TrkB agonist, 7,8-dihydroxyflavone, reduces the clinical and pathological severity of a murine model of multiple sclerosis

Tapas K Makar; Vamshi K C Nimmagadda; Ishwar S Singh; Kristal Lam; Fahad Mubariz; Susan I V Judge; David Trisler; Christopher T Bever Jr

doi:10.1016/j.jneuroim.2016.01.002

TrkB agonist, 7,8-dihydroxyflavone, reduces the clinical and pathological severity of a murine model of multiple sclerosis

J Neuroimmunol. 2016 Mar 15:292:9-20. doi: 10.1016/j.jneuroim.2016.01.002. Epub 2016 Jan 6.

Authors

Tapas K Makar¹, Vamshi K C Nimmagadda², Ishwar S Singh³, Kristal Lam⁴, Fahad Mubariz⁵, Susan I V Judge⁶, David Trisler⁷, Christopher T Bever Jr⁸

Affiliations

¹ Department of Neurology, University of Maryland, Baltimore, MD 21201, United States; Research Service, VA Medical Center, Baltimore, MD 21201, United States; VA Multiple Sclerosis Center of Excellence East, Baltimore, MD 21201, United States. Electronic address: tmakar@som.umaryland.edu.
² Department of Neurology, University of Maryland, Baltimore, MD 21201, United States; Research Service, VA Medical Center, Baltimore, MD 21201, United States. Electronic address: vnimmagadda@som.umaryland.edu.
³ Research Service, VA Medical Center, Baltimore, MD 21201, United States; Department of Medicine, University of Maryland, Baltimore, MD 21201, United States. Electronic address: isingh@umaryland.edu.
⁴ Department of Neurology, University of Maryland, Baltimore, MD 21201, United States. Electronic address: knl2fv@virginia.edu.
⁵ Department of Neurology, University of Maryland, Baltimore, MD 21201, United States. Electronic address: fahadm1@umbc.edu.
⁶ Department of Neurology, University of Maryland, Baltimore, MD 21201, United States; Research Service, VA Medical Center, Baltimore, MD 21201, United States; VA Multiple Sclerosis Center of Excellence East, Baltimore, MD 21201, United States. Electronic address: sjudge@som.umaryland.edu.
⁷ Department of Neurology, University of Maryland, Baltimore, MD 21201, United States; Research Service, VA Medical Center, Baltimore, MD 21201, United States; VA Multiple Sclerosis Center of Excellence East, Baltimore, MD 21201, United States. Electronic address: GTrisler@som.umaryland.edu.
⁸ Department of Neurology, University of Maryland, Baltimore, MD 21201, United States; Research Service, VA Medical Center, Baltimore, MD 21201, United States; VA Multiple Sclerosis Center of Excellence East, Baltimore, MD 21201, United States. Electronic address: christopher.bever@va.gov.

PMID: 26943953
DOI: 10.1016/j.jneuroim.2016.01.002

Abstract

7,8-Dihydroxyflavone (DHF), is a recently described TrkB agonist that readily crosses the blood brain barrier. We treated C57Bl/6 mice with MOG--induced EAE daily with DHF starting on the day of disease induction. Clinical severity of impairment was reduced throughout the course of disease. Pathological examination of brains and spinal cords on day 28 showed that DHF treatment increased the phosphorylation of TrkB and activated downstream signaling pathways including AKT and STAT3 and reduced inflammation, demyelination and axonal loss compared to EAE controls. DHF treatment duplicated the central nervous system effects of brain derived neurotrophic factor in the EAE.

Keywords: Central nervous system; Demyelination; Experimental autoimmune encephalomyelitis; Inflammation; Neuroprotection; Remyelination; TrkB Signal Transduction.

Published by Elsevier B.V.

Publication types

Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

2',3'-Cyclic-Nucleotide Phosphodiesterases / metabolism
Animals
Apoptosis / drug effects
Brain / drug effects
Brain / metabolism
Brain / pathology*
Cytokines / metabolism
Disease Models, Animal
Encephalomyelitis, Autoimmune, Experimental / drug therapy*
Encephalomyelitis, Autoimmune, Experimental / immunology
Encephalomyelitis, Autoimmune, Experimental / pathology*
Female
Flavones / therapeutic use*
Humans
Mice
Mice, Inbred C57BL
Multiple Sclerosis / drug therapy*
Myelin Basic Protein / metabolism
Myelin-Oligodendrocyte Glycoprotein / toxicity
Peptide Fragments / toxicity
Severity of Illness Index
Signal Transduction / drug effects
Spinal Cord / drug effects
Spinal Cord / metabolism
Spinal Cord / pathology*
Time Factors
bcl-2-Associated X Protein / metabolism

Substances

6,7-dihydroxyflavone
Cytokines
Flavones
Myelin Basic Protein
Myelin-Oligodendrocyte Glycoprotein
Peptide Fragments
bcl-2-Associated X Protein
myelin oligodendrocyte glycoprotein (35-55)
2',3'-Cyclic-Nucleotide Phosphodiesterases

Grants and funding

I01 BX002034/BX/BLRD VA/United States