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 altered microglia density and oligodendrocytes differentiation, which was associated with less evident microstructural damage on MRI.

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Theiler's murine encephalomyelitis virus (TMEV) is a naturally occurring enteric infection, easily passed from mouse to mouse in communal housing. However, TMEV is often inoculated intracerebrally (IC) to produce a mouse model of multiple sclerosis (MS). It has long been accepted that maintaining colonies of IC-infected mice within laboratory animal facilities poses a risk of spreading infection from mouse to mouse via the fecal-oral route as well as contaminated equipment or personnel. Interestingly, the extent of virus shedding from IC-inoculated mice has not been investigated, although several publications have remarked on the lack of virus in the peripheral body of this MS mouse model. Viral shedding, thus infectivity, would require that TMEV escape the central nervous system (CNS) and be found in bodily secretions. We hypothesized that if the virus can escape the CNS, it would be found circulating within blood or other secretions postinjection (PI), after the blood-brain barrier has been experimentally breached. The data presented show no TMEV RNA was found in the serum, saliva, or feces during the acute and chronic infection stages, although all subjects were positive for TMEV RNA in the CNS. These results, in conjunction with published anecdotal evidence, suggest that mice IC-inoculated with TMEV are not contagious, and thus a relaxation of containment methods is warranted. This report is an example of a collaborative effort between biosafety and research professionals to identify and collect scientifically relevant data to inform a risk assessment.