Abstract

Objective: We assessed the effect of teriflunomide (AubagioO) treatment on the inflammatory response within the brain tissue of a TMEV mice by using a histological approach in combination with neuroimaging. Background: Teriflunomide reduces disability progression and brain atrophy in multiple sclerosis (MS) patients. However, the exact mechanism of action by which teriflunomide exerts these effects is currently unknown. We hypothesized that teriflunomide can decrease macrophage/microglia density in the Theiler’s Murine Encephalomyelitis Virus (TMEV) model, an immune-mediated chronic model of MS. Design/Methods: Forty eight mice were IC injected with TMEV at 6–8 weeks of age and treated with teriflunomide (n=24) or placebo (n=24). They were examined with MRI and behavioral testing at 2, 6, and 9 months post-injection. Of those, 18 teriflunomide and 17 control treated animals’ brain tissue was histologically analyzed to sample from different brain regions for microglial density. The histological outcomes were correlated with the MRI outcomes. Results: There was a trend for decreased microglial density within the corpus callosum (CC) of teriflunomide compared to the control group (141.1±21.7 SEM vs. 214.74±34.79 SEM, Iba1 + cells/mm 2 , p=0.087). Decreased microglial density in the basal ganglia in the teriflunomide group was associated with increased fractional anisotropy and decreased mean diffusivity. On the contrary, increased microglial density in the control group, was associated with increased basal ganglia volume potentially indicating inflammation, but not in the teriflunomide one. Conclusions: Teriflunomide decreased microglial cells density within CC, indicating less inflammation in the chronic phase of the disease. The decreased microglial density in teriflunomide group was associated with less microstructural damage, as measured by diffusion tensor imaging indices. Teriflunomide potentially modified the course of the TMEV disease, by altering associations between some histological measures and MRI measured parameters of tissue integrity. Study Supported by: This study was supported by Genzyme, which is a wholly owned subsidiary of Sanofi. Research reported in this publication was also supported by the National Center for Advancing Translational Sciences of the National Institutes of Health under award Number UL1TR001412. The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH. Disclosure: Dr. Pol has nothing to disclose. Dr. Modica has nothing to disclose. Dr. Schweser has nothing to disclose. Dr. Sveinsson has nothing to disclose. Dr. Sudyn has nothing to disclose. Dr. Bertolino has nothing to disclose. Dr. Preda has nothing to disclose. Dr. Dwyer has nothing to disclose. Dr. Hagemeier has nothing to disclose. Dr. Siebert has nothing to disclose. Dr. Zivadinov has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Robert Zivadinov received personal compensation from EMD Serono, Genzyme-Sanofi, Claret Medical, Celgene and Novartis for speaking and consultant fees. Dr. Zivadinov has received research support from RZ received financial support for research activities from Genzyme-Sanofi, Novartis, Claret Medical, Intekrin-Coherus and Quintiles IMS.