Accessible Unlicensed Requires Authentication Published by De Gruyter January 23, 2015

Antinociceptive effects of FTY720 during trauma-induced neuropathic pain are mediated by spinal S1P receptors

Dong Dong Zhang, Bona Linke, Jing Suo, Aleksandra Zivkovic, Yannick Schreiber, Nerea Ferreirós, Marina Henke, Gerd Geisslinger, Holger Stark and Klaus Scholich
From the journal Biological Chemistry

Abstract

FTY720 (fingolimod) is, after its phosphorylation by sphingosine kinase (SPHK) 2, a potent, non-selective sphingosine-1-phosphate (S1P) receptor agonist. FTY720 has been shown to reduce the nociceptive behavior in the paclitaxel model for chemotherapy-induced neuropathic pain through downregulation of S1P receptor 1 (S1P1) in microglia of the spinal cord. Here, we investigated the mechanisms underlying the antinociceptive effects of FTY720 in a model for trauma-induced neuropathic pain. We found that intrathecal administration of phosphorylated FTY720 (FTY720-P) decreased trauma-induced pain behavior in mice, while intraplantar administered FTY720-P had no effect. FTY720-P, but not FTY720, reduced the nociceptive behavior in SPHK2-deficient mice, suggesting the involvement of S1P receptors. Fittingly, intrathecal administration of antagonists for S1P1 or S1P3, W146 and Cay10444 respectively, abolished the antinociceptive effects of systemically administered FTY720, demonstrating that activation of both receptors in the spinal cord is necessary to induce antinociceptive effects by FTY720. Accordingly, intrathecal administration of S1P1 receptor agonists was not sufficient to evoke an antinociceptive effect. Taken together, the data show that, in contrast to its effects on chemotherapy-induced neuropathy, FTY720 reduces trauma-induced neuropathic pain by simultaneous activation of spinal S1P1 and S1P3 receptor subtypes.


Corresponding author: Klaus Scholich, Institut für Klinische Pharmakologie, pharmazentrum frankfurt/ZAF, E.S., Klinikum der Goethe-Universität Frankfurt, Theodor-Stern-Kai 7, D-60590 Frankfurt/Main, Germany, e-mail:

Acknowledgments

We would like to thank Namir Abazi for assistance with the label-free assay. This work was supported by the Deutsche Forschungsgemeinschaft (DFG) grants SCHO817–3, SFB1039 TPA08, INST 208/664–1. FU, and an unrestricted grant from Mundipharma Research GmbH & Co KG.

References

Albert, R., Hinterding, K., Brinkmann, V., Guerini, D., Muller-Hartwieg, C., Knecht, H., Simeon, C., Streiff, M., Wagner, T., Welzenbach, K., et al. (2005). Novel immunomodulator FTY720 is phosphorylated in rats and humans to form a single stereoisomer. Identification, chemical proof, and biological characterization of the biologically active species and its enantiomer. J. Med. Chem. 48, 5373–5377.Search in Google Scholar

Anliker, B. and Chun, J, (2004). Lysophospholipid G protein-coupled receptors. J. Biol. Chem. 279, 20555–20558.Search in Google Scholar

Billich, A., Bornancin, F., Devay, P., Mechtcheriakova, D., Urtz, N., and Baumruker, T. (2003). Phosphorylation of the immunomodulatory drug FTY720 by sphingosine kinases. J. Biol. Chem. 278, 47408–47415.Search in Google Scholar

Brinkmann, V. (2007). Sphingosine 1-phosphate receptors in health and disease: mechanistic insights from gene deletion studies and reverse pharmacology. Pharmacol. Ther. 115, 84–105.Search in Google Scholar

Brinkmann, V., Davis, M.D., Heise, C.E., Albert, R., Cottens, S., Hof, R., Bruns, C., Prieschl, E., Baumruker, T., Hiestand, P., et al. (2002). The immune modulator FTY720 targets sphingosine 1-phosphate receptors. J. Biol. Chem. 277, 21453–21457.Search in Google Scholar

Camprubi-Robles, M., Mair, N., Andratsch, M., Benetti, C., Beroukas, D., Rukwied, R., Langeslag, M., Proia, R.L., Schmelz, M., Ferrer Montiel, A.V., et al. (2013). Sphingosine-1-phosphate-induced nociceptor excitation and ongoing pain behavior in mice and humans is largely mediated by S1P3 receptor. J. Neurosci. 33, 2582–2592.Search in Google Scholar

Chen, X., Wiemer, A.J., Hohl, R.J., and Wiemer, D.F. (2002). Stereoselective synthesis of the 5′-hydroxy-5′-phosphonate derivatives of cytidine and cytosine arabinoside. J. Org. Chem. 67, 9331–9339.Search in Google Scholar

Colombaioni, L. and Garcia-Gil, M. (2004). Sphingolipid metabolites in neural signalling and function. Brain Res. Brain Res. Rev. 46, 328–355.Search in Google Scholar

Coste, O., Brenneis, C., Linke, B., Pierre, S., Maeurer, C., Becker, W., Schmidt, H., Gao, W., Geisslinger, G., and Scholich, K. (2008a). Sphingosine 1-phosphate modulates spinal nociceptive processing. J. Biol. Chem. 283, 32442–32451.Search in Google Scholar

Coste, O., Pierre, S., Marian, C., Brenneis, C., Angioni, C., Schmidt, H., Popp, L., Geisslinger, G., and Scholich, K. (2008b). Antinociceptive activity of the S1P-receptor agonist FTY720. J. Cell. Mol. Med. Med 12, 995–1004.Search in Google Scholar

Crossland, L.K. and Servis, K.L. (1970). Facile synthesis of methanesulfonate esters. J. Org. Chem. 35, 3195–3195.Search in Google Scholar

Darios, F., Wasser, C., Shakirzyanova, A., Giniatullin, A., Goodman, K., Munoz-Bravo, J.L., Raingo, J., Jorgacevski, J., Kreft, M., Zorec, R., et al. (2009). Sphingosine facilitates SNARE complex assembly and activates synaptic vesicle exocytosis. Neuron 62, 683–694.Search in Google Scholar

Decosterd, I. and Woolf, C.J. (2000). Spared nerve injury: an animal model of persistent peripheral neuropathic pain. Pain 87, 149–158.Search in Google Scholar

Durand, P., Peralba, P., Sierra, F., and Renaut, P. (2000). A new efficient synthesis of the Immuusuppresive Agent FTY-720. Synthesis 4, 505–506.Search in Google Scholar

Finley, A., Chen, Z., Esposito, E., Cuzzocrea, S., Sabbadini, R., and Salvemini, D. (2013). Sphingosine 1-phosphate mediates hyperalgesia via a neutrophil-dependent mechanism. PLoS One 8, e55255.Search in Google Scholar

Fujita, T., Hirose, R., Yoneta, M., Sasaki, S., Inoue, K., Kiuchi, M., Hirase, S., Chiba, K., Sakamoto, H., and Arita, M. (1996). Potent immunosuppressants, 2-alkyl-2-aminopropane-1,3-diols. J. Med. Chem. 39, 4451–4459.Search in Google Scholar

Grammatikos, G., Muhle, C., Ferreiros, N., Schroeter, S., Bogdanou, D., Schwalm, S., Hintereder, G., Kornhuber, J., Zeuzem, S., Sarrazin, C., et al. (2014). Serum acid sphingomyelinase is upregulated in chronic hepatitis C infection and non alcoholic fatty liver disease. Biochim. Biophys. Acta 1841, 1012–1020.Search in Google Scholar

Groves, A., Kihara, Y., and Chun, J. (2013). Fingolimod: direct CNS effects of sphingosine 1-phosphate (S1P) receptor modulation and implications in multiple sclerosis therapy. J. Neurol. Sci. 328, 9–18.Search in Google Scholar

Hla, T. and Dannenberg, A.J. (2012). Sphingolipid signaling in metabolic disorders. Cell Metab. 16, 420–434.Search in Google Scholar

Jaillard, C., Harrison, S., Stankoff, B., Aigrot, M.S., Calver, A.R., Duddy, G., Walsh, F.S., Pangalos, M.N., Arimura, N., Kaibuchi, K., et al. (2005). Edg8/S1P5: an oligodendroglial receptor with dual function on process retraction and cell survival. J. Neurosci. 25, 1459–1469.Search in Google Scholar

Janes, K., Little, J.W., Li, C., Bryant, L., Chen, C., Chen, Z., Kamocki, K., Doyle, T., Snider, A., Esposito, E., et al. (2014). The development and maintenance of paclitaxel-induced neuropathic pain require activation of the sphingosine 1-phosphate receptor subtype 1. J. Biol. Chem. 289, 21082–21097.Search in Google Scholar

Karliner, J.S. (2009). Sphingosine kinase regulation and cardioprotection. Cardiovasc Res. 82, 184–192.Search in Google Scholar

Lim, K.G., Tonelli, F., Li, Z., Lu, X., Bittman, R., Pyne, S., and Pyne, N.J. (2011). FTY720 analogues as sphingosine kinase 1 inhibitors: enzyme inhibition kinetics, allosterism, proteasomal degradation, and actin rearrangement in MCF-7 breast cancer cells. J. Biol. Chem. 286, 18633–18640.Search in Google Scholar

Mair, N., Benetti, C., Andratsch, M., Leitner, M.G., Constantin, C.E., Camprubi-Robles, M., Quarta, S., Biasio, W., Kuner, R., Gibbins, I.L., et al. (2011). Genetic evidence for involvement of neuronally expressed S1P receptor in nociceptor sensitization and inflammatory pain. PLoS One 6, e17268.Search in Google Scholar

Mulgaonkar, S., Tedesco, H., Oppenheimer, F., Walker, R., Kunzendorf, U., Russ, G., Knoflach, A., Patel, Y., and Ferguson, R. (2006). FTY720/cyclosporine regimens in de novo renal transplantation: a 1-year dose-finding study. Am. J. Transplant 6, 1848–1857.Search in Google Scholar

Payne, S.G., Oskeritzian, C.A., Griffiths, R., Subramanian, P., Barbour, S.E., Chalfant, C.E., Milstien, S., and Spiegel, S. (2006). The immunosuppressant drug FTY720 inhibits cytosolic phospholipase A2 independently of sphingosine-1-phosphate receptors. Blood 109, 1077–1085.Search in Google Scholar

Pchejetski, D., Bohler, T., Brizuela, L., Sauer, L., Doumerc, N., Golzio, M., Salunkhe, V., Teissie, J., Malavaud, B., Waxman, J., et al. (2010). FTY720 (fingolimod) sensitizes prostate cancer cells to radiotherapy by inhibition of sphingosine kinase-1. Cancer Res. 70, 8651–8661.Search in Google Scholar

Pierre, S.C., Hausler, J., Birod, K., Geisslinger, G., and Scholich, K. (2004). PAM mediates sustained inhibition of cAMP signaling by sphingosine-1-phosphate. EMBO J. 23, 3031–3040.Search in Google Scholar

Pyne, S., Lee, S.C., Long, J., and Pyne, N.J. (2009). Role of sphingosine kinases and lipid phosphate phosphatases in regulating spatial sphingosine 1-phosphate signalling in health and disease. Cell Signal. 21, 14–21.Search in Google Scholar

Saba, J.D. and Hla, T. (2004). Point-counterpoint of sphingosine 1-phosphate metabolism. Circ. Res. 94, 724–734.Search in Google Scholar

Sanna, M.G., Liao, J., Jo, E., Alfonso, C., Ahn, M.Y., Peterson, M.S., Webb, B., Lefebvre, S., Chun, J., Gray, N., et al. (2004). Sphingosine 1-phosphate (S1P) receptor subtypes S1P1 and S1P3, respectively, regulate lymphocyte recirculation and heart rate. J. Biol. Chem. 279, 13839–13848.Search in Google Scholar

Schmidtko, A., Gao, W., Sausbier, M., Rauhmeier, I., Sausbier, U., Niederberger, E., Scholich, K., Huber, A., Neuhuber, W., Allescher, H.D., et al. (2008). Cysteine-rich protein 2, a novel downstream effector of cGMP/cGMP-dependent protein kinase I-mediated persistent inflammatory pain. J. Neurosci. 28, 1320–1330.Search in Google Scholar

Scott, C.W. and Peters, M.F. (2010). Label-free whole-cell assays: expanding the scope of GPCR screening. Drug Discov. Today 15, 704–716.Search in Google Scholar

Sisignano, M., Bennett, D.L., Geisslinger, G., and Scholich, K. (2014). TRP-channels as key integrators of lipid pathways in nociceptive neurons. Progr. Lipid Res. 53, 93–107.Search in Google Scholar

Spiegel, S. and Milstien, S. (2002). Sphingosine 1-phosphate, a key cell signaling molecule. J. Biol. Chem. 277, 25851–25854.Search in Google Scholar

Spiegel, S. and Milstien, S. (2003). Sphingosine-1-phosphate: an enigmatic signalling lipid. Nat. Rev. Mol. Cell. Biol. 4, 397–407.Search in Google Scholar

Spiegel, S. and Milstien, S. (2011). The outs and the ins of sphingosine-1-phosphate in immunity. Nat. Rev. Immunol. 11, 403–415.Search in Google Scholar

Spiegel, S., Milstien, S., and Grant, S. (2012). Endogenous modulators and pharmacological inhibitors of histone deacetylases in cancer therapy. Oncogene 31, 537–551.Search in Google Scholar

Tedesco-Silva, H., Mourad, G., Kahan, B.D., Boira, J.G., Weimar, W., Mulgaonkar, S., Nashan, B., Madsen, S., Charpentier, B., Pellet, P., et al. (2005). FTY720, a novel immunomodulator: efficacy and safety results from the first phase 2A study in de novo renal transplantation. Transplantation 79, 1553–1560.Search in Google Scholar

Van Brocklyn, J.R., Lee, M.J., Menzeleev, R., Olivera, A., Edsall, L., Cuvillier, O., Thomas, D.M., Coopman, P.J., Thangada, S., Liu, C.H., et al. (1998). Dual actions of sphingosine-1-phosphate: extracellular through the Gi-coupled receptor Edg-1 and intracellular to regulate proliferation and survival. J. Cell Biol. 142, 229–240.Search in Google Scholar

Zemann, B., Kinzel, B., Muller, M., Reuschel, R., Mechtcheriakova, D., Urtz, N., Bornancin, F., Baumruker, T., and Billich, A. (2006). Sphingosine kinase type 2 is essential for lymphopenia induced by the immunomodulatory drug FTY720. Blood 107, 1454–1458.Search in Google Scholar

Zhang, Y.H., Fehrenbacher, J.C., Vasko, M.R., and Nicol, G.D. (2006a). Sphingosine-1-phosphate via activation of a G-protein-coupled receptor(s) enhances the excitability of rat sensory neurons. J. Neurophysiol. 96, 1042–1052.Search in Google Scholar

Zhang, Y.H., Vasko, M.R., and Nicol, G.D. (2006b). Intracellular sphingosine 1-phosphate mediates the increased excitability produced by nerve growth factor in rat sensory neurons. J. Physiol. 575, 101–113.Search in Google Scholar

Zhang, Z., Zhang, Z., Fauser, U., Artelt, M., Burnet, M., and Schluesener, H.J. (2007). FTY720 attenuates accumulation of EMAP-II+ and MHC-II+ monocytes in early lesions of rat traumatic brain injury. J. Cell. Mol. Med. Med 11, 307–314.Search in Google Scholar

Zivkovic, A.S. and Stark, H. (2010). Efficient chromatograpy-free synthesis of the oxy-anylogue of fingolimod. Tetrahedron Lett. 51, 3769–3771.Search in Google Scholar

Supplemental Material:

The online version of this article (DOI: 10.1515/hsz-2014-0276) offers supplementary material, available to authorized users.

Received: 2014-11-27
Accepted: 2015-1-16
Published Online: 2015-1-23
Published in Print: 2015-6-1

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