Phosphorylated FTY720 stimulates ERK phosphorylation in astrocytes via S1P receptors

Osinde, Maribel; Müllershausen, Florian; Dev, Kumlesh K.

doi:10.1016/j.neuropharm.2006.11.010

Cited by 101 publications

(82 citation statements)

References 55 publications

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“…2F and Fig. S2A), as was reported in HEK293 cells and cultured astrocytes (22,23). Similar results were obtained with the S1P1-specific agonists pKRP203 (100 nM) and SEW2871 (100 nM) (Fig.…”

Section: Resultssupporting

confidence: 87%

“…These effects all depend on ongoing neuronal activity. Functionally relevant synaptic activity takes more than a week to develop in cultures of embryonic neurons, which explains why previous reports did not detect fingolimod-induced ERK1/2 phosphorylation in immature neurons (22). Although increased ERK1/2 phosphorylation has been described in astrocytes after phospho-fingolimod addition (22)-and our experiments confirm S1P1 receptor expression in cultured astrocytes-phospho-fingolimod did not increase the levels of BDNF in these cells, indicating that the increase in BDNF is neuron-specific.…”

Section: Discussionmentioning

confidence: 97%

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

Deogracias

Yazdani

Dekkers

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

229

212

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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.

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Section: Resultssupporting

confidence: 87%

Section: Discussionmentioning

confidence: 97%

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

Deogracias

Yazdani

Dekkers

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

229

212

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“…Activation of Erk1/2 and Akt by HDL Is Blocked by Pertussis Toxin and an S1P1 Antagonist-Previous studies have shown that S1P-mediated activation of Erk and Akt is PTX-sensitive (16,17) and mediated by the S1P receptor, S1P1 (18,19). We performed multiplex microbead suspension array analysis to evaluate the effect of PTX on HDL-induced activation of Erk1/2 and Akt in endothelial cells.…”

Section: Hdl-induced Enhancement Of Teer Is Pertussis Toxinsensitive-mentioning

confidence: 99%

High Density Lipoprotein-associated Sphingosine 1-Phosphate Promotes Endothelial Barrier Function

Argraves

Gazzolo

Groh

et al. 2008

Journal of Biological Chemistry

113

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High density lipoproteins (HDL) are major plasma carriers of sphingosine 1-phosphate (S1P). Here we show that HDL increases endothelial barrier integrity as measured by electric cell substrate impedance sensing. S1P was implicated as the mediator in this process through findings showing that pertussis toxin, an inhibitor of G i -coupled S1P receptors, as well as antagonists of the S1P receptor, S1P1, inhibited barrier enhancement by HDL. Additional findings show that HDL stimulates endothelial cell activation of Erk1/2 and Akt, signaling pathway intermediates that have been implicated in S1P-dependent endothelial barrier activity. HDL was also found to promote endothelial cell motility, a process that may also relate to endothelial barrier function in the context of a vascular injury response. The effects of HDL on endothelial cell Erk1/2 and Akt activation and motility were suppressed by pertussis toxin and S1P1 antagonists. However, both HDL-induced barrier enhancement and HDL-induced motility showed a greater dependence on Akt activation as compared with Erk1/2 activation. Together, the findings indicate that HDL has endothelial barrier promoting activities, which are attributable to its S1P component and signaling through the S1P1/Akt pathway.Sphingosine 1-phosphate (S1P) 2 is a plasma-borne lysosphingolipid that has been shown to regulate endothelial barrier integrity (1). For example, treatment of cultured endothelial cells with S1P associated with the carrier albumin acts to increase endothelial barrier activity as indicated by increased transendothelial electrical resistance (2, 3). Moreover, S1P administration greatly reduces lung capillary leakage induced in mice by lipopolysaccharide treatment (4). Mechanistically, S1P acts to enhance tight junction formation in neighboring endothelial cells by influencing subcellular distributions of tight junction components including ZO-1 and claudin-5 (5). In addition, S1P induces endothelial cortical actin assembly (1) and relocation of endothelial cell junctional adhesion molecules including platelet endothelial cell adhesion molecule and vascular endothelial-cadherin to cell-cell junctional areas (5).In plasma, S1P is found associated with multiple lipoproteins including low density lipoproteins, very low density lipoproteins, and high density lipoproteins (HDL). However, the bulk of the lipoprotein particle-associated S1P (54%) is bound to HDL (6). A number of recent studies point to the S1P cargo of HDL as being a mediator of many of the cardiovascular effects of HDL including the ability to promote vasodilation, vasoconstriction, and angiogenesis, protect against ischemia/reperfusion injury, and inhibit/reverse atherosclerosis (7). One important cardiovascular-related effect of S1P that has not yet been attributed to HDL is regulation of endothelial barrier activity, a major physiological function of the endothelium. Here we investigate the role of HDL as a regulator of endothelial barrier integrity processes known to be dependent on S1P signaling. EXPERIMEN...

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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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Phosphorylated FTY720 stimulates ERK phosphorylation in astrocytes via S1P receptors

Cited by 101 publications

References 55 publications

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

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

High Density Lipoprotein-associated Sphingosine 1-Phosphate Promotes Endothelial Barrier Function

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

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