheral neurotransmitters and inflammatory mediators from sensory nerves. In this review, we will examine the evidence supporting the use of BoNTs in bladder pain from basic science models and review the clinical studies on therapeutic applications of BoNT for BPS/IC

A mechanobiological model of the urinary bladder : integrative modelling of outlet obstruction

We present the first model to simulate the adaptive growth and remodeling (G&R) response of the bladder wall to bladder outlet obstruction (BOO). The model is calibrated and validated with an experimental rodent model of BOO. The bladder is modeled as a multi-layered, nonlinear elastic spherical membrane using a constrained mixture model that includes both passive and active components. The mechanical model is integrated with a shorter time scale micturition model that accounts for the active mechanics of voiding and dependence of flowrate on urethral resistance. Over a second time scale, constituents are configured and subsequently remodel to achieve a homeostatic state at the onset of voiding. Simulations of remodeling in response to the tenfold increase in outlet resistance arising from BOO, predict an initial loss of voiding capacity. Subsequent smooth muscle cell (SMC) hypertrophy enables the bladder wall to generate sufficient active tension to restore voiding functionality. Consistent with the experimental observations, the model predicts: hypertrophy of SMC and enlargement of the bladder over realistic timescales; collagen remodeling to maintain its role as a protective sheath; and increased voiding duration with lower average flow rate. This integrative G&R modeling approach provides fundamental insight into the adaptation of the bladder’s structural-functional relationship in response to outlet obstruction

Relaxin-2 therapy reverses radiation-induced fibrosis and restores bladder function in mice

Aim: To determine the efficacy of human relaxin-2 (hRLX2) in reversing radiation-induced bladder fibrosis and lower urinary tract dysfunction (LUTD). Radiation cystitis is a consequence of radiotherapy for pelvic malignancies. Acutely, irradiation leads to reactive oxygen/nitrogen species in urothelial cells, apoptosis, barrier disruption, and inflammation. Chronically, this results in collagen deposition, bladder fibrosis, and attenuated storage and voiding functions. In severe cases, cystectomies are performed as current therapies do not reverse fibrosis. Methods: We developed a mouse model for selective bladder irradiation (10 Gray; 1 Gy=100 rads) resulting in chronic fibrosis within 6 weeks, with decreased bladder compliance, contractility, and overflow incontinence. Seven weeks post-irradiation, female C57Bl/6 mice were continuously infused with hRLX2 (400μg/kg/day/14 days) or vehicle (saline) via subcutaneous osmotic pumps. Mice were evaluated in vivo using urine spot analysis, cystometrograms and external urethral sphincter electromyograms; and in vitro using length-tension measurements, Western blots, histology, and immunohistochemistry. Results: hRLX2 reversed fibrosis, decreased collagen content, improved bladder wall architecture, and increased bladder compliance, detrusor smooth muscle Cav1.2 expression and detrusor contractility in mice with chronic radiation cystitis. hRLX2 treatment outcomes were likely caused by the activation of RXFP1/2 receptors which are expressed on the detrusor. Conclusion: hRLX2 may be a new therapeutic option for rescuing bladders with chronic radiation cystitis

Targeting p75 neurotrophin receptors ameliorates spinal cord injury-induced detrusor sphincter dyssynergia in mice

Aims: To determine the role of p75 neurotrophin receptor (p75NTR) and the therapeutic effect of the selective small molecule p75NTR modulator, LM11A-31, in spinal cord injury (SCI) induced lower urinary tract dysfunction (LTUD) using a mouse model. Methods: Adult female T8-T9 transected mice were gavaged daily with LM11A-31 (100mg/kg) for up to 6 weeks, starting 1 day before, or 7 days following injury. Mice were evaluated in vivo using urine spot analysis, cystometrograms (CMGs), and external urethral sphincter (EUS) electromyograms (EMGs); and in vitro using histology, immunohistochemistry, and Western blot. Results: Our studies confirm highest expression of p75NTRs in the detrusor layer of the mouse bladder and lamina II region of the dorsal horn of the lumbar-sacral (L6-S1) spinal cord which significantly decreased following SCI. LM11A-31 prevented or ameliorated the detrusor sphincter dyssynergia (DSD) and detrusor overactivity (DO) in SCI mice, significantly improving bladder compliance. Furthermore, LM11A-31 treatment blocked the SCI-related urothelial damage and bladder wall remodeling. Conclusion: Drugs targeting p75NTRs can moderate DSD and DO in SCI mice, may identify pathophysiological mechanisms, and have therapeutic potential in SCI patients

Recent advances in pharmacological management of urinary incontinence [version 1; referees: 2 approved]

Lower urinary tract symptoms—in particular, storage disorders (for example, urinary incontinence) as well as bladder underactivity—are major health-related problems that increase with age. Yet lower urinary tract symptoms remain under-diagnosed and poorly managed, and incontinence has been cited as the major reason for institutionalization in elderly populations and is one of the most common conditions in primary care practice. Although lifestyle and behavior therapy has been used as a useful treatment regimen for urge incontinence, medications (often used as adjunct) can provide additional benefit. This review will include current therapies used for treatment of urinary incontinence