Fingolimod, a sphingosine-1 phosphate receptor modulator, increases BDNF levels and improves symptoms of a mouse model of Rett syndrome

Abstract

The functional relevance of brain-derived neurotrophic factor (BDNF) is beginning to be well appreciated not only in mice, but also in humans. Because reduced levels typically correlate with impaired neuronal function, increasing BDNF levels with well-tolerated drugs diffusing into the central nervous system may help in ameliorating functional deficits. With this objective in mind, we used the sphingosine-1 phosphate receptor agonist fingolimod, a drug that crosses the blood–brain barrier. In addition, fingolimod has recently been introduced as the first oral treatment for multiple sclerosis. In cultured neurons, fingolimod increases BDNF levels and counteracts NMDA-induced neuronal death in a BDNF-dependent manner. Ongoing synaptic activity and MAPK signaling is required for fingolimod-induced BDNF increase, a pathway that can also be activated in vivo by systemic fingolimod administration. Mice lacking Mecp2, a gene frequently mutated in Rett syndrome, show decreased levels of BDNF, and fingolimod administration was found to partially rescue these levels as well as the size of the striatum, a volumetric sensor of BDNF signaling in rodents. These changes correlate with increased locomotor activity of the Mecp2 -deficient animals, suggesting that fingolimod may improve the functional output of the nervous system, in addition to its well-documented effects on lymphocyte egress from lymph nodes.

Effect of Fingolimod on Neural Stem Cells: A Novel Mechanism and Broadened Application for Neural Repair

“…28,29,45 Similarly, FTY720 treatment induced production of neurotrophic factors BDNF and GDNF, promoted NSC proliferation, and drove embryonic stem cells to differentiate into the OLG lineage. 28,[46][47][48] Furthermore, it has also been shown that FTY720 can enhance remyelination in organotypic slice cultures. 27,49,50 In vivo studies demonstrated that FTY720 is effective at treating acute EAE by promoting OPC proliferation and differentiation and by stimulating the sonic hedgehog (Shh) signaling pathway.…”

Galactosylsphingosine (psychosine)-induced demyelination is attenuated by sphingosine 1-phosphate signalling

“…S1PRs have also been shown to limit events of demyelination and promote remyelination, which are probably mediated by the dampening of pro-inflammatory cytokine levels (Miron et al, 2010;Sheridan and Dev, 2012). Overall, therefore, S1PRs represent an important drug target that can be exploited for use in neuroinflammatory, demyelinating and neurodegenerative diseases, as documented by a growing body of literature (Asle-Rousta et al, 2013;Deogracias et al, 2012). Here we investigate whether regulation of S1P signalling alters psychosine-induced astrocyte dysfunction, pro-inflammatory cytokine release and demyelination.…”

Fingolimod Exerts only Temporary Antiepileptogenic Effects but Longer-Lasting Positive Effects on Behavior in the WAG/Rij Rat Absence Epilepsy Model

“…As previously reported, this epigenetic regulation by fingolimod could also lead to an augmented expression of growth factors such as BDNF that play a fundamental role in synaptic plasticity process, which are involved in memory formation and retention [21,[80][81][82]. In any case, the role of HDAC modulation in epilepsy and more specifically in WAG/Rij rats still does not permit us to either support or discard its involvement in fingolimod effects, also considering the potential of HDAC modulation in epileptogenesis and animal behavior [34,83,84].…”