Abstract Details

Title Metabolic interference protects against a mouse model of multiple sclerosis.

Topic Multiple Sclerosis

Presentation(s) S55 - MS Basic Science (3:52 PM-4:03 PM)

Poster/Presentation
Number 003

Objective To test whether drugs modulating cellular metabolism protect against CNS autoimmune disease.

Background Activated leukocytes exhibit remarkable changes in their metabolic program with the preferential use of glycolysis for cellular energy generation. Blocking glycolysis inhibits effector T cell differentiation and promotes regulatory T cell formation. Pharmacologic modulation of cellular metabolism might therefore present a novel anti-inflammatory treatment strategy for CNS autoimmune disease. Here, we use a combination therapy of three drugs inhibiting glycolysis and glutamine metabolism that was shown to successfully prevent allograft rejection in mice. We hypothesized that this pharmacologic regimen would protect against clinical disability in a mouse model of multiple sclerosis.

Design/Methods Wild type female C57BL/6 mice were subjected to experimental autoimmune encephalomyelitis (EAE) at 11 weeks of age. Starting on the day of induction and continuing through the course of the 40 day experiment, mice were administered an oral gavage of combination therapy with metformin (an AMPK activator, 150mg/kg/day, daily), 2-deoxyglucose (2-DG, a hexokinase inhibitor and ATP depleting agent, 500mg/kg/day, daily), and 6-diazo-5-oxy-L-norleucine (DON, a glutamine metabolism inhibitor, 0.8mg/kg/day, every other day) vs. control solution (n=10 each group). Spinal cord tissue was harvested for immunohistochemistry and flow cytometry.

Results Mice receiving the combination therapy showed marked protection against EAE compared to controls, exhibiting statistically significant differences in mean score from days 15-40 (p<0.0001 two way ANOVA with Bonferroni correction), total mean score (2.4 vs. 0.48, p<0.00001, two tailed t-test), disability onset (Day 13.6 vs. Day 22.85, p<0.0005, two tailed t-test), and peak score of disease (3.65 vs. 1.35, p<0.005, two tailed t-test). Of note, 40% of animals in the treatment group did not show any clinical symptoms. Immunohistochemistry for markers of immune cell infiltration, reactive astrocytosis and demyelination are in progress, as well as flow cytometry to measure changes in the patterns of monocyte and T cell differentiation.

Conclusions A pharmacologic regimen blocking glycolysis and glutamine metabolism demonstrates strong protective effects against a mouse model of MS, supporting the translational potential of metabolic interference in MS and other CNS autoimmune diseases. Immunomodulatory mechanisms of these agents are currently under active investigation.

Authors/Disclosures
PRESENTER	No disclosure on file
	No disclosure on file
Sam H. Horng, MD, PhD	The institution of Dr. Horng has received research support from National Institutes of Health . The institution of Dr. Horng has received research support from Jayne and Harvey Beker Foundation .

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