Effect of Botulinum Toxin A on Neurogenic Detrusor Overactivity in Chronic Spinal Cord Injured Patients - An Investigation of Sensory Receptor Expressionsbetween Responders and Non-responders

In recent decades, treatment of neurogenic detrusor overactivity (NDO) with onabotulinumtoxinA has emerged as an alternative method for the management of urological complications due to spinal cord injury (SCI) or multiple sclerosis. Injection of 200-300 U of onabotulinumtoxinA into the detrusor muscle can reduce contractility, improve bladder compliance, and restore urinary continence in patients with NDO. However, detrusor underactivity will develop after injection of 300 U of onabotulinumtoxinA and improvement of urodynamic and quality of life parameters lasted 9 months. Currently, a 200 U single injection of onabotulinumtoxinA into the detrusor has been recommended as standard treatment for NDO. However, the therapeutic duration of this dosage on NDO was shorter than that of a 300 U injection.

OnabotulinumtoxinA effectively improves lower urinary tract symptoms by inhibiting signal transmission at the neuromuscular and neuroglandular junctions. OnabotulinumtoxinA cleaves synaptosome-associated protein 25 and inhibits signal transmission by disrupting fusion of neurotransmitter- containing vesicles with the neuronal wall. In the urinary bladder, release of acetylcholine from both pre- and postganglionic parasympathetic nerves is blocked after onabotulinumtoxinA administration. This toxin was also found to modulate afferent activity of the bladder associated with reduced urgency and urgency urinary incontinence symptoms in NDO patients. Although the impact of onabotulinumtoxinA on the sympathetic nervous system within the urinary bladder is unclear, it has an inhibitory effect on release of norepinephrine to α- and β3-adrenoreceptors (β3-ARs) which regulate bladder neck contraction and detrusor relaxation, respectively.

A previous study reported decreased expression of adhesion and junction proteins E-cadherin and zonula occludens-1 (ZO-1), respectively, and increased suburothelial inflammation with apoptosis in patients with chronic SCI bladders.The urothelial inflammation and dysfunction in SCI bladders might also alter sensory protein expression, such as in purinergic receptor P2X3, transient receptor potential vallinoid receptor subfamily 1, adenosine triphosphate, and nitric oxide. Urothelial dysfunction might also result in increased excitability of the C-fibers which become predominantly afferent nerves of the micturition reflex after SCI. In humans with NDO, the levels of bladder P2X2, P2X3, and muscarinic receptors M2 and M3 were reduced after detrusor onabotulinumtoxinA injection, suggesting this toxin inhibits DO by inhibiting both the sensory and motor arms of the micturition reflex. In addition, β3-ARs are known to promote urine storage in the bladder by inducing detrusor relaxation in animal and human bladders. In humans, β3-AR is the predominant β-receptor subtype in the urinary bladder. There has been no report on β3-AR changes in SCI bladder urothelium before or after onabotulinumtoxin treatment.

After onabotulinumtoxinA injection, patients may be symptom-free for a period of 3-6 months before symptoms relapse. Most studies of onabotulinumtoxinA on NDO come from animal models, and only a few human studies have been noted. The current study investigated changes in urothelial dysfunction and sensory protein expression in the bladder urothelium with time after a single onabotulinumtoxin injection in SCI patients.

Materials and Methods