RICERCA ITALIANA     

Nerve Growth Factor (NGF) bladder tissue levels in patients with detrusor overactivity before and after therapy and relationship with lipid mediators production.

Università degli Studi di Perugia

Abstract

Experimental studies indicate that detrusor overactivity after neurogenic disease (spinal cord injury) or non neurogenic bladder outlet obstruction (BOO) may be induced by an enhancement of the micturition reflex mediated by the action of Nerve Growth Factor (NGF) at the level of C afferent fibers into the bladder wall. Indeed, recent observations indicate that other complex mechanisms may be implicated in the genesis and in the maintaining of detrusor overactivity after BOO.
Endogenous cannabinoids (anandamide), are able to relief detrusor overactivity induced by intravesical administration of NGF by means of a inhibitory action at the level of C afferent fibers. Some products of oxidative stress, as intravesical isoprostanes, may determine an excitatory influence on the development of the dysfunction. In addition, human bladder is able to produce prostaglandins by the cyclooxygenase (COX) pathway, which appear to be also involved in involuntary bladder contractions. All these mechanisms have to be investigated and confirmed in humans.
Treatment of detrusor overactivity may rely on the block of the afferent arm of the micturition reflex. Vanilloid agents, used intravesically, by interacting with specific receptors induce desensitation of the C afferent fibers. They have been shown to increase bladder capacity and decrease urge incontinence in patients with neurogenic, as well as non neurogenic forms of detrusor overactivity. Intravesical injection of >>>

Principal Investigator

Massimo PORENA Università degli Studi di PERUGIA

Research Objectives

Detrusor overactivity is a urodynamic dysfunction characterized by the presence of uninhibited detrusor contractions during the filling phase of the micturition reflex. It may be due to neurogenic or non neurogenic causes and, in both cases, the physiopathological explanation is a concomitant condition of bladder outlet obstruction. Recent experimental and clinical evidences suggest that both neurogenic and non neurogenic detrusor overactivity are induced at least in part by phenotypic changes in unmyelinated C-fiber bladder afferent pathways, mediated by the action of a neurothrophic factor, named Nerve Growth Factor (NGF). NGF increases in hypertrophied bladders in rats with spinal cord injury or with a partial urethral ligation. NGF determines an upregulation of receptors at the level of the afferent C fibers, which become mechanoreceptors and initiate the voiding reflex.
In the pathophysiology of detrusor overactivity, an important role seems to be performed by oxidative stress markers. Isoprostanes, prostaglandin-like end products of arachidonic acid peroxidation, are produced by a free radical-catalyzed mechanism and are unique markers of oxidative stresses; it seems that they should be involved in the genesis or maintaining of detrusor overactivity. In addition, human bladder is able to produce prostaglandins by the cyclooxygenase (COX) pathway which appear to be also involved in involuntary bladder contractions. However, it is still unclear whether >>>

First Results

Statistical analysis
Initially, a technique of exploratory data analysis can be applied, followed by a multivariate analysis to investigate the relationships among different variables in the study.
Moreover, the most important factor in the design of the present study is the sample-size to obtain an adequate statistical power.
In a previous study (unpublished preliminary results), the following results have been obtained in patients with neurogenic detrusor overactivity and bladder outlet obstruction:
NGF. NGF bladder content: 151.9 ± 64.6 (ng/ml)
UDC-t. Uninhibited detrusor contractions threshold: 163.2 ± 61.4 (ml)
UDC-p. Uninhibited detrusor contractions pressure: 55.1 ± 18.5 (cmH20)
CBC. Cystometric bladder capacity: 228.6 ± 75.6 (ml)
A usefull sample size can be obtained by hypotizing that the variables in the study can be very close to the normal distribuition.
In the following table, sample- sizes per group needed to obtain a statistical power (1-b) of 0.80, by assuming the coefficient a=0.05 for some effect sizes (in increases or reductions) are reported.

Variables Effect-size
--------------- 10%---- 20%---- 30%---40%
NGF--(ng/ml)--- 284---- 71---- 32------18
UDC-t--(ml)---- 223---- 56---- 25------14
UDC-p-(cmH2O)-178---- 45---- 20------11
CBC--(ml)------ 173---- 43---- 20------11

As in the above mentioned study variation rates between 35 >>>

Timescale

24 months

National and international background

Detrusor overactivity is a urodynamic dysfunction characterized by the presence of uninhibited detrusor contractions, leading to urinary incontinence, during the filling phase of the micturition reflex. It may be due to neurogenic or non neurogenic causes and, in both cases, the physiopathological explanation is a concomitant condition of bladder outlet obstruction (BOO) . 1
Spinal cord injury rostral to the lumbosacral level impairs voluntary and supraspinal control of voiding, leading to reorganization of the neural pathways regulating bladder and urethral sphincter function. 2 Spinal cord injury initially induces an areflexic bladder and urinary retention, followed by the emergence of automatic voiding mediated by spinal reflex mechanisms. The bladder become hyperactive and bladder sphincter coordination is impaired (detrusor sphincter dyssynergia), leading to outlet obstruction.2 These lower urinary tract dysfunction then produce various problems, such as urinary incontinence, recurrent urinary tract infections and vesicoureteral reflux with or without upper urinary tract deterioration.
Clinical and experimental studies indicate that detrusor overactivity after spinal cord injury or different types of obstruction are induced at least in part by phenotypic changes in unmyelinated C-fiber bladder afferent pathways. 1,3 Multiple mechanisms may be involved in the plasticity of bladder afferent neurons in pathological conditions. For example, it has been >>>