Article

Mechanism of Action of Oral Fingolimod (FTY720) in Multiple Sclerosis

Department of Molecular Biology, Helen L. Dorris Child and Adolescent Neuropsychiatric Disorder Institute, The Scripps Research Institute, La Jolla, CA, USA.
Clinical neuropharmacology (Impact Factor: 2.01). 03/2010; 33(2):91-101. DOI: 10.1097/WNF.0b013e3181cbf825
Source: PubMed

ABSTRACT

Fingolimod (FTY720) is a first-in-class orally bioavailable compound that has shown efficacy in advanced clinical trials for the treatment of multiple sclerosis (MS). In vivo, fingolimod is phosphorylated to form fingolimod-phosphate, which resembles naturally occurring sphingosine 1-phosphate (S1P), an extracellular lipid mediator whose major effects are mediated by cognate G protein-coupled receptors. There are at least 5 S1P receptor subtypes, known as S1P subtypes 1-5 (S1P1-5), 4 of which bind fingolimod-phosphate. These receptors are expressed on a wide range of cells that are involved in many biological processes relevant to MS. S1P1 plays a key role in the immune system, regulating lymphocyte egress from lymphoid tissues into the circulation. Fingolimod-phosphate initially activates lymphocyte S1P1 via high-affinity receptor binding yet subsequently induces S1P1 down-regulation that prevents lymphocyte egress from lymphoid tissues, thereby reducing autoaggressive lymphocyte infiltration into the central nervous system (CNS). S1P receptors are also expressed by many CNS cell types and have been shown to influence cell proliferation, morphology, and migration. Fingolimod crosses the blood-brain barrier and may therefore have direct CNS effects, distinguishing it from immunologically targeted MS therapies. Prophylactic administration of fingolimod to animals with experimental autoimmune encephalitis (EAE), a model of MS, completely prevents development of EAE features, whereas therapeutic administration significantly reduces clinical severity of EAE. Therapeutic efficacy observed in animal studies has been substantiated in phase 2 and 3 trials involving patients with relapsing or relapsing-remitting MS.

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Available from: hans-peter Hartung, Oct 05, 2015
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    • "FTY720-P binds to S1PR 1 , and impairs egress of both B and T cells from lymphoid organs. It also binds to S1PR 5 , which is expressed on surface of NK-Cells and plays an important role in their migration [23]. Therefore, Fingolimod may affect migration of every types of neoplastic cells in both Hodgkin and non-Hodgkin lymphoma. "
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    ABSTRACT: Lymphomas (Hodgkin’s (10%) and non-Hodgkin’s (90%) lymphomas) are a group of blood cell tumors arising from lymphocytes and lymphadenopathy is the most common primary presentation of the disease. In non-Hodgkin lymphomas, the prognosis is worse. As the disease initiates, neoplastic cells may spread to and involve other lymph nodes and extra nodal regions. The disease is staged based on desperation of neoplastic cells and the prognosis highly depends on the stage of the disease at the time of diagnosis. Fingolimod is an immunomodulating drug, approved for treating relapsing forms of multiple sclerosis. Fingolimod impairs migration of lymphocytes from lymph nodes and it is hypothesized that Fingolimod could alleviate and decrease disease burden of lymphoma as it sequesters malignant cells within involved lymph nodes and it decelerates progression of the disease, increases efficacy of other treatment options and it is synergistic with anti-VEGF medications, it is an anti-metastatic, antiinflammatory, cytostatic/cytotoxic agent and it boosts function of immune system in deterioration of neoplastic cells. Therefore, the agent can be used not only to treat lymphoma, but also to control and prevent relapse of the disease in those who are remitted.
    Full-text · Article · Dec 2015
    • "FTY720-P suppresses the egress of autoaggressive lymphocytes from lymphoid tissues. Thereby, it prevents their infiltration of the central nervous system (CNS) and reduces the potential for inflammatory tissue damage [29] [30] [31] [32] [33] [34] [35] [36] [37]. FTY720 ameliorates clinical scores in several rodent EAE models [38] [39] [40] [41] [42] [43] [44]. "
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    ABSTRACT: Experimental autoimmune encephalomyelitis (EAE) is a widely-used rodent model for multiple sclerosis (MS), but a single model can hardly capture all features of MS. We investigated whether behavioral parameters in addition to clinical motor function scores could be used to assess treatment efficacy during score-free intervals in the relapsing-remitting EAE model in SJL/J mice. We studied the effects of the clinical reference compounds FTY720 (fingolimod, 0.5mg/kg/day) and dimethyl fumarate (DMF, 20-30mg/kg/day) on clinical scores in several rodent EAE models in order to generate efficacy profiles. SJL/J mice with relapsing-remitting EAE were studied using behavioral tests, including rotarod, gait analysis, locomotor activity and grip strength. SJL/J mice were also examined according to Crawley's sociability and preference for social novelty test. Prophylactic treatment with FTY720 prevented clinical scores in three of the four EAE rodent models: Dark Agouti (DA) and Lewis rats and C57BL/6J mice. Neither prophylactic nor late-therapeutic treatment with FTY720 reduced clinical scores or reversed deficits in the rotarod test in SJL/J mice, but we observed effects on motor functions and sociability in the absence of clinical scores. Prophylactic treatment with FTY720 improved the gait of SJL/J mice whereas late-therapeutic treatment improved manifestations of reduced social (re)cognition or preference for social novelty. DMF was tested in three EAE models and did not improve clinical scores at the dose used. These data indicate that improvements in behavioral deficits can occur in absence of clinical scores, which indicate subtle drug effects and may have translational value for human MS.
    No preview · Article · Dec 2015 · Behavioural Brain Research
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    • "In addition to MS, S1P signaling has also been implicated in other CNS pathologies including Sandhoff disease and demyelination [21, 26–30]. Prior reports implicated S1P signaling in cerebral ischemia where it was presumed to act through effects on immune cells, including elevated S1P levels [31] and that the nonselective S1P receptor modulator, FTY720 (fingolimod), a current therapy for MS [17] [18] [19] [20], reduces brain damage in cerebral ischemia [32– 36]. Intriguingly, fingolimod improved outcomes in a proofof-concept clinical trial of 23 patients with intracerebral hemorrhage at both acute (days) and chronic (months) time points [37], consistent with S1P signaling effects in human stroke. "
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    ABSTRACT: Initial and recurrent stroke produces central nervous system (CNS) damage, involving neuroinflammation. Receptor-mediated S1P signaling can influence neuroinflammation and has been implicated in cerebral ischemia through effects on the immune system. However, S1P-mediated events also occur within the brain itself where its roles during stroke have been less well studied. Here we investigated the involvement of S1P signaling in initial and recurrent stroke by using a transient middle cerebral artery occlusion/reperfusion (M/R) model combined with analyses of S1P signaling. Gene expression for S1P receptors and involved enzymes was altered during M/R, supporting changes in S1P signaling. Direct S1P microinjection into the normal CNS induced neuroglial activation, implicating S1P-initiated neuroinflammatory responses that resembled CNS changes seen during initial M/R challenge. Moreover, S1P microinjection combined with M/R potentiated brain damage, approximating a model for recurrent stroke dependent on S1P and suggesting that reduction in S1P signaling could ameliorate stroke damage. Delivery of FTY720 that removes S1P signaling with chronic exposure reduced damage in both initial and S1P-potentiated M/R-challenged brain, while reducing stroke markers like TNF- α . These results implicate direct S1P CNS signaling in the etiology of initial and recurrent stroke that can be therapeutically accessed by S1P modulators acting within the brain.
    Full-text · Article · Nov 2015 · Mediators of Inflammation
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