Current Knowledge and Novel Frontiers in Lower Urinary Tract Dysfunction after Spinal Cord Injury

Abstract

This review article aims to summarize the recent advancement in basic research on lower urinary tract dysfunction (LUTD) following spinal cord injury (SCI) above the sacral level. We particularly focused on the neurophysiologic mechanisms controlling the lower urinary tract (LUT) function and the SCI-induced changes in micturition control in animal models of SCI. The LUT has two main functions, the storage and voiding of urine, that are regulated by a complex neural control system. This neural system coordinates the activity of two functional units in the LUT: the urinary bladder and an outlet including bladder neck, urethra, and striated muscles of the pelvic floor. During the storage phase, the outlet is closed and the bladder is quiescent to maintain a low intravesical pressure and continence, and during the voiding phase, the outlet relaxes and the bladder contracts to promote efficient release of urine. SCI impairs voluntary control of voiding as well as the normal reflex pathways that coordinate bladder and sphincter function. Following SCI, the bladder is initially areflexic but then becomes hyperreflexic due to the emergence of a spinal micturition reflex pathway. However, the bladder does not empty efficiently because coordination between the bladder and urethral sphincter is lost. In animal models of SCI, hyperexcitability of silent C-fiber bladder afferents is a major pathophysiological basis of neurogenic LUTD, especially detrusor overactivity. Reflex plasticity is associated with changes in the properties of neuropeptides, neurotrophic factors, or chemical receptors of afferent neurons. Not only C-fiber but also Aδ-fiber could be involved in the emergence of neurogenic LUTD such as detrusor sphincter dyssynergia following SCI. Animal research using disease models helps us to detect the different contributing factors for LUTD due to SCI and to find potential targets for new treatments.

Molecular Mechanism Operating in Animal Models of Neurogenic Detrusor Overactivity: A Systematic Review Focusing on Bladder Dysfunction of Neurogenic Origin

“…While it is difficult to grasp and integrate the enormous number of published results, it is clear that NDO pathophysiology is complex and, consequently, its treatment and management is difficult. Like other researchers [ 18 ] and following the present review, we propose that many key players are active and interacting at different stages of disease progression. It is likely that future interventions will result from the combination of different drugs simultaneously targeting different molecules.…”

“…The fine molecular mechanisms involved in NDO emergence and maintenance are currently better understood [ 18 ], but remain challenging for clinicians and researchers. A fully effective treatment, able to revert urinary dysfunction, remains to be identified and there is ample need to improve symptomatic care for NDO patients and, as a consequence, their quality of life.…”

Schwann cell-derived exosomes containing MFG-E8 modify macrophage/microglial polarization for attenuating inflammation via the SOCS3/STAT3 pathway after spinal cord injury

“…After SCI, long-term dysuria and urine retention will lead to the hypertrophy of the bladder wall with a high ratio of collagen to muscle [ 30 , 31 ]. It was found that the thickness of the bladder wall after SCI was correlated with the recovery of bladder function, and that the mechanism might cause changes in altered c-fiber efferent activity [ 31 – 33 ] and the expression of some protein receptors [ 34 – 37 ]. Our electrophysiological assay has shown that SCDEs can promote the recovery of nerve conduction function after SCI by inhibiting inflammation, which may involve an improvement in the activity of C-afferent fibers.…”

Vinpocetine Ameliorates Metabolic-Syndrome-Associated Bladder Overactivity in Fructose-Fed Rats by Restoring Succinate-Modulated cAMP Levels and Exerting Anti-Inflammatory Effects in the Bladder Detrusor Muscle

“…Rahnamai et al [ 37 ] reported the roles of prostaglandins and PDE in the development of proinflammatory OABs and suggested treatment with COX-2 inhibitors and PDE inhibitors for OABs. Accordingly, celecoxib was included in the present study as a reference treatment for OABs [ 38 , 39 ]. The inclusion of celecoxib in the experimental design also helped to consolidate the conclusion on the dual protective actions of vinpocetine on MetS-associated OABs via the anti-inflammation and preservation of cAMP in the detrusor muscles ( Figure 7 ).…”