Novel role of sphingosine kinase 1 as a mediator of neurotrophin‐3 action in oligodendrocyte progenitors

Saini, Harsimran; Coelho, Rochelle P.; Goparaju, Sravan K.; Jolly, Puneet S.; Maceyka, Michael; Spiegel, Sarah; Sato‐Bigbee, Carmen

doi:10.1111/j.1471-4159.2005.03451.x

Cited by 69 publications

(62 citation statements)

References 86 publications

(202 reference statements)

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“…Although the neurotrophic factors NT-3, BDNF, and GDNF are reported to be induced or to interact with FTY720 during OPC differentiation, 47,56 no significant difference was observed in our study, indicating that FTY720-induced NSC differentiation is not through induction by these neurotrophic factors. We then focus on the S1P receptors, the designated interaction partners of phosphorylated FTY720, and their downstream signaling during NSC differentiation.…”

Section: Discussioncontrasting

confidence: 47%

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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Section: Discussioncontrasting

confidence: 47%

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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“…[3] In addition to playing a role in the immune system, all S1P receptors except S1P4 are also found differentially expressed in the central nervous system [4] and on various tumor cell types. [5,6] Although the precise regulation of these receptors by locally released S1P remains unclear, S1P receptors are thought to play a role in such events as astrocyte migration, [7] oligodendrocyte differentiation, and cell survival [8,9] and neurogenesis. [10,11] To assess the relevance of individual S1P receptor subtypes for the activity of FTY720-P, selective agonists are required.…”

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confidence: 99%

Design and Synthesis of Selective and Potent Orally Active S1P5 Agonists

et al. 2010

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The immunomodulatory drug fingolimod (FTY720, 2-amino-2-[2-(4-octylphenyl)ethyl]propane-1,3-diol), derived from a fungal metabolite myriocin), is phosphorylated in vivo by sphingosine kinases to produce (R)-FTY720-phosphate (FTY720-P). [1,2] FTY720-P activates sphingosine-1-phosphate (S1P) receptors S1P1, S1P3, S1P4, and S1P5 at low nanomolar concentrations and is inactive toward the S1P2 receptor.[1] The FTY720-P-mediated activation of the S1P1 receptor on lymphocytes induces receptor internalization, which attenuates T-cell response to S1P gradients, preventing their egress from secondary lymphoid tissues. [3] In addition to playing a role in the immune system, all S1P receptors except S1P4 are also found differentially expressed in the central nervous system [4] and on various tumor cell types. [5,6] Although the precise regulation of these receptors by locally released S1P remains unclear, S1P receptors are thought to play a role in such events as astrocyte migration, [7] oligodendrocyte differentiation, and cell survival [8,9] and neurogenesis. [10,11] To assess the relevance of individual S1P receptor subtypes for the activity of FTY720-P, selective agonists are required. Because S1P5 receptors are expressed on oligodendrocytes, and S1P5 receptors are thought to play a role in oligodendrocyte differentiation and survival, we focused on the development of S1P5 agonists. By using a highthroughput screening calcium mobilization assay with GPCR priming and FLIPR technology, [12] we discovered benzamide 1, which has good in vitro potency toward the S1P5 receptor (EC 50 = 270 nm), but has modest selectivity against S1P1 (EC 50 = 3140 nm) and S1P4 (EC 50 = 100 nm). Herein we report our studies of various benzamide modifications carried out to improve the selectivity, bioactivity, pharmacokinetic properties, and ancillary profile of 1, ultimately resulting in the discovery of potent and very selective S1P5 agonists.To guide the optimization process, homology models of all S1P receptors were built from a crystal structure of bovine rhodopsin (PDB ID: 1F88). [13] Docking experiments of 1 into these models revealed a possible location of the binding site, some essential features of the interactions, and indicated potential regions for gaining selectivity and improving potency. In these complexes (Figure 1), 1 adopts a twisted conformation with the aniline ring,~708 out of the benzamide plane and stabilized by a hydrogen bond between the aniline NH group and the amide carbonyl. In the S1P5 receptor complex, the amide group forms a hydrogen bond with OG1-Thr120. The benzamide phenyl ring lies in a large hydrophobic pocket surrounded by Phe196, Phe201, Phe268, Leu119, Trp264, Leu267, and Leu271. The aniline ring undergoes a T-shaped interaction with Phe116 and hydrophobic contacts with Leu271 and Leu292. The ortho-methyl substituents fill a small pocket formed by Tyr89, Val115, and Leu292 on one side, and sit at the face of Phe196 on the other side. Inspection of sequence alignments (Figure 2) revealed two positions, o...

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“…Samples (15 l) were subjected to SDS-polyacrylamide gel electrophoresis in 12% acrylamide, and the proteins were electrotransferred to nitrocellulose. The membranes were then subjected to immunoblot analysis as previously reported (Saini et al, 2005), with minor modifications. Nonspecific antibody binding to the blots was blocked by incubation in 10 mM Na 2 HPO 4 , 2.7 mM KCl, and 137 mM NaCl, pH 7.4, (PBS) containing 3% nonfat dry milk and 0.05% Tween 20 (blocking solution) for 1 h at room temperature.…”

Section: Methodsmentioning

confidence: 99%

“…Because of its similarity to S1P, FTY720-P is able to bind to all of the high-affinity S1P receptors except S1P 2 (Brinkmann and Lynch, 2002). We have previously found that S1P signaling plays a crucial role as a mediator in the stimulation of OLG progenitor survival by neurotrophin-3 (NT-3) (Saini et al, 2005). This observation led us to hypothesize that FTY720 could, like S1P, have a direct effect on the OLG progenitors.…”

mentioning

confidence: 99%

The Immunomodulator FTY720 Has a Direct Cytoprotective Effect in Oligodendrocyte Progenitors

Coelho

Payne²,

Bittman³

et al. 2007

J Pharmacol Exp Ther

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132

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The immunomodulator 2-amino-2-[2-(4-octylphenyl)ethyl]-1,3-propanediol (FTY720) has promising therapeutic effects in multiple sclerosis (MS), a degenerative disease in which demyelination of the central nervous system is accompanied by death of oligodendrocytes (OLGs), the myelin-producing cells. In vivo phosphorylation of FTY720 generates an agonist for G protein-coupled receptors for sphingosine-1-phosphate, a lipid mediator that plays a crucial role in the stimulation of OLG survival by neurotrophin-3 (NT-3). The mechanisms underlying the action of FTY720 in MS are not clearly understood, although the effects of this drug in autoimmune diseases are thought to stem from its ability to reduce lymphocyte infiltration and inflammation. Interestingly, we now found that FTY720 also has a direct effect on OLG progenitors. Treatment of these cells with FTY720 causes activation of extracellular signal-regulated kinase 1/2 and Akt, accompanied by protection from apoptosis. However, FTY720 also arrested OLG differentiation. Importantly, this effect was counteracted by NT-3, which not only enhanced the survival of OLG progenitors induced by FTY720 but also stimulated their maturation. Altogether, these observations suggest that in addition to its immunosuppressive functions, FTY720 could also have a beneficial effect in MS by direct action on OLG progenitors. However, the finding that FTY720 blocks the differentiation of these cells raises the question of whether MS therapies with FTY720 should include the use of differentiation-enhancing factors such as NT-3. This approach would ensure both protection of existing OLG progenitor pools against immune-mediated insults as well as stimulation of remyelination by enhancing the maturation of these cells.Multiple sclerosis (MS) is a chronic degenerative and debilitating disease of the central nervous system (CNS) characterized by inflammation and demyelination (McQualter and Bernard, 2007). The pathological hallmarks of MS also include axonal degeneration (Trapp et al., 1999) and death of oligodendrocytes (OLGs) (Barnett and Prineas, 2004;Lucchinetti et al., 2004), the cells that make the myelin membrane in the CNS. Although the cause of MS remains unknown, the presence of serum antibodies against different myelin constituents and the existence of multiple inflammatory foci in brain and spinal cord support the idea of a predominant autoimmune component. For this reason, most therapeutic approaches involve the use of anti-inflammatory drugs and immunosuppressants.2-Amino-2-[2-(4-octylphenyl)ethyl]-1,3-propanediol (FTY720, also known as Fingolimod), is among the latest immunomodulatory agents under evaluation for the treatment of MS. This synthetic drug was developed by chemical modification of ISP-I (myriocin), a sphingosine-like metabolite produced by the fungus Isaria sinclairii. FTY720 has been shown to prolong allograft survival in different animal models of transplantation (Chiba et al., 1996) and exert a protective effect in animal models of autoimmune diseases (Ma...

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Novel role of sphingosine kinase 1 as a mediator of neurotrophin‐3 action in oligodendrocyte progenitors

Cited by 69 publications

References 86 publications

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

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

Design and Synthesis of Selective and Potent Orally Active S1P5 Agonists

The Immunomodulator FTY720 Has a Direct Cytoprotective Effect in Oligodendrocyte Progenitors

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