Coronavirus-induced demyelination of neural pathways triggers neurogenic bladder overactivity in a mouse model of multiple sclerosis

McMillan, Matthew T.; Pan, Xiaoqing; Smith, Ariana L.; Newman, Diane K.; Weiss, Susan R.; Ruggieri, Michael R.; Malykhina, Anna P.

doi:10.1152/ajprenal.00151.2014

Cited by 19 publications

(53 citation statements)

References 49 publications

(81 reference statements)

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“…At 4 weeks post-inoculation, the average CSS for CIE mice is approximately 1 [14] , [15] . The average maximum CSS for the mice used in this study was 2.0±0.12 (range 1–5).…”

Section: Resultsmentioning

confidence: 99%

“…A Clinical Symptom Score (CSS) was determined for each animal following induction of CIE based on the following observations: 0, normal with no clinical signs; 1, loss of tail tonicity/kyphosis; 2, tail paralysis/severe kyphosis; 3, partial hind limb paralysis; 4, complete hind limb paralysis; 5, complete hind limb paralysis and forelimb paresis/paralysis. In this model, most animals show significant CSS scores within a few days and the CSS score peaks 2 weeks post-inoculation and then declines [14] , [15] . Thus, CSS scores were determined for each animal until the CSS score declined for 3 days, usually during the second week.…”

Section: Methodsmentioning

confidence: 92%

“…CIE in mice leads to neurogenic detrusor overactivity, which has recently been characterized [14] , [15] . Cystometry recordings in awake, unrestrained animals revealed that CIE mice have shortened inter-micturition intervals, lower voided volumes, and an elevated number of non-voiding contractions in comparison with controls.…”

Section: Discussionmentioning

confidence: 99%

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Alterations in Nerve-Evoked Bladder Contractions in a Coronavirus-Induced Mouse Model of Multiple Sclerosis

et al. 2014

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BackgroundPatients with neurodegenerative diseases such as multiple sclerosis, Parkinson’s, and Alzheimer’s often present with lower urinary tract symptoms (LUTS, urinary frequency, urgency, nocturia and retention) resulting from damage to the peripheral and central nervous systems. These studies were designed to examine the changes in the function of the bladder that may underlie neurogenic bladder dysfunction using a mouse model of demyelination in the CNS.MethodsBladders from 12 week old male C57BL/6J mice with coronavirus-induced encephalomyelitis (CIE, a chronic, progressive demyelinating disease model of human MS), and age-matched controls, were cut into 5–7 strips and suspended in physiological muscle baths for tension measurement in response to agonists and electric field stimulation (EFS). Experiments were performed on intact and denuded (with mucosa removed) bladder strips.ResultsThe maximum effect of EFS was not significantly different between CIE and control bladders. Nerve-evoked EFS contractions (tetrodotoxin-sensitive) were blocked by a combination of atropine (cholinergic antagonist) and α,β-methylene ATP (an ATP analog that desensitizes purinergic receptors). In response to EFS, the α,β-methylene ATP-resistant (cholinergic) component of contraction was significantly reduced, while the atropine-resistant (purinergic) component was significantly increased in CIE bladders. Removal of the mucosa in CIE bladders restored the cholinergic component. Bethanechol (muscarinic receptor agonist) potency was significantly increased in CIE bladders.ConclusionsOur data demonstrate a deficit in the nerve-evoked cholinergic component of contraction that is not due to the ability of the smooth muscle to respond to acetylcholine. We conclude that neurodegenerative bladder dysfunction in this model of multiple sclerosis may be due, in part, to pathologic changes in the mucosa that causes suppression of muscarinic receptor-mediated contractile response and augmentation of purinergic response of the underlying muscle. Further studies utilizing CIE mice should help elucidate the pathological changes in the mucosa resulting from demyelination in the CNS.

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“…At 4 weeks post-inoculation, the average CSS for CIE mice is approximately 1 [14] , [15] . The average maximum CSS for the mice used in this study was 2.0±0.12 (range 1–5).…”

Section: Resultsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 92%

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Alterations in Nerve-Evoked Bladder Contractions in a Coronavirus-Induced Mouse Model of Multiple Sclerosis

et al. 2014

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“…Spontaneous void spot assay. To evaluate voiding habits, void spot assays were conducted at 3, 7, and 14 days after the surgery as previously described (n ϭ 12 per group) (25,47). Briefly, mice were individually placed onto a steel wire mesh (0.64-cm 2 opening) floor elevated from the cage bottom by 1 cm in a clean cage.…”

Section: Methodsmentioning

confidence: 99%

“…The catheter was tunneled subcutaneously and exteriorized at the scapula region, where it was sutured to the skin. The catheter was filled with sterile saline after confirming no leakage at the bladder and then plugged to prevent leakage (25). The abdominal incision was closed, and animals were transferred to individual cages after the recovery from anesthesia.…”

Section: Methodsmentioning

confidence: 99%

Preventative effects of a HIF inhibitor, 17-DMAG, on partial bladder outlet obstruction-induced bladder dysfunction

Iguchi

Dönmez

Malykhina

et al. 2017

American Journal of Physiology-Renal Physiology

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Posterior urethral valves are the most common cause of partial bladder outlet obstruction (PBOO) in the pediatric population. Pathological changes in the bladder developed during PBOO are responsible for long-lasting voiding dysfunction in this population despite early surgical interventions. Increasing evidence showed PBOO induces an upregulation of hypoxia-inducible factors (HIFs) and their transcriptional target genes, and they play a role in pathophysiological changes in the obstructed bladders. We hypothesized that blocking HIF pathways can prevent PBOO-induced bladder dysfunction. PBOO was surgically created by ligation of the bladder neck in male C57BL/6J mice for 2 wk. PBOO mice received intraperitoneal injection of either saline or 17-DMAG (alvespimycin, 3 mg/kg) every 48 h starting from postsurgery. Sham-operated animals received injection of saline on the same schedule as PBOO mice and served as controls. The bladders were harvested after 2 wk, and basal activity and evoked contractility of the detrusor smooth muscle (DSM) were evaluated in vitro. Bladder function was assessed in vivo by void spot assay and cystometry in conscious, unrestrained mice. Results indicated the 17-DMAG treatment preserved DSM contractility and partially prevented the development of detrusor over activity in obstructed bladders. In addition, PBOO caused a significant increase in the frequency of micturition, which was significantly reduced by 17-DMAG treatment. The 17-DMAG treatment improved urodynamic parameters, including increases in the bladder pressure at micturition and nonvoid contractions observed in PBOO mice. These results demonstrate that treatment with 17-DMAG, a HIF inhibitor, significantly alleviated PBOO-induced bladder pathology in vivo.

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Cuprizone‐mediated demyelination reversibly degrades voiding behavior in mice while sparing brainstem reflex

Ramasamy

Hardy

Crocker

et al. 2022

J of Neuroscience Research

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Multiple sclerosis (MS) is a chronic, progressively debilitating demyelinating disease of the central nervous system (CNS). Nearly 80% of MS patients experience lower urinary tract dysfunction early in their diagnosis. This significantly affects the quality of life, and in latter stages of disease is a leading cause of hospitalization. Previously, animal models have shown that inflammatory demyelination in the CNS causes profound bladder dysfunction, but the confounding influence of systemic inflammation limits the potential interpretation of the contribution of CNS demyelination to bladder dysfunction. Since the micturition circuit has myelinated neuronal connections in the cortex, brainstem, and spinal cord, we examined alterations in bladder function in the cuprizone model characterized by demyelinating lesions in the cortex and corpus callosum that are independent of T‐cell–mediated autoimmunity. Herein, we report that a 4‐week dietary cuprizone treatment in C57Bl/6J mice induced alterations in voiding behavior with increased micturition frequency and reduced volume voided, similar to human MS bladder dysfunction. Subsequently, recovery from cuprizone treatment restored normal bladder function. Demyelination and remyelination were confirmed by Luxol Fast Blue staining of the corpus callosum. Additionally, we also determined that an 8‐week cuprizone treatment, resulting in chronic demyelination lacking spontaneous remyelination potential, is associated with an exacerbated voiding phenotype. Interestingly, while cuprizone‐induced CNS demyelination severely affected conscious (cortical) urinary behavior, the brainstem and spinal cord reflex remained unchanged, as confirmed by urethane‐anesthetized cystometry. This is the first study to show that cortical demyelination independent of inflammation can negatively impact urinary function.

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Coronavirus-induced demyelination of neural pathways triggers neurogenic bladder overactivity in a mouse model of multiple sclerosis

Cited by 19 publications

References 49 publications

Alterations in Nerve-Evoked Bladder Contractions in a Coronavirus-Induced Mouse Model of Multiple Sclerosis

Alterations in Nerve-Evoked Bladder Contractions in a Coronavirus-Induced Mouse Model of Multiple Sclerosis

Preventative effects of a HIF inhibitor, 17-DMAG, on partial bladder outlet obstruction-induced bladder dysfunction

Cuprizone‐mediated demyelination reversibly degrades voiding behavior in mice while sparing brainstem reflex

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