Molecular Mechanisms of Neurogenic Lower Urinary Tract Dysfunction after Spinal Cord Injury

Abstract

This article provides a synopsis of current progress made in fundamental studies of lower urinary tract dysfunction (LUTD) after spinal cord injury (SCI) above the sacral level. Animal models of SCI allowed us to examine the effects of SCI on the micturition control and the underlying neurophysiological processes of SCI-induced LUTD. Urine storage and elimination are the two primary functions of the LUT, which are governed by complicated regulatory mechanisms in the central and peripheral nervous systems. These neural systems control the action of two functional units in the LUT: the urinary bladder and an outlet consisting of the bladder neck, urethral sphincters, and pelvic-floor striated muscles. During the storage phase, the outlet is closed, and the bladder is inactive to maintain a low intravenous pressure and continence. In contrast, during the voiding phase, the outlet relaxes, and the bladder contracts to facilitate adequate urine flow and bladder emptying. SCI disrupts the normal reflex circuits that regulate co-ordinated bladder and urethral sphincter function, leading to involuntary and inefficient voiding. Following SCI, a spinal micturition reflex pathway develops to induce an overactive bladder condition following the initial areflexic phase. In addition, without proper bladder-urethral-sphincter coordination after SCI, the bladder is not emptied as effectively as in the normal condition. Previous studies using animal models of SCI have shown that hyperexcitability of C-fiber bladder afferent pathways is a fundamental pathophysiological mechanism, inducing neurogenic LUTD, especially detrusor overactivity during the storage phase. SCI also induces neurogenic LUTD during the voiding phase, known as detrusor sphincter dyssynergia, likely due to hyperexcitability of Aδ-fiber bladder afferent pathways rather than C-fiber afferents. The molecular mechanisms underlying SCI-induced LUTD are multifactorial; previous studies have identified significant changes in the expression of various molecules in the peripheral organs and afferent nerves projecting to the spinal cord, including growth factors, ion channels, receptors and neurotransmitters. These findings in animal models of SCI and neurogenic LUTD should increase our understanding of pathophysiological mechanisms of LUTD after SCI for the future development of novel therapies for SCI patients with LUTD.

Keywords: Aδ-fiber afferent; C-fiber afferent; detrusor overactivity; detrusor–sphincter dyssynergia; fibrosis; spinal-cord injury.

Figure 1

Human CMG and EUS-EMG recordings are representative. (A) Cystometry and EUS-EMG recordings under normal conditions reveal that voluntary bladder contraction induces synergic urethral relaxation. (B) After spinal-cord damage, cystometry and EUS-EMG recordings reveal uninhibited bladder contractions (detrusor overactivity) and detrusor sphincter dyssynergia. EUS-EMG: external urethral sphincter electromyography.

Figure 2

Diagram showing hypothetical mechanisms underlying storage and voiding dysfunction induced by increased expression of neurotrophic factors following SCI. Injury to the spinal cord causes DSD, leading to functional urethral obstruction, reduced voiding efficiency, urinary retention, and bladder hypertrophy, resulting in increased levels of NGF in the bladder. NGF is taken up by TrkA-expressing C-fiber afferent nerves and transported to lumbosacral DRG cells and central afferent nerve terminals. The levels of NGF are also increased in the spinal cord after SCI. NGF then sensitizes C-fiber bladder afferent pathways to cause or enhance neurogenic DO in SCI. BDNF is also increased in the bladder and the spinal cord after SCI. BDNF is expressed on larger sized bladder afferent neurons, presumably Aδ-fiber afferents, which express mechanosensitive receptors such as ASIC, and Piezo2. Hyperexcitability of Aδ-fiber bladder afferent pathways causes or enhances DSD, leading to inefficient voiding. Systemic application of BDNF antibodies reduces BDNF levels in bladder afferent pathways and improves DSD. SCI: spinal-cord injury, DSD: detrusor-sphincter dyssynergia, NGF: nerve growth factor, DRG: dorsal root ganglion, DO: detrusor overactivity, BDNF: brain-derived neurotrophic factor. Arrows indicate the increase or decrease of molecules.

Figure 3

Summary of the potential molecular targets for the treatments of LUTD after SCI. Multiple targets for the better/new treatments of LUTD due to SCI were reviewed in this article. Some targets are responsible for the storage dysfunction, such as DO, and others are for the voiding dysfunction, such as DSD and inefficient voiding. These molecular targets could hopefully be translated for the development of future clinical treatment modalities of SCI patients with LUTD.