MP17-08 NEUROGENIC BLADDER DYSFUNCTION IN A MURINE MODEL OF MULTIPLE SCLEROSIS IS CAUSED BY CORONOVIRUS-INDUCED DEMYELINATION OF THE NERVOUS SYSTEM

Abstract

INTRODUCTION AND OBJECTIVES: Neurogenic bladder dysfunction develops in patients with different neurodegenerative disorders including multiple sclerosis (MS). Lower urinary tract symptoms are reported in the majority of MS patients with the most common complaints of urinary urgency and frequency. The objective of this work was to evaluate neurogenic bladder dysfunction in a murine model of multiple sclerosis induced by a neurotrophic strain A59 of mouse hepatitis virus (MHV-A59). METHODS: Adult mice (C57BL/6J, 8 wks of age, N1⁄484) received single inoculation of MHV-A59 leading to the occurrence of coronavirus-induced encephalomyelitis (CIE). Animals were monitored daily for 4 wks for clinical signs of neurologic impairment. Clinical Symptom Score (CSS, 0-5) was assigned based on the level of tail tonicity, kyphosis and limb paresis/paralysis. Micturition patterns were assessed by filter paper assay and cystometric recordings in unrestrained mice. Contractile responses of the detrusor were evaluated in vitro by tension measurements in response to agonists and electric field stimulation (EFS). RESULTS: Inoculation with MHV-A59 virus induced a significant neural deficit with average CSS of 2.6 0.5 at 2 wks post-inoculation accompanied by 25 5 % of weight loss (p 0.001 to baseline). Histological analysis of spinal cord sections revealed multiple demyelinated lesions. Cystometric recordings confirmed neurogenic bladder overactivity at 4 wks post-inoculation including shortened inter-micturition interval, lower voided volume and elevated number of non-micturition contractions (p 0.05 to control group). In response to EFS, the cholinergic component of contraction was significantly reduced in mucosa intact CIE mouse bladders, while the atropine-resistant (purinergic) component was increased. Removal of the mucosa from CIE mouse bladders increased the cholinergic and decreased the purinergic components. CONCLUSIONS: Our results suggest that coronovirus-induced demyelination of the central nervous system causes the development of neurogenic bladder dysfunction that is similar to detrusor overactivity observed in MS patients. The underlying mechanisms may include an alteration in nerve-evoked contractions mediated by a urothelium dependent suppression of muscarinic and augmentation of purinergic mediated response in the bladder detrusor.