Central nervous system-directed effects of FTY720 (fingolimod)

Miron, Véronique E.; Schubart, Anna; Antel, Jack P.

doi:10.1016/j.jns.2008.06.031

Cited by 164 publications

(138 citation statements)

References 69 publications

(105 reference statements)

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“…An increasing number of studies have stressed that fingolimod also has a direct effect on several cells within the CNS, including astrocytes, oligodendrocytes, microglia, and neurons (Miron, Schubart, & Antel, 2008; Soliven et al., 2011). As for endothelial cells, our previous study revealed direct BBB‐modulating effects which included the enhancement of the barrier properties of the BBB by upregulation of claudin‐5 expression and inhibition of the increase in VCAM‐1 levels in BMECs induced by MS sera (Nishihara et al., 2015).…”

Section: Discussionmentioning

confidence: 99%

Fingolimod promotes blood–nerve barrier properties in vitro

et al. 2018

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ObjectiveThe main effect of fingolimod is thought to be functional antagonism of lymphocytic S1P1 receptors and the prevention of lymphocyte egress from lymphoid tissues, thereby reducing lymphocyte infiltration into the nervous system. However, a growing number of reports suggest that fingolimod also has a direct effect on several cell types in the nervous system. Although we previously reported that fingolimod enhances blood–brain barrier (BBB) functions, there have been no investigations regarding the blood–nerve barrier (BNB). In this study, we examine how fingolimod affects the BNB.MethodsAn immortalized human peripheral nerve microvascular endothelial cell line (HPnMEC) was used to evaluate BNB barrier properties. We examined tight junction proteins and barrier functions of HPnMECs in conditioned medium with or without fingolimod‐phosphate and blood sera from patients with typical chronic inflammatory demyelinating polyneuropathy (CIDP).ResultsIncubation with fingolimod‐phosphate increased levels of claudin‐5 mRNA and protein as well as TEER values in HPnMECs. Conversely, typical CIDP sera decreased claudin‐5 mRNA/protein levels and TEER values in HPnMECs; however, pretreatment with fingolimod‐phosphate inhibited the effects of the typical CIDP sera.ConclusionsFingolimod‐phosphate directly modifies the BNB and enhances barrier properties. This mechanism may be a viable therapeutic target for CIDP, and fingolimod may be useful in patients with typical CIDP who have severe barrier disruption.

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Section: Discussionmentioning

confidence: 99%

Fingolimod promotes blood–nerve barrier properties in vitro

et al. 2018

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“…44 For example, in vitro studies have shown the dose-dependent effect of FTY720 on axon preservation, neural cell survival, OPC process extension and differentiation, and cytoskeletal dynamics, all of which are frequently linked to improved remyelination. 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.…”

Section: Discussionmentioning

confidence: 99%

“…[22][23][24] FTY720 primarily reduces CNS infiltration and alleviates MS severity, especially in remitting-relapsing (RR) MS, while it lacks efficacy when the disease reaches the secondary progressive stage (SP) of MS. 22,25,26 The lipophilic nature of FTY720 allows it to easily cross the blood-brain barrier (BBB) and reach physiologically meaningful concentrations in CNS tissue. 27,28 Because S1P receptors are expressed on all cell types within the CNS, FTY720 has the potential to exert effects directly on CNS cells. [27][28][29][30] The effects and underlying mechanisms of FTY720 on immunomodulation have been well studied; however, its effects in NSC differentiation and OLG generation or remyelination are not clear.…”

Section: Introductionmentioning

confidence: 99%

“…27,28 Because S1P receptors are expressed on all cell types within the CNS, FTY720 has the potential to exert effects directly on CNS cells. [27][28][29][30] The effects and underlying mechanisms of FTY720 on immunomodulation have been well studied; however, its effects in NSC differentiation and OLG generation or remyelination are not clear. Whether FTY720 can induce a growth-promoting environment and enhance the therapeutic effect of transplanted NSCs in MS and EAE remains to be determined.…”

Section: Introductionmentioning

confidence: 99%

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

Zhang

Ćirić

et al. 2017

Molecular Therapy

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Inflammatory demyelination and axonal damage of the CNS are hallmarks of multiple sclerosis (MS) and its animal model, experimental autoimmune encephalomyelitis (EAE). Fingolimod (FTY720), the first FDA-approved oral medication for MS, suppresses acute disease but is less effective at the chronic stage, and whether it has a direct effect on neuroregeneration in MS and EAE remains unclear. Here we show that FTY720, at nanomolar concentrations, effectively protected survival of neural stem cells (NSCs) and enhanced their development into mature oligodendrocytes (OLGs) in vitro, primarily through the S1P3 and S1P5 receptors. In vivo, treatment with either FTY720 or NSCs alone had no effect on the secondary progressive stage of remitting-relapsing EAE, but a combination therapy with FTY720 and NSCs promoted significant recovery, including ameliorated clinical signs and CNS inflammatory demyelination, enhanced MBP synthesis and remyelination, inhibited axonal degeneration, and reduced astrogliosis. Moreover, FTY720 significantly improved incorporation and survival of transplanted NSCs in the CNS and drove their differentiation into more OLGs but fewer astrocytes, thus promoting remyelination and CNS repair processes in situ. Our data demonstrate a novel effect of FTY720 on NSC differentiation and remyelination, broadening its possible application to NSC-based therapy in the secondary progressive stage of MS.

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“…After systemic administration fingolimod readily accesses the CNS where endogenous sphingosine kinases generate the active form of the drug and where it exerts multiple effects acting on resident cells (Bdirect^CNS mechanism) [21], such as promoting the neuroprotective effects of microglia through a downregulation of proinflammatory cytokine production [22], and protecting neurons against excitotoxic death by inhibiting p38 mitogen-activated protein kinase activation [23].…”

Section: Introductionmentioning

confidence: 99%

Fingolimod: A Disease-Modifier Drug in a Mouse Model of Amyotrophic Lateral Sclerosis

et al. 2016

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Fingolimod phosphate (FTY720), the first approved oral therapy for multiple sclerosis, primarily acts as an immunomodulator. Its concomitant effects in the central nervous system, however, indicate a potentially broader spectrum of activity in neurodegenerative diseases. In the present study, we investigated the possible effects of fingolimod in a mouse model of amyotrophic lateral sclerosis (ALS), a neurodegenerative disease characterized by a strong neuroinflammatory component. Fingolimod (0.1 and 1 mg/kg i.p.) was administered to mSOD1 G93A mice, a well-characterized mouse model of ALS, starting from the onset of motor symptoms to the end stage of the disease. The drug was able to improve the neurological phenotype (p < 0.05) and to extend the survival (p < 0.01) of ALS mice. The beneficial effect of fingolimod administration was associated with a significant modulation of neuroinflammatory and protective genes (CD11b, Foxp3, iNOS, Il1β, Il10, Arg1, and Bdnf) in motor cortex and spinal cord of animals. Our data show, for the first time, that fingolimod is protective in ALS mice and that its beneficial effects are accompanied by a modulation of microglial activation and innate immunity. Considering that the treatment was started in already symptomatic mice, our data strongly support fingolimod as a potential new therapeutic approach to ALS.

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Central nervous system-directed effects of FTY720 (fingolimod)

Cited by 164 publications

References 69 publications

Fingolimod promotes blood–nerve barrier properties in vitro

Fingolimod promotes blood–nerve barrier properties in vitro

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

Fingolimod: A Disease-Modifier Drug in a Mouse Model of Amyotrophic Lateral Sclerosis

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