Demyelination-Remyelination of the Rat Caudal Cerebellar Peduncle Evaluated with Magnetic Resonance Imaging

Abstract

Remyelination is common under physiological conditions and usually occurs as a response to a pathological demyelinating event. Its potentiation is an important goal for the development of therapies against pathologies such as multiple sclerosis and white matter injury. Visualization and quantification in vivo of demyelination and remyelination processes are essential for longitudinal studies that will allow the testing and development of pro-myelinating strategies. In this study, ethidium bromide (EB) was stereotaxically injected into the caudal cerebellar peduncle (c.c.p.) in rats to produce demyelination; the resulting lesion was characterized (i) transversally through histology using Black-Gold II (BGII) staining, and (ii) longitudinally through diffusion-weighted magnetic resonance imaging (dMRI), by computing fractional anisotropy (FA) and diffusivity parameters to detect microstructural changes. Using this characterization, we evaluated, in the lesioned c.c.p., the effect of N-butyl-β-carboline-3-carboxylate (β-CCB), a potentiator of GABAergic signaling in oligodendrocytes. The dMRI analysis revealed significant changes in the anisotropic and diffusivity properties of the c.c.p. A decreased FA and increased radial diffusivity (λ_⊥) were evident following c.c.p. lesioning. These changes correlated strongly with an apparent decrease in myelin content as evidenced by BGII. Daily systemic β-CCB administration for 2 weeks in lesioned animals increased FA and decreased λ_⊥, suggesting an improvement in myelination, which was supported by histological analysis. This study shows that structural changes in the demyelination-remyelination of the caudal cerebellar peduncle (DRCCP) model can be monitored longitudinally by MRI, and it suggests that remyelination is enhanced by β-CCB treatment. This article is part of a Special Issue entitled: Honoring Ricardo Miledi - outstanding neuroscientist of XX-XXI centuries.

Keywords: GABAergic signaling, β-carbolines; OPC; diffusion tensor imaging; white matter.