Fingolimod Modulates Dendritic Architecture in a BDNF-Dependent Manner

Abstract

The brain-derived neurotrophic factor (BDNF) plays crucial roles in both the developing and mature brain. Moreover, alterations in BDNF levels are correlated with the cognitive impairment observed in several neurological diseases. Among the different therapeutic strategies developed to improve endogenous BDNF levels is the administration of the BDNF-inducing drug Fingolimod, an agonist of the sphingosine-1-phosphate receptor. Fingolimod treatment was shown to rescue diverse symptoms associated with several neurological conditions (i.e., Alzheimer disease, Rett syndrome). However, the cellular mechanisms through which Fingolimod mediates its BDNF-dependent therapeutic effects remain unclear. We show that Fingolimod regulates the dendritic architecture, dendritic spine density and morphology of healthy mature primary hippocampal neurons. Moreover, the application of Fingolimod upregulates the expression of activity-related proteins c-Fos and pERK1/2 in these cells. Importantly, we show that BDNF release is required for these actions of Fingolimod. As alterations in neuronal structure underlie cognitive impairment, we tested whether Fingolimod application might prevent the abnormalities in neuronal structure typical of two neurodevelopmental disorders, namely Rett syndrome and Cdk5 deficiency disorder. We found a significant rescue in the neurite architecture of developing cortical neurons from Mecp2 and Cdkl5 mutant mice. Our study provides insights into understanding the BDNF-dependent therapeutic actions of Fingolimod.

Molecular Pharmacology and Novel Potential Therapeutic Applications of Fingolimod

“…In patients with MS, treatment with fingolimod significantly increased BDNF secretion from T cells, suggesting that neuroprotective effects of fingolimod therapy are through BDNF enhancement ( Golan et al, 2019 ). Fingolimod regulates dendritic architecture and morphology of healthy mature primary hippocampal neurons alongside BDNF dependent enhancement in c-Fos and pERK1/2 proteins ( Patnaik et al, 2020 ). We have recently shown that BDNF enhancement by fingolimod correlates with upregulation in oligodendrocyte mRNA levels in the EPI-NCSCs ( Pournajaf et al, 2020 ).…”

“…In 2013, Doi and others found that fingolimod-P can suppress Amyloid β–induced neurotoxicity in primary mouse cortical neurons by enhancing BDNF expression and acting on TrkB/ERK1/2 signaling pathway ( Doi et al, 2013 ). Recently, it has been shown that with the aid of BDNF, 10 nM fingolimod can modulate dysregulated dendritic architecture in primary hippocampal neurons ( Patnaik et al, 2020 ). Moreover, fingolimod can downregulate AD’s neuroinflammation by reducing activated microglia, astrocytosis, and plaque density ( Aytan et al, 2016 ; Kartalou et al, 2020 ).…”

“…Recently, it has been shown that with the aid of BDNF, 10 nM fingolimod can modulate dysregulated dendritic architecture in primary hippocampal neurons (Patnaik et al, 2020). Moreover, fingolimod can downregulate AD's neuroinflammation by reducing activated microglia, astrocytosis, and plaque density (Aytan et al, 2016;Kartalou et al, 2020).…”

Mass Generation, Neuron Labeling, and 3D Imaging of Minibrains

“…Labeling neurons and subsequent morphological reconstruction of the neurons provides information about the dendrite morphometric and axonal properties that are crucial for network establishment. These properties can give valuable insight in large scale disease modeling and drug testing screens ( DePoy et al, 2014 ; Miguéns et al, 2015 ; Cheng et al, 2017 ; Martínez-Cerdeño, 2017 ; Patnaik et al, 2020 ). Much is yet to be understood as to how human neuron morphology is driven in 3D brain in vitro models where all connectivity pathways are miniaturized.…”

Mass Generation, Neuron Labelling and 3D Imaging of Minibrains

“…Morphological reconstruction of the neurons provides information about the dendrite morphometric and axonal properties that are crucial for network establishment. These properties can give valuable insight in large scale disease modelling and drug testing screens 2,3 . Much is yet to be understood as to how human neuron morphology is driven in brain organoids where all connectivity pathways are miniaturized.…”