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bioRxiv · 10.64898/2026.02.27.707919

Fingolimod acutely facilitates the activation of TRKB

Brunello, C. A.·Araujo, J. P.·Seiffert, N.·Kaurinkoski, K.·Casarotto, P. C.·Biojone, C.
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Abstract

Fingolimod (FNG) is a sphingosine-1-phosphate receptor agonist currently prescribed for the treatment of remitting-relapsing multiple sclerosis. However, an increasing body of evidence indicates that FNG has a variety of other effects on the central nervous system, making it a good candidate to target other brain disorders that display loss of neuronal cells and synaptic plasticity. FNG treatments induce production of brain-derived neurotrophic factor (BDNF), which promotes neuronal plasticity, arborization and survival via signaling through its cognate receptor TRKB. In this study we characterize the relationship between FNG and TRKB in vitro and in vivo following acute treatments. We found that FNG induces TRKB activation in primary neuronal cultures in a BDNF-dependent way, indicating a rapid effect of FNG. This effect is different from the one elicited by antidepressants and is likely mediated by modulation of plasma membrane properties, as the enhancement of fluoxetine binding and dimerization of the cholesterol-insensitive TRKB mutant Y433F mimic the effects of cholesterol. Moreover, acute FNG treatment normalizes the generalization of conditioned fear response seen in heterozygous BDNF null female mice without affecting the wild-type littermates. Taken together, our data indicate that FNG allosterically promotes TRKB signaling and thereby induces the increase in BDNF production, which mediates the therapeutic effects of the drug on neuronal plasticity.

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Brunello, C. A., Araujo, J. P., Seiffert, N., Kaurinkoski, K., Casarotto, P. C., Biojone, C.. 2026-03-02. Fingolimod acutely facilitates the activation of TRKB. https://doi.org/10.64898/2026.02.27.707919

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