Teriflunomide's Effect on Glia in Experimental Demyelinating Disease: A Neuroimaging and Histologic Study

Abstract

BACKGROUND AND PURPOSE: Teriflunomide reduces disability progression and brain atrophy in multiple sclerosis patients. The exact mechanism of action by which teriflunomide exerts these effects is currently unknown. We assessed the effect of teriflunomide on brain glial cells in the Theiler's murine encephalomyelitis virus (TMEV) by using a histological approach in combination with neuroimaging. METHODS: Forty-eight SJL female mice received an intracerebral injection of TMEV at 6–8 weeks of age and were then treated with teriflunomide (n = 24) or placebo (n = 24) for 9 months. They were examined with MRI and behavioral testing at 2, 6, and 9 months postinduction (mPI). Of those, 18 teriflunomide-treated and 17 controls mice were analyzed histologically at 9 mPI to sample from different brain regions for myelination status, microglial density, and oligodendroglial lineage. The histological and MRI outcomes were correlated. RESULTS: Corpus callosum microglial density was numerically lower in the teriflunomide-treated mice compared to the control group (141.1 ± 21.7 SEM vs. 214.74 ± 34.79 SEM, Iba1 + cells/mm 2 , P =.087). Basal ganglia (BG) microglial density in the teriflunomide group exhibited a negative correlation with fractional anisotropy (P =.021) and a positive correlation with mean diffusivity (P =.034), indicating less inflammation and axonal damage. Oligodendroglial lineage cell and myelin density were not significantly different between treatment groups. However, a significant positive correlation between BG oligodendrocytes and BG volume (P =.027), and with N-acetyl aspartate concentration (P =.008), was found in the teriflunomide group, indicating less axonal loss. CONCLUSION: Teriflunomide altered microglia density and oligodendrocytes differentiation, which was associated with less evident microstructural damage on MRI.