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

Area of Science:

• Neuroscience
• Urology
• Pathology

Background:

• Multiple sclerosis (MS) is a CNS demyelinating disease impacting nearly 80% of patients with lower urinary tract dysfunction.
• Existing animal models often involve systemic inflammation, confounding the specific role of CNS demyelination in bladder dysfunction.

Purpose of the Study:

• To investigate the impact of CNS demyelination, independent of autoimmunity, on bladder function using the cuprizone model.
• To determine if cortical demyelination contributes to urinary dysfunction observed in MS patients.

Main Methods:

• Mice were fed a cuprizone-containing diet for 4 or 8 weeks to induce demyelination in the cortex and corpus callosum.
• Voiding behavior was assessed by monitoring micturition frequency and volume voided.
• Cystometry under urethane anesthesia was performed to evaluate brainstem and spinal cord reflex function.
• Luxol Fast Blue staining confirmed demyelination and remyelination.

Main Results:

• A 4-week cuprizone treatment induced urinary dysfunction, characterized by increased micturition frequency and reduced voided volume, mirroring human MS bladder issues.
• Recovery from 4-week treatment restored normal bladder function, indicating potential for reversibility.
• Chronic demyelination (8 weeks) led to exacerbated voiding dysfunction.
• Cortical demyelination significantly impaired conscious urinary behavior, while brainstem and spinal cord reflexes remained intact.

Conclusions:

• Cortical demyelination, independent of systemic inflammation, can cause significant lower urinary tract dysfunction.
• This finding provides novel insights into the mechanisms underlying urinary problems in multiple sclerosis.
• The cuprizone model offers a valuable tool for studying the specific effects of CNS demyelination on bladder control.