Prevention of neurogenic detrusor overactivity in spinal cord transected rats with early anticholinergic treatment

Przydacz M1, Loutochin G1, Biardeau X1, Cammisotto P2, Zimoch J3, Campeau L1, Corcos J1

Research Type

Basic Science / Translational

Abstract Category

Neurourology

Abstract 510
Open Discussion ePosters
Scientific Open Discussion ePoster Session 28
Friday 31st August 2018
12:55 - 13:00 (ePoster Station 2)
Exhibition Hall
Pharmacology Detrusor Overactivity Incontinence Animal Study
1. Department of Urology, Jewish General Hospital, McGill University, Montreal, Quebec, Canada, 2. Lady Davis Research Institute, McGill University, Montreal, Quebec, Canada, 3. Tissue Biology Research Unit, Department of Surgery, University Children's Hospital Zurich, Zurich, Switzerland
Presenter
J

Jacques Corcos

Links

Poster

Abstract

Hypothesis / aims of study
After spinal cord injury (SCI), detrusor overactivity (DO) leads to incontinence affecting patient’s quality of life and jeopardizes kidney function. Currently, the only recognized method preventing DO is electrical neuromodulation implemented immediately after SCI. However, this technique is expensive and not widely available. Therefore, the aim of this experiment was to assess the urodynamic effects of early fesoterodine fumarate (FF) administration in preventing DO in a spinal cord transected (SCT) rat model and investigate whether observed effects were due to alternations in expression patterns of bladder muscarinic receptors.
Study design, materials and methods
33 Sprague-Dawley rats were allocated to 6 groups – Group 1: 3 normal controls; Group 2: 6 SCT controls; Group 3: 6 SCT rats + FF 0.18 mg/kg/d; Group 4: 6 SCT rats + FF 0.12 mg/kg/d; Group 5: 6 SCT rats + FF 0.18 mg/kg/d + 72-h wash-out period; Group 6: 6 SCT rats + FF 0.12 mg/kg/d + 72-h wash-out period. SCT was performed at T10 and FF was administered subcutaneously from post-op day 1 by an osmotic pump in peri-device space. The pump was implanted at the time of SCT. Cystometry was undertaken 6 weeks after SCT in awaked rats right before the animals were sacrificed. Then, the bladders were collected. Changes of bladders layers were assessed by hematoxylin/eosin and Masson’s trichrome staining. Distribution of the receptors was investigated by immunofluorescence staining against muscarinic receptors (M1 to M5). Their prevalence was analyzed by Western blots. Comparisons were conducted using Kruskall-Wallis test (post-hoc Dunn test).
Results
Urodynamic data: 6 weeks after SCT, intermicturition pressure was lower in low dose treated group (Group 4) compared to SCT controls (p<0.05). Maximum pressure was lower in most of the SCT treated rats (Groups 3–5) (p<0.01). Threshold pressure was lower in full time treated rats (Group 3–4) (p<0.05). Morphological data: No changes were observed within the bladders layers in terms of degree of fibrosis and muscle hypertrophy. Expression of M2 receptors was lower in groups with washout period (Groups 5 and 6) (p<0.01) whereas expression of M3 receptors was higher in Groups 4 and 5 (p<0.01).
Interpretation of results
Early FF administration at the time of transection modulates bladder overactivity and modifies profile of bladder muscarinic receptors. The treatment effect is sustained after a washout period.
Concluding message
Early FF administration in a SCT rat model prevents the onset of DO. The evidence is strong enough to support clinical trials analyzing long-term prevention of DO in patients after SCI with the presented approach.
Figure 1
Disclosures
Funding This study was supported by an unrestricted grant from Pfizer Canada and Mitacs Canada. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. The present study (No. 2014–7459) was approved by our institutional Research Ethics Committee. Clinical Trial No Subjects Animal Species Rats Ethics Committee The present study (No. 2014–7459) was approved by our institutional Research Ethics Committee (Jewish General Hospital, McGill University).