Pilot functional magnetic resonance imaging study of clemastine‐aided functional recovery on a mouse model of demyelination

Abstract

ABSTRACT Background Multiple sclerosis (MS) is a chronic demyelinating disease characterized by autoimmune attacks on myelin sheaths. Its deleterious effects may be reversed by remyelination, a process that restores the integrity of myelin sheaths and, consequently, neuronal function. However, the functional implications of demyelination and remyelination in MS, as well as the potential impact of therapeutic interventions, remain incompletely understood. We used noninvasive longitudinal resting‐state functional magnetic resonance imaging in a cuprizone murine model of demyelination to investigate these unsolved questions. Methods Three groups of (n = 6) animals were studied. A control group was fed with standard food for 5 weeks while two treatment groups (cuprizone and clemastine) suffered progressive demyelination by feeding them with 2% cuprizone. At Week 5 (W5), all animals returned to the standard diet and studied for another 5‐week period to compare controls vs spontaneous (cuprizone group) vs clemastine‐aided (clemastine group) remyelination group. Group clemastine was treated with this antihistaminic (oral gavage) during the remyelination period (Weeks 5–10). Anatomical magnetic resonance imaging (T2w‐MRI) and resting state functional MRI (rs‐FMRI) studies were conducted on weeks W0, W2, W5 (maximal demyelination) W7 and W10 (remyelination). MRI images were processed with the FMRIB Software Library, involving seed‐free functional imaging and seed‐based correlation. This study uses the t‐test and the D'Agostino–Pearson normality test to make an assessment. Results The principal findings of our research include: (1) cuprizone‐treated animals suffer an initial phase of elevated connectivity at Week 2 with respect to controls, transitioning to reduced connectivity at Week 5; (2) different temporal trajectories across brain regions, reflecting varying susceptibility to demyelination; (3) while spontaneous remyelination normalizes connectivity in most networks at Week 10 (5 weeks after ceasing cuprizone intoxication), the thalamocortical axis exhibits lasting disruption even 6 months after normalization of diet; and (4) on the contrary, clemastine‐aided remyelination re‐establishes normal thalamocortical connectivity at 6 months after demyelination. Conclusion This approach provides insights into the dynamic processes of demyelination and remyelination, informing the development of more effective interventions for MS.

Keywords

• clemastine
• cuprizone
• demyelination
• magnetic resonance imaging
• remyelination