The use of the neurotroxins in the prevention of neurogenic detrusor overactivity

Oliveira R1, Coelho A1, Chambel S S1, Silva R1, Cruz F2, Duarte Cruz C1

Research Type

Pure and Applied Science / Translational

Abstract Category

Neurourology

Abstract 497
Open Discussion ePosters
Scientific Open Discussion Session 28
Friday 31st August 2018
12:40 - 12:45 (ePoster Station 1)
Exhibition Hall
Basic Science Detrusor Overactivity Pathophysiology Prevention Spinal Cord Injury
1. Dept. of Biomedicine, Faculty of Medicine, Porto, Portugal; Translational NeuroUrology Group, Instituto de Investigação e Inovação em Saúde, Porto, Portugal; Instituto de Biologia Molecular e Celular, Porto, Portugal, 2. Dept. of Urology, Hostpital São João, Porto, Portugal; Translational NeuroUrology Group, Instituto de Investigação e Inovação em Saúde, Porto, Portugal; Instituto de Biologia Molecular e Celular, Porto, Portugal
Presenter
C

Célia Duarte Cruz

Links

Poster

Abstract

Hypothesis / aims of study
Bladder dysfunction is one of the most perturbing consequences of spinal cord injuries (SCI) and a top priority in SCI management (1). Urinary incontinence arises as a consequence neurogenic detrusor overactivity (NDO), reflecting neuroplasticity after disruption of neuronal pathways controlling lower urinary tract. NDO affects about 80% of SCI patients and occurs due to the development of a spinal micturition reflex at the lumbosacral spinal cord level, exclusively mediated by type C bladder sensory afferents (2). NDO is characterized by frequent and strong bladder contractions and, together with detrusor-sphincter dyssinergia (DSD), leads to frequent episodes of urinary incontinence and periods of very high intravesical pressures that threaten the upper urinary tract.
Currently, treatment is only initiated when NDO is stable-fixed, reducing the chances of NDO effacement and preservation of upper urinary tract. Here, we tested a preventive strategy with resiniferatoxin (RTX) and botulinum toxin A (BoNT/A) aiming to effectively block the emergence of NDO.
Study design, materials and methods
Female Wistar rats were divided into 5 groups, submitted to spinal cord transection at T8/T9 level or sham surgeries and treated as described in Table 1.
Four weeks after surgery animals were anesthetized with urethane and underwent 1 hour-cystometry followed by collection of L5-S1 spinal cord segments and bladder tissue. Immunohistochemistry and Western immunoblotting techniques were used to investigate changes in sprouting pattern of peripheral and central neuronal fibres related to treatment.
Results
Four weeks after SCT, animals treated with intravesical vehicle and intradetrusor saline presented the typical pattern of NDO, noticed by an increase in frequency and amplitude of bladder contractions and a strong increase in intravesical pressures (Table 2). Early treatment with RTX strongly reduced maximal bladder pressure and amplitude of bladder contractions to levels found for sham group. These effects where accompanied by a decrease in bladder expression of TRPV1, the molecular target for RTX, CGRP and GAP43, markers of sensory fibres and neuronal growth, respectively. No changes were found in the expression of CGRP and GAP43 in the spinal cord of animals treated with RTX.
Intradetrusor injections of BoNT/A during spinal shock lead to a slight reduction on peak pressure and a significant reduction in the amplitude of bladder contractions. Preliminary observations suggest a decrease in the expression of SNAP-25, the molecular target of the toxin, GAP43, TRPV1, TH and VAChT in the bladder of animals treated with BoNT/A.
Interpretation of results
Early interventions with RTX and BoNT/A lead to a significant decrease on the amplitude of bladder contractions with the former neurotoxin strongly decreasing maximal bladder pressures. A decrease in the amplitude of bladder contractions was found following both treatments, possibly reflecting less effective detrusor contractions and some degree of urinary retention. 
The more beneficial effects were found for RTX, reflecting its direct activity on TRPV1-expressing bladder afferents. These are the key players in initiating the process of NDO emergence. BoNT/A, on the other hand, has a broader effect, targeting cholinergic, adrenergic and sensory bladder afferents expressing the toxin’s molecular target SNAP-25, producing some degree of improvement but less pronounced effectiveness (3).
We forward that early treatment with these neurotoxins, possibly during spinal shock, may prevent or attenuate NDO, decreasing the frequency of urinary incontinence episodes and reducing intravesical pressures.
Concluding message
Early treatments after SCI with RTX and BoNT/A resulted in a significant improvement on bladder function in a rat model of NDO. Both RTX and BoNT/A lead to significant decrease in the amplitude of bladder contractions but only RTX was capable of preventing high intravesical pressures. Therefore, we suggest that a restricted modulation of bladder sensory afferents at early stages of disease progression might be a useful strategy in the prevention of NDO development.
Figure 1
Figure 2
References
  1. Panicker, J. N., Fowler, C. J., & Kessler, T. M. (2015). Lower urinary tract dysfunction in the neurological patient: clinical assessment and management. The Lancet Neurology, 14(7), 720-732.
  2. De Groat, W. C., Kawatani, M., Hisamitsu, T., Cheng, C. L., Ma, C. P., Thor, K., ... & Roppolo, J. R. (1990). Mechanisms underlying the recovery of urinary bladder function following spinal cord injury. Journal of the autonomic nervous system, 30, S71-S77
  3. Coelho, A., Cruz, F., Cruz, C. D., & Avelino, A. (2012). Spread of onabotulinumtoxinA after bladder injection. Experimental study using the distribution of cleaved SNAP-25 as the marker of the toxin action. European urology, 61(6), 1178-1184
Disclosures
Funding Raquel Oliveira PhD fellowship NORTE2020 - NORTE-08-5369-FSE-000026. Ana Coelho Post-doc fellowship FCT - SFRH/BPD/108468/2015). Study funded by: International PhD Program in Neurosciences, Faculty of Medicine University of Porto, FEDER - COMPETE 2020, Portugal 2020, and FCT/Ministério da Ciência, Tecnologia e Ensino Superior - POCI-01-0145-FEDER-007274. Funding also came from Prémio Melo e Castro 2016 from Santa Casa da Misericórdia de Lisboa. Clinical Trial No Subjects Animal Species Rat (Wistar) Ethics Committee ORBEA
28/03/2024 06:16:24