FTY720 sustains and restores neuronal function in the DA rat model of MOG-induced experimental autoimmune encephalomyelitis

Balatoni, Balázs; Storch, Maria K.; Swoboda, E; Schönborn, Vinzenz; Kozieł, Agnieszka; Lambrou, George N.; Hiestand, Peter; Weissert, Robert; Foster, Carolyn A.

doi:10.1016/j.brainresbull.2007.06.023

Cited by 150 publications

(98 citation statements)

References 53 publications

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“…The proposed mechanism of action for pFTY720 is reported as being dependent on internalisation of S1PRs in T cells, which limits their S1P-mediated egress from lymph nodes and thus attenuates the inflammatory response in the brains of multiple sclerosis patients (Adachi and Chiba, 2008). Importantly, a number of studies have now demonstrated that compounds such as pFTY720 can also regulate neuronal and glial cell function (Balatoni et al, 2007;Choi et al, 2011;Fischer et al, 2011;Osinde et al, 2007). Indeed, we and others have shown that S1PRs regulate a number of intracellular signalling pathways in astrocytes and promote astrocyte migration (Mullershausen et al, , 2009).…”

Section: Introductionmentioning

confidence: 99%

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

O’Sullivan

Dev

2015

Journal of Cell Science

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Globoid cell leukodystrophy (Krabbe disease) is a rare infantile neurodegenerative disorder. Krabbe disease is caused by deficiency in the lysosomal enzyme galactocerebrosidase (GALC) resulting in accumulation, in the micromolar range, of the toxic metabolite galactosylsphingosine ( psychosine) in the brain. Here we find that psychosine induces human astrocyte cell death probably via an apoptotic process in a concentration-and time-dependent manner (EC50∼15 μM at 4 h). We show these effects of psychosine are attenuated by pre-treatment with the sphingosine 1-phosphate receptor agonist pFTY720 (fingolimod) (IC50∼100 nM). Psychosine (1 μM, 10 μM) also enhances LPS-induced (EC50∼100 ng/ml) production of pro-inflammatory cytokines in mouse astrocytes, which is also attenuated by pFTY720 (1 μM). Most notably, for the first time, we show that psychosine, at a concentration found in the brains of patients with Krabbe disease (EC50∼100 nM), directly induces demyelination in mouse organotypic cerebellar slices in a manner that is independent of pro-inflammatory cytokine response and that pFTY720 (0.1 nM) significantly inhibits. These results support the idea that psychosine is a pathogenic agent in Krabbe disease and suggest that sphingosine 1-phosphate signalling could be a potential drug target for this disorder.

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Section: Introductionmentioning

confidence: 99%

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

O’Sullivan

Dev

2015

Journal of Cell Science

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“…Promising results in phase II trials with relapsing MS patients mirror the striking efficacy of FTY720 in MS models of experimental autoimmune encephalomyelitis (EAE), shown by preventive and therapeutic treatment (Brinkmann et al, 2002;Fujino et al, 2003;Webb et al, 2004;Kataoka et al, 2005;Balatoni et al, 2007). FTY720 is converted in vivo to its biologically active phosphate ester metabolite (FTY720-P), which acts as a high-affinity agonist for four of the five known G-protein-coupled S1P receptors, namely S1P 1 and S1P [3][4][5] (Brinkmann et al, 2002;Mandala et al, 2002).…”

mentioning

confidence: 99%

Brain Penetration of the Oral Immunomodulatory Drug FTY720 and Its Phosphorylation in the Central Nervous System during Experimental Autoimmune Encephalomyelitis: Consequences for Mode of Action in Multiple Sclerosis

Foster

Howard²,

Schweitzer³

et al. 2007

J Pharmacol Exp Ther

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312

253

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FTY720[2-amino-2-[2-(4-octylphenyl)ethyl]propane-1,3-diol hydrochloride] is an oral sphingosine-1-phosphate receptor modulator under development for the treatment of multiple sclerosis (MS). The drug is phosphorylated in vivo by sphingosine kinase 2 to its bioactive form, FTY720-P. Although treatment with FTY720 is accompanied by a reduction of the peripheral lymphocyte count, its efficacy in MS and experimental autoimmune encephalomyelitis (EAE) may be due to additional, direct effects in the central nervous system (CNS). We now show that FTY720 localizes to the CNS white matter, preferentially along myelin sheaths. Brain trough levels of FTY720 and FTY720-P in rat EAE are of the same magnitude and dose dependently increase; they are in the range of 40 to 540 ng/g in the brain tissue at efficacious doses and exceed blood concentrations severalfold. In a rat model of chronic EAE, prolonged treatment with 0.03 mg/kg was efficacious, but limiting the dosing period failed to prevent EAE despite a significant decrease in blood lymphocytes. FTY720 effectiveness is likely due to a culmination of mechanisms involving reduction of autoreactive T cells, neuroprotective influence of FTY720-P in the CNS, and inhibition of inflammatory mediators in the brain.FTY720 is an oral sphingosine-1-phosphate (S1P) receptor modulator (Baumruker et al., 2007) under development for the treatment of multiple sclerosis (MS), representing the first of a new class of immunomodulatory agents. Promising results in phase II trials with relapsing MS patients mirror the striking efficacy of FTY720 in MS models of experimental autoimmune encephalomyelitis (EAE), shown by preventive and therapeutic treatment (Brinkmann et al., 2002;Fujino et al., 2003;Webb et al., 2004;Kataoka et al., 2005;Balatoni et al., 2007). FTY720 is converted in vivo to its biologically active phosphate ester metabolite (FTY720-P), which acts as a high-affinity agonist for four of the five known G-protein-coupled S1P receptors, namely S1P 1 and S1P 3-5 (Brinkmann et al., 2002;Mandala et al., 2002). Sphingosine kinase (SPHK) 2 is the primary enzyme required for FTY720-P formation, as we and others subsequently confirmed in SPHK2 knockout mice (Kharel et al., 2005;Zemann et al., 2006). The fact that SPHK1 null mice become lymphopenic after FTY720 administration further supports the view that SPHK2 is sufficient for the functional activation of FTY720 (Allende et al., 2004).Emerging evidence suggests that the effectiveness of FTY720 in the central nervous system (CNS) extends beyond immunomodulation to encompass other aspects of MS pathophysiology, including an influence on the blood-brain barrier and glial repair mechanisms that could ultimately contribute to restoration of nerve function (Baumruker et al., 2007; This work was supported by Novartis Pharma AG. 1

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“…Second, the inclusion of unrelated antigens when inducing EAE has led to developing disease mechanisms and therapies that have otherwise failed clinical trials Many of the current therapies used in the treatment of MS have emerged from studies of EAE, and it is not surprising that they are targeted toward regulation of immune cell responses. Such recent treatments include Fingolimod (FTY720) directed against the sphingosine-1-phosphate receptor that regulates T and B cell responses appears to directly stimulate remyelination in the CNS [53,54], and Natalizumab directed toward adhesion molecules on lymphocytes blocks the entrance of those cells in the parenchyma of the CNS [55]. Such therapies, while modulating relapse activity, have generated unexpected side effects in the setting of clinical applications that have in certain cases limited their utilization.…”

Section: Immunological Models For Cns Demyelinationmentioning

confidence: 99%

Model Systems to Define Remyelination Therapies

Miller¹,

Karl²,

Tognatta³

et al. 2018

Neuroplasticity - Insights of Neural Reorganization

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Demyelinating diseases of the central nervous system (CNS), such as multiple sclerosis (MS), are characterized by multiple focal demyelinating lesions, resulting in various functional deficits. The pathology of MS is defined by local loss of myelin sheaths in the brain and spinal cord associated with infiltration of peripheral immune cells. Classically, MS starts with a series of relapses and remissions, followed several years later by a more progressive form of the disease and a steady functional decline. Although the mechanism of disease initiation is poorly understood, disease progression is associated with immune system activation toward CNS antigens including myelin proteins. Animal models of MS have been critical in the development of MS therapies, with experimental allergic encephalitis (EAE) being the most common. This model has been instrumental in defining the role of T cells in disease progression and in the development of targeted therapies. Understanding the biology of myelin repair has, however, largely come from other model systems including local targeted demyelination in vivo, slice preparations, and in vitro. This has led to the identification of a diverse array of potential new targets to modulate disease progression. Development of these new avenues is the target of intensive ongoing research.

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FTY720 sustains and restores neuronal function in the DA rat model of MOG-induced experimental autoimmune encephalomyelitis

Cited by 150 publications

References 53 publications

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

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

Brain Penetration of the Oral Immunomodulatory Drug FTY720 and Its Phosphorylation in the Central Nervous System during Experimental Autoimmune Encephalomyelitis: Consequences for Mode of Action in Multiple Sclerosis

Model Systems to Define Remyelination Therapies

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