Botulinum toxin A modulates afferent fibers in neurogenic detrusor overactivity

Conte, Antonella; Giannantoni, Antonella; Proietti, Silvia; Giovannozzi, Silvia; Fabbrini, Giovanni; Rossi, Aroldo; Porena, Massimo; Berardelli, Alfredo

doi:10.1111/j.1468-1331.2011.03618.x

Cited by 30 publications

(30 citation statements)

References 30 publications

(40 reference statements)

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“…The selective β3-adrenoceptor agonist mirabegron [13], [14] has been recently proposed to treat OAB, however its effectiveness in patients with NDO remains uncertain. Newer therapies such as intravesical botulinum toxin [3], [15] are not only invasive and expensive but are also associated with safety concerns [3], [6], [16]. Therefore, novel approaches to treat NDO are urgently needed.…”

Section: Introductionmentioning

confidence: 99%

Neurogenic Detrusor Overactivity Is Associated with Decreased Expression and Function of the Large Conductance Voltage- and Ca2+-Activated K+ Channels

et al. 2013

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Patients suffering from a variety of neurological diseases such as spinal cord injury, Parkinson’s disease, and multiple sclerosis often develop neurogenic detrusor overactivity (NDO), which currently lacks a universally effective therapy. Here, we tested the hypothesis that NDO is associated with changes in detrusor smooth muscle (DSM) large conductance Ca2+-activated K+ (BK) channel expression and function. DSM tissue samples from 33 patients were obtained during open bladder surgeries. NDO patients were clinically characterized preoperatively with pressure-flow urodynamics demonstrating detrusor overactivity, in the setting of a clinically relevant neurological condition. Control patients did not have overactive bladder and did not have a clinically relevant neurological disease. We conducted quantitative polymerase chain reactions (qPCR), perforated patch-clamp electrophysiology on freshly-isolated DSM cells, and functional studies on DSM contractility. qPCR experiments revealed that DSM samples from NDO patients showed decreased BK channel mRNA expression in comparison to controls. Patch-clamp experiments demonstrated reduced whole cell and transient BK currents (TBKCs) in freshly-isolated DSM cells from NDO patients. Functional studies on DSM contractility showed that spontaneous phasic contractions had a decreased sensitivity to iberiotoxin, a selective BK channel inhibitor, in DSM strips isolated from NDO patients. These results reveal the novel finding that NDO is associated with decreased DSM BK channel expression and function leading to increased DSM excitability and contractility. BK channel openers or BK channel gene transfer could be an alternative strategy to control NDO. Future clinical trials are needed to evaluate the value of BK channel opening drugs or gene therapies for NDO treatment and to identify any possible adverse effects.

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Section: Introductionmentioning

confidence: 99%

Neurogenic Detrusor Overactivity Is Associated with Decreased Expression and Function of the Large Conductance Voltage- and Ca2+-Activated K+ Channels

et al. 2013

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“…The long-term effectiveness of newer therapies such as mirabegron, a selective ␤ 3 -adrenoceptor agonist (6,9), and botulinum toxin (8,26,33) remains uncertain, and in some cases their use presents safety concerns (26,28). The lack of safe and universally effective OAB treatments continues to spur the scientific community to seek novel therapeutic approaches to control OAB.…”

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confidence: 96%

Novel regulatory mechanism in human urinary bladder: central role of transient receptor potential melastatin 4 channels in detrusor smooth muscle function

Hristov

Smith

Parajuli

et al. 2016

American Journal of Physiology-Cell Physiology

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Transient receptor potential melastatin 4 (TRPM4) channels are Ca(2+)-activated nonselective cation channels that have been recently identified as regulators of detrusor smooth muscle (DSM) function in rodents. However, their expression and function in human DSM remain unexplored. We provide insights into the functional role of TRPM4 channels in human DSM under physiological conditions. We used a multidisciplinary experimental approach, including RT-PCR, Western blotting, immunohistochemistry and immunocytochemistry, patch-clamp electrophysiology, and functional studies of DSM contractility. DSM samples were obtained from patients without preoperative overactive bladder symptoms. RT-PCR detected mRNA transcripts for TRPM4 channels in human DSM whole tissue and freshly isolated single cells. Western blotting and immunohistochemistry with confocal microscopy revealed TRPM4 protein expression in human DSM. Immunocytochemistry further detected TRPM4 protein expression in DSM single cells. Patch-clamp experiments showed that 9-phenanthrol, a selective TRPM4 channel inhibitor, significantly decreased the transient inward cation currents and voltage step-induced whole cell currents in freshly isolated human DSM cells. In current-clamp mode, 9-phenanthrol hyperpolarized the human DSM cell membrane potential. Furthermore, 9-phenanthrol attenuated the spontaneous phasic, carbachol-induced and nerve-evoked contractions in human DSM isolated strips. Significant species-related differences in TRPM4 channel activity between human, rat, and guinea pig DSM were revealed, suggesting a more prominent physiological role for the TRPM4 channel in the regulation of DSM function in humans than in rodents. In conclusion, TRPM4 channels regulate human DSM excitability and contractility and are critical determinants of human urinary bladder function. Thus, TRPM4 channels could represent promising novel targets for the pharmacological or genetic control of overactive bladder.

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“…Therefore, the guarding time for these patients to prevent urinary incontinence could be shorter than that for OAB patients in general. Intravesical onabotulinumtoxinA injections decrease detrusor contractility and also modulate afferent fibers in NDO [25]. A higher dose of onabotulinumtoxinA could impair detrusor contractility and sensory input too much, causing large PVR volumes, difficult urination, or overflow incontinence.…”

Section: Discussionmentioning

confidence: 99%

Efficacy and Safety of Intravesical OnabotulinumtoxinA Injection on Elderly Patients with Chronic Central Nervous System Lesions and Overactive Bladder

2014

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PurposeIntravesical injection of onabotulinumtoxinA is an effective treatment for overactive bladder (OAB). Nonetheless, the treatment outcome is unclear in OAB patients with central nervous system (CNS) lesions. This study evaluated the efficacy and safety of intravesical onabotulinumtoxinA treatment in elderly patients with chronic cerebrovascular accidents (CVAs), Parkinson’s disease (PD) and dementia.Materials and MethodsPatients with CVA, PD, dementia, and OAB refractory to antimuscarinic therapy were consecutively enrolled in the study group. Age-matched OAB patients without CNS lesions were selected to serve as a control group. OnabotulinumtoxinA (100 U) was injected into the bladder suburothelium at 20 sites. The clinical effects, adverse events, and urodynamic parameters were assessed at baseline and 3 months post-treatment. The Kaplan-Meier method was used to compare long-term success rates between groups.ResultsA total of 40 patients with OAB due to CVA (23), PD (9), dementia (8) and 160 control patients were included in this retrospetive analysis. Improvement of urgency severity scale, increased bladder capacity and increased post-void residual volume were comparable between the groups at 3 months. Patients with CNS lesions did not experience increased risks of acute urinary retention and urinary tract infection; nonetheless, patients with CVA experienced a higher rate of straining to void. Long-term success rates did not differ between the patients with and without CNS lesions.ConclusionIntravesical injection of 100 U of onabotulinumtoxinA effectively decreased urgency symptoms in elderly OAB patients with CNS lesions. The adverse events were acceptable, and long-term effects were comparable to OAB patients in general. Nonetheless, the possibility of longstanding urinary retention and chronic catheterization need careful evaluation for this very vulnerable population before choosing intravesical onabotulinumtoxinA treatment.

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Botulinum toxin A modulates afferent fibers in neurogenic detrusor overactivity

Abstract: These findings show that BoNT/A injected into the detrusor muscle in patients with PD and SCI modulates bladder afferent activity. Modulation of bladder afferents possibly explains why BoNT/A improves detrusor overactivity.

Cited by 30 publications

References 30 publications

Neurogenic Detrusor Overactivity Is Associated with Decreased Expression and Function of the Large Conductance Voltage- and Ca2+-Activated K+ Channels

Neurogenic Detrusor Overactivity Is Associated with Decreased Expression and Function of the Large Conductance Voltage- and Ca2+-Activated K+ Channels

Novel regulatory mechanism in human urinary bladder: central role of transient receptor potential melastatin 4 channels in detrusor smooth muscle function

Efficacy and Safety of Intravesical OnabotulinumtoxinA Injection on Elderly Patients with Chronic Central Nervous System Lesions and Overactive Bladder

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