Effect of teriflunomide on cortex-basal ganglia-thalamus (CxBGTh) circuit glutamatergic dysregulation in the Theiler's Murine Encephalomyelitis Virus mouse model of multiple sclerosis

Abstract

BackgroundPathology of gray matter is associated with development of physical and cognitive disability in patients with multiple sclerosis. In particular, glutamatergic dysregulation in the cortex-basal ganglia-thalamus (CxBGTh) circuit could be associated with decline in these behaviors.ObjectivesTo investigate the effect of an immunomodulatory therapy (teriflunomide, Aubagio®) on changes of the CxBGTh loop in the Theiler’s Murine Encephalomyelitis Virus, (TMEV) mouse model of MS.MethodsForty-eight (48) mice were infected with TMEV, treated with teriflunomide (24) or control vehicle (24) and followed for 39 weeks. Mice were examined with MRS and volumetric MRI scans (0, 8, 26, and 39 weeks) in the cortex, basal ganglia and thalamus, using a 9.4T scanner, and with behavioral tests (0, 4, 8, 12, 17, 26, and 39 weeks). Within conditions, MRI measures were compared between two time points by paired samples t-test and across multiple time points by repeated measures ANOVA (rmANOVA), and between conditions by independent samples t-test and rmANOVA, respectively. Data were considered as significant at the p<0.01 level and as a trend at p<0.05 level.ResultsIn the thalamus, the teriflunomide arm exhibited trends toward decreased glutamate levels at 8 and 26 weeks compared to the control arm (p = 0.039 and p = 0.026), while the control arm exhibited a trend toward increased glutamate between 0 to 8 weeks (p = 0.045). In the basal ganglia, the teriflunomide arm exhibited a trend toward decreased glutamate earlier than the control arm, from 0 to 8 weeks (p = 0.011), resulting in decreased glutamate compared to the control arm at 8 weeks (p = 0.016).ConclusionsTeriflunomide may reduce possible excitotoxicity in the thalamus and basal ganglia by lowering glutamate levels.

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

“…One mPI, 24 mice received Terflunomide in .6% carboxymethylcellulose/.5%, at 20 mg/kg dose, through oral gavage daily. This dosage resembles human dose . The remaining 23 control (one animal died prior to treatment) mice received matching volume of vehicle solution …”

“…Induction and maintenance of anesthesia and animal care were conducted as previously described . The magnetic resonance spectroscopy (MRS) and volumetric data were acquired and analyzed, as previously reported .…”

“…For measuring volumes, brain images acquired using a multiecho gradient echo (MEGRE) sequence were segmented . This automated segmentation was done using a previously described multiatlas approach .…”

“…For measuring volumes, brain images acquired using a multiecho gradient echo (MEGRE) sequence were segmented . This automated segmentation was done using a previously described multiatlas approach . To generate the atlases, regions of interest (ROI) were outlined manually using 3D Slicer (http://www.slicer.org) in 10 scans from three different representative animals, with the visual aid of Mouse BIRN Atlasing Toolkit‐ready Labeled Atlas v0.6.2 .…”

“…Teriflunomide treatment increased viral clearance and reduced serum TMEV antibody concentration in TMEV‐infected mice . Furthermore, longitudinal MRI analysis of TMEV‐infected mice suggested that teriflunomide suppressed cellular excitotoxicity in the thalamus (Th) and basal ganglia (BG) . In this study, we aimed to understand how teriflunomide affects TMEV progression at two levels.…”