Animal modeling of lower urinary tract dysfunction associated with multiple sclerosis: Part I: Justification of the mouse model for MS research

Abstract

Lower urinary tract symptoms and dysfunction (LUTS/LUTD) contribute to loss of quality of life, morbidity, and need for medical intervention in most patients with multiple sclerosis (MS). Although MS is an inflammatory neurodegenerative disease, clinical manifestations including continence control disorders have traditionally been attributed to the loss of neural signaling due to neurodegeneration. Clinical approaches to MS-LUTS/LUTD have focused on addressing symptoms in the context of urodynamic dysfunctions as pathophysiologic understandings are incomplete. The mouse model provides a useful research platform for the discovery of more detailed molecular, cellular, and tissue-level knowledge of the disease and its clinical manifestations. The aim of this two-part review is to provide a state-of-the-art update on the use of the mouse model for MS research, with a focus on lower urinary tract symptoms. Part I presents a summary of the current understanding of MS pathophysiology, the impact on lower urinary tract symptoms, and briefly introduces the types of mouse models available to study MS. Part II presents the common animal models that are currently available to study MS, their mechanism, relevance to MS-LUTS/LUTD and their urinary pathophysiology, advantages, and disadvantages.

Keywords: animal model; bladder; mouse; multiple sclerosis.

Figure I:

The different disease courses of Multiple Sclerosis: Relapsing-remitting MS (RRMS), with relapses of disease separated by periods without clinical progression; Secondary progressive disease (SPMS), with steady clinical progression and gradual neurological deterioration following an initial relapsing disease process; Primary progressive MS, (PPMS), with clinical progression and neurological deterioration from the onset, most frequently without relapses; Progressive-relapsing MS (PRMS), the rarest variant (not shown here) with a few acute exacerbations superimposed on the gradual PPMS-like course. Brain atrophy starts from the beginning of the disease and increases over time as an indicator of total tissue-wasting. With time, neurodegeneration and the disease burden gradually increase.

Figure II:

Location of MS lesion (indicated by red spots) corresponding to the type of LUTD developed. A) The micturition circuit: includes the CNS connected to the bladder detrusor smooth muscle via afferent and efferent peripheral neurons. Effective communication between the CNS and bladder is key to ensure healthy bladder function. In the CNS, the pontine micturition center (PMC) located in the brainstem continuously receives the status of the bladder (full/empty) via afferent sensory neurons and is thought to act like an on/off switch by responding reflexes to the bladder to either void or keep filling based on the input received. The PMC relays these commands downstream using myelinated neurons that project into the lumbosacral spinal cord, from where the efferent peripheral sympathetic and parasympathetic neurons project into the bladder detrusor smooth muscles and urethral sphincter to facilitate urination. Upstream, the PMC receives projections from the prefrontal cortex which is also rich in myelinated neurons; B) Lesions in the cortex, above the pontine micturition center (PMC): leads to loss of cortical/voluntary inhibition of the brainstem/PMC detrusor reflex, resulting in neurogenic detrusor overactivity (NDO); C) Lesions between PMC and lumbosacral spinal cord: leads to loss of coordination between the sphincter and the detrusor characterized by detrusor sphincter dyssynergia (DSD), and clinically can result in high-pressure obstructive voiding, voiding inefficiency, and potentially urinary retention. Neurogenic detrusor overactivity with DSD (NDO-DSD) mechanistically describes the incontinence resulting from NDO-induced pressure exceeding the resistance of the reflex closed urethra. Additionally, formerly quiescent afferent C fibers can become mechanosensitive and respond to bladder stretch, leading to NDO without outlet obstruction; D) Lesions at the sacral cord: Loss of motor innervation of the detrusor due to sacral lesions compromises the strength and durability of voiding detrusor contraction, resulting in detrusor under-activity (DU) or contractility. In addition, loss of urethral (sphincter) resistance due to loss of neuromuscular contractile drive can cause incontinence. Created with BioRender.com