Contributions
Abstract: P624
Type: Poster
Abstract Category: Therapy - disease modifying - Immunomodulation/Immunosuppression
Background: Theiler"s Murine Encephalomyelitis Virus (TMEV) infection produces an immune-mediated demyelinating disease when induced via intracerebral inoculation. Similar to multiple sclerosis (MS), subjects exhibit atrophy and iron accumulation in the brain and motor impairment. Teriflunomide (Aubagio®) is an immunomodulatory treatment for MS which decreases immune cell proliferation and has been shown to decrease demyelination and axonal loss. This study investigated the effect of teriflunomide on neurochemistry in TMEV.
Objective: We evaluated the effect of teriflunomide on the cortico-basal ganglionic-thalamo-cortical circuit (CxBGTh) by 9.4T MRI and behavior in TMEV model of MS. Glutamate excitotoxicity in this loop may play a role in pathology and phenotype of the disease.
Methods: Forty-eight mice were tested at pre-disease baseline, injected with TMEV, then tested again at 8 and 26 weeks. Therapeutic intervention began 4 weeks after induction, with daily dosing of either 20mg/kg teriflunomide or vehicle placebo (24 mice each). MRI and spectroscopy was used to acquire volume and metabolite spectra, and cognitive and motor ability were tested.
Results: Glutamate was decreased in teriflunomide subjects compared to placebo subjects at 8 weeks in the basal ganglia and thalamus, and at 26 weeks in the thalamus (p< 0.05, independent samples t-test). GABA change over time differed between the two conditions in the basal ganglia (p< 0.05, two-way repeated measures ANOVA). GABA decreased steadily with each time point in placebo subjects (p< 0.05 paired t-tests between 0-8 and 8-26 weeks), but the decrease in GABA was delayed until 8-26 weeks in teriflunomide subjects (p< 0.001 paired t-test between 8-26 weeks only). There was a significant relationship between lower motor ability at 26 weeks and decreased volume over 26 weeks in the basal ganglia and thalamus (p< 0.05, Pearson), and worse clinical signs at 26 weeks and decreased volume over 26 weeks in the thalamus (p< 0.05, Pearson) in placebo subjects, which was not evident in teriflunomide subjects.
Conclusions: These findings suggest that teriflunomide reduces glutamate in the CxBGTh, delaying TMEV-associated decrease in GABA and preventing potential TMEV-associated excitotoxicity. Teriflunomide may also play a role in reducing the relationship of motor decline and clinical progression with tissue pathology.
Disclosure: Study supported by: Genzyme
Claire M Modica, Ferdinand Schweser, Nicola Bertolino, Michelle L Sudyn, Danielle M Siebert, Jacqueline C Krawiecki, Marilena Preda, Michele Sveinsson have nothing to disclose.
Michael G. Dwyer has received personal compensation from Claret Medical and EMD Serono, and research grant support from Novartis.
Robert Zivadinov received personal compensation from Teva Pharmaceuticals, Biogen Idec, EMD Serono, Genzyme-Sanofi, Claret Medical, IMS Health and Novartis for speaking and consultant fees. He received financial support for research activities from Teva Pharmaceuticals, Genzyme-Sanofi, Novartis, Claret Medical, Intekrin and IMS Health.
Abstract: P624
Type: Poster
Abstract Category: Therapy - disease modifying - Immunomodulation/Immunosuppression
Background: Theiler"s Murine Encephalomyelitis Virus (TMEV) infection produces an immune-mediated demyelinating disease when induced via intracerebral inoculation. Similar to multiple sclerosis (MS), subjects exhibit atrophy and iron accumulation in the brain and motor impairment. Teriflunomide (Aubagio®) is an immunomodulatory treatment for MS which decreases immune cell proliferation and has been shown to decrease demyelination and axonal loss. This study investigated the effect of teriflunomide on neurochemistry in TMEV.
Objective: We evaluated the effect of teriflunomide on the cortico-basal ganglionic-thalamo-cortical circuit (CxBGTh) by 9.4T MRI and behavior in TMEV model of MS. Glutamate excitotoxicity in this loop may play a role in pathology and phenotype of the disease.
Methods: Forty-eight mice were tested at pre-disease baseline, injected with TMEV, then tested again at 8 and 26 weeks. Therapeutic intervention began 4 weeks after induction, with daily dosing of either 20mg/kg teriflunomide or vehicle placebo (24 mice each). MRI and spectroscopy was used to acquire volume and metabolite spectra, and cognitive and motor ability were tested.
Results: Glutamate was decreased in teriflunomide subjects compared to placebo subjects at 8 weeks in the basal ganglia and thalamus, and at 26 weeks in the thalamus (p< 0.05, independent samples t-test). GABA change over time differed between the two conditions in the basal ganglia (p< 0.05, two-way repeated measures ANOVA). GABA decreased steadily with each time point in placebo subjects (p< 0.05 paired t-tests between 0-8 and 8-26 weeks), but the decrease in GABA was delayed until 8-26 weeks in teriflunomide subjects (p< 0.001 paired t-test between 8-26 weeks only). There was a significant relationship between lower motor ability at 26 weeks and decreased volume over 26 weeks in the basal ganglia and thalamus (p< 0.05, Pearson), and worse clinical signs at 26 weeks and decreased volume over 26 weeks in the thalamus (p< 0.05, Pearson) in placebo subjects, which was not evident in teriflunomide subjects.
Conclusions: These findings suggest that teriflunomide reduces glutamate in the CxBGTh, delaying TMEV-associated decrease in GABA and preventing potential TMEV-associated excitotoxicity. Teriflunomide may also play a role in reducing the relationship of motor decline and clinical progression with tissue pathology.
Disclosure: Study supported by: Genzyme
Claire M Modica, Ferdinand Schweser, Nicola Bertolino, Michelle L Sudyn, Danielle M Siebert, Jacqueline C Krawiecki, Marilena Preda, Michele Sveinsson have nothing to disclose.
Michael G. Dwyer has received personal compensation from Claret Medical and EMD Serono, and research grant support from Novartis.
Robert Zivadinov received personal compensation from Teva Pharmaceuticals, Biogen Idec, EMD Serono, Genzyme-Sanofi, Claret Medical, IMS Health and Novartis for speaking and consultant fees. He received financial support for research activities from Teva Pharmaceuticals, Genzyme-Sanofi, Novartis, Claret Medical, Intekrin and IMS Health.