Nerve growth factor in bladder dysfunction: Contributing factor, biomarker, and therapeutic target

Abstract

In the last two decades, nerve growth factor (NGF), initially described as a prototypical trophic factor in the development of sensory and sympathetic innervation, has emerged as a complex regulator of neural plasticity along the micturition pathways. This review aims to summarize the current experimental and clinical evidence for a role of NGF in urinary bladder. Experimental administration of NGF elicits the states of increased sensation, urgency, and bladder hyperreflexia, resembling pathologies associated with bladder overactivity and inflammatory pain, such as overactive bladder syndrome (OAB) and interstitial cystitis/painful bladder syndrome (IC/PBS). There is strong experimental evidence, including the effective therapeutic targeting, on the direct causal role of NGF in rodent models of bladder outlet obstruction, spinal cord injury, diabetic bladder dysfunction, and interstitial inflammation. In humans, there are attempts to employ urinary NGF levels as a diagnostic marker in various forms of OAB and IC/PBS. In near future, use of novel experimental tools, such as urothelium-specific NGF transgenic mice or more specific low-molecular weight NGF receptor modulators, may provide better understanding of several unresolved issues in NGF-related bladder dysfunction. Moreover, successful experimental therapeutic approaches, such as NGF sequestering proteins or modified NGF antibodies, await the translation to the clinical treatment of bladder disorders.

Urothelial Signaling

“…The urothelium is a prominent site of NGF expression in several species (221). Abundant NGF staining was reported in the urothelium of normal rats with a weaker signal in detrusor muscle.…”

“…The urothelium seems to be a site with abundant expression of both NGF and its receptors, and NGF has been found to be elevated in the bladders and urine of patients with various types of storage LUTS, including BOO due to benign prostate hyperplasia (BPH), diabetic cystopathy, NDO (often caused by spinal cord injury), and IDO (with no apparent underlying pathology), BPS/IC, and also in models of bladder inflammation in animals (187,221). Bladder NGF lowers the threshold for bladder TRPV1 signaling, and TRPV1 is essential for NGF-driven bladder dysfunction (105).…”

The Role of Brain-Derived Neurotrophic Factor (BDNF) in the Development of Neurogenic Detrusor Overactivity (NDO)

“…In the bladder significant cellular remodeling occurs, including smooth muscle hypertrophy, patchy denervation, and changes in interstitial cell (IC) populations (Johnston et al, 2012). Several studies suggest that neurotrophins (NTs) may be important mediators of such plastic changes (Ochodnický et al, 2011(Ochodnický et al, , 2012Cruz, 2014), in particular, NGF, a neurotrophin that plays a key role in the regulation of the peripheral nervous system Vizzard, 2006). Immunoneutralization of this NT has been shown to block bladder dysfunction in SCI rats (Seki et al, 2002(Seki et al, , 2004.…”

Enhanced production of nitric oxide may contribute to the induction of detrusor underactivity in sucrose fed rats

“…Alterations in the bladder levels of some of these transmitters have been considered as useful biomarkers for assessing LUTS [6]. For instance, detrusor overactivity, bladder outlet obstruction or painful bladder syndrome usually show alterations in the normal levels for ATP, nerve growth factor or NO [7][8][9][10]. Although DU can be observed in disorders where either the efferent or the afferent branches of the micturition reflex have been impaired [11], other potential changes in sensory transmitters are poorly understood [2].…”