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

PLoS One. 2017 Aug 10;12(8):e0182729. doi: 10.1371/journal.pone.0182729. eCollection 2017.

Abstract

Background: Pathology 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.

Objectives: To 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.

Methods: Forty-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.

Results: In 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).

Conclusions: Teriflunomide may reduce possible excitotoxicity in the thalamus and basal ganglia by lowering glutamate levels.

MeSH terms

  • Animals
  • Basal Ganglia / drug effects*
  • Basal Ganglia / metabolism
  • Cell Line
  • Corpus Callosum / drug effects
  • Corpus Callosum / metabolism
  • Crotonates / pharmacology*
  • Disease Models, Animal
  • Drug Evaluation, Preclinical
  • Excitatory Amino Acid Agents / pharmacology
  • Female
  • Glutamic Acid / metabolism
  • Mesocricetus
  • Mice
  • Multiple Sclerosis / drug therapy*
  • Myelitis / drug therapy
  • Thalamus / drug effects*
  • Thalamus / metabolism
  • Toluidines / pharmacology*
  • gamma-Aminobutyric Acid / metabolism

Substances

  • Crotonates
  • Excitatory Amino Acid Agents
  • Toluidines
  • teriflunomide
  • Glutamic Acid
  • gamma-Aminobutyric Acid