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bioRxiv · 10.1101/2021.04.19.440405

Central nervous system infusion of TrkB agonist, 7,8-dihydroxyflavone, is ineffective in promoting myelin repair in cuprizone and experimental autoimmune encephalomyelitis mouse models of multiple sclerosis

Fletcher, J. L.·Wood, R. J.·Prawdiuk, A. R.·O'Rafferty, R.·Ehrlich, O.·Gonsalvez, D. G.·Murray, S. S.
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Abstract

Small molecular weight functional mimetics of brain-derived neurotrophic factor (BDNF) which act via the TrkB receptor have been developed to overcome the pharmacokinetic limitations of BDNF as a therapeutic for neurological disease. Activation of TrkB on oligodendrocytes has been identified as a potential strategy for myelin repair in demyelinating conditions. Here, we tested the efficacy of intracerebroventricular infusion of TrkB agonist 7,8-dihydroxyflavone (DHF) to promote myelin repair in the cuprizone model and alter the course of experimental autoimmune encephalomyelitis (EAE). In these two distinct mouse models used for the preclinical testing of remyelinating therapeutics, we found that DHF infusion increased the percentage of myelin basic protein and density of oligodendrocyte progenitor cells (OPCs) in the corpus callosum of female C57BL/6 mice after cuprizone demyelination. However, DHF did not alter the percentage of axons myelinated or increase the density of post-mitotic oligodendrocytes in this model. Direct cerebrospinal fluid infusion of DHF also had no effect on the clinical course of EAE, and examination of the lumbar spinal cord after 21 days of treatment revealed extensive demyelination. These results indicate that direct cerebrospinal fluid infusion of DHF is ineffective at promoting myelin repair in toxin-induced and inflammatory models of demyelination.

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Fletcher, J. L., Wood, R. J., Prawdiuk, A. R., O'Rafferty, R., Ehrlich, O., Gonsalvez, D. G., Murray, S. S.. 2021-04-19. Central nervous system infusion of TrkB agonist, 7,8-dihydroxyflavone, is ineffective in promoting myelin repair in cuprizone and experimental autoimmune encephalomyelitis mouse models of multiple sclerosis. https://doi.org/10.1101/2021.04.19.440405

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