Evaluating potential therapies for bladder dysfunction in a mouse model of multiple sclerosis with high-resolution ultrasonography

Abstract

Background

In multiple sclerosis (MS), demyelinating and neurodegenerative lesions develop throughout the central nervous system, which result in a loss of neurotransmission. As a result, people with MS exhibit a wide range of symptoms including dysfunction of the bladder, which can lead to urinary incontinence or retention. Such signs can develop in animal models of MS. Current assessments of bladder properties in animal models are generally invasive, electrophysiological techniques.

Objective

The use of a non-invasive, ultrasound system for measuring bladder volume in a mouse model of MS.

Methods

Chronic relapsing experimental autoimmune encephalomyelitis was induced in mice. The bladder volume was assessed using ultrasonography, during the disease course and following therapy with bethanechol chloride.

Results

It was demonstrated that volumes obtained ultrasonically positively-correlated (r = 0.960) with the urine volumes obtained by manual expression. It was also shown for the first time that bladder size increased significantly in mice with residual neurological deficit. Indeed, this increase in bladder size showed a strong, positive-correlation (r = 0.951) with the hind limb spasticity. Following treatment with bethanechol chloride, bladder volume significantly decreased in mice with chronic experimental autoimmune encephalomyelitis.

Conclusion

This study demonstrates a novel outcome measure in experimental MS that allows; repeated, non-invasive, high resolution ultrasonic monitoring of bladder function.

Keywords

bladder experimental autoimmune encephalomyelitis multiple sclerosis spasticity therapy ultrasound

Get full access to this article

View all access options for this article.

References

1 Compston A Coles A . Multiple sclerosis. Lancet 2002; 359: 1221–1231.

2 Haensch CA Jorg J . Autonomic dysfunction in multiple sclerosis. J Neurol 2006; 253(Suppl. 1): I3–I9.

3 Litwiller SE Frohman EM Zimmern PE . Multiple sclerosis and the urologist. J Urol 1999; 161: 743–757.

4 Fowler CJ Griffiths D de Groat WC . The neural control of micturition. Nat Rev Neurosci 2008; 9: 453–466.

5 Kalsi V Fowler CJ . Therapy Insight: bladder dysfunction associated with multiple sclerosis. Nat Clin Pract Urol 2005; 2: 492–501.

6 Chancellor MB Anderson RU Boone TB . Pharmacotherapy for neurogenic detrusor overactivity. Am J Phys Med Rehabil 2006; 85: 536–545.

7 McMahon SB Abel C . A model for the study of visceral pain states: chronic inflammation of the chronic decerebrate rat urinary bladder by irritant chemicals. Pain 1987; 28: 109–127.

8 McMahon SB . Neuronal and behavioural consequences of chemical inflammation of rat urinary bladder. Agents Actions 1988; 25: 231–233.

9 Mizusawa H Igawa Y Nishizawa O Ichikawa M Ito M Andersson KE . A rat model for investigation of bladder dysfunction associated with demyelinating disease resembling multiple sclerosis. Neurourol Urodyn 2000; 19: 689–699.

10.

10 Vignes JR Deloire MS Petry KG Nagy F . Characterization and restoration of altered inhibitory and excitatory control of micturition reflex in experimental autoimmune encephalomyelitis in rats. J Physiol 2007; 578: 439–450.

11.

11 Altuntas CZ; Daneshgari F; Liu G; . Bladder dysfunction in mice with experimental autoimmune encephalomyelitis. J Neuroimmunol 2008; 203: 58–63.

12.

12 Kornhuber HH Schutz A . Efficient treatment of neurogenic bladder disorders in multiple sclerosis with initial intermittent catheterization and ultrasound-controlled training. Eur Neurol 1990; 30: 260–267.

13.

13 Fowler CJ . Investigation of the neurogenic bladder. J Neurol Neurosurg Psychiatry 1996; 60: 6–13.

14.

14 Keirstead HS Fedulov V Cloutier F Steward O Duel BP . A noninvasive ultrasonographic method to evaluate bladder function recovery in spinal cord injured rats. Exp Neurol 2005; 194: 120–127.

15.

15 Baker D O’Neill JK Gschmeissner SE Wilcox CE Butter C Turk JL . Induction of chronic relapsing experimental allergic encephalomyelitis in Biozzi mice. J Neuroimmunol 1990; 28: 261–270.

16.

16 Baker D Pryce G Croxford JL . Cannabinoids control spasticity and tremor in a multiple sclerosis model. Nature 2000; 404: 84–87.

17.

17 Osinski MA Seifert TR Cox BF Gintant GA . An improved method of evaluation of drug-evoked changes in gastric emptying in mice. J Pharmacol Toxicol Methods 2002; 47: 115–120.

18.

18 Araki I Matsui M Ozawa K Takeda M Kuno S . Relationship of bladder dysfunction to lesion site in multiple sclerosis. J Urol 2003; 169: 1384–1387.

19.

19 Ukkonen M Elovaara I Dastidar P Tammela TL . Urodynamic findings in primary progressive multiple sclerosis are associated with increased volumes of plaques and atrophy in the central nervous system. Acta Neurol Scand 2004; 109: 100–105.

20.

20 Cabranes A Pryce G Baker D Fernandez-Ruiz J . Changes in CB1 receptors in motor-related brain structures of chronic relapsing experimental allergic encephalomyelitis mice. Brain Res 2006; 1107: 199–205.

21.

21 Pryce G Ahmed Z Hankey DJ . Cannabinoids inhibit neurodegeneration in models of multiple sclerosis. Brain 2003; 126: 2191–2202.

22.

22 Brown P . Pathophysiology of spasticity. J Neurol Neurosurg Psychiatry 1994; 57: 773–777.

23.

23 Awad SA Wilson JW Fenemore J Kiruluta HG . Dysfunction of the detrusor and urethra in multiple sclerosis: the role of drug therapy. Can J Surg 1982; 25: 259–262.

24.

24 el-Salmy S Downie JW Awad SA . Bladder and urethral function and supersensitivity to subcutaneously administered bethanechol in cats with chronic cauda equina lesions. J Urol 1985; 134: 1011–1018.