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Sphingosin-1-phosphate Receptor 1: a Potential Target to Inhibit Neuroinflammation and Restore the Sphingosin-1-phosphate Metabolism

  • Zeynab Kolahdooz (a1), Sanaz Nasoohi (a2), Masoumeh Asle-Rousta (a3), Abolhassan Ahmadiani (a1) (a4) and Leila Dargahi (a5)...


Background: Recent evidence suggests that an extreme shift may occur in sphingosine metabolism in neuroinflammatory contexts. Sphingosine 1-phosphate (S1P)-metabolizing enzymes (SMEs) regulate the level of S1P. We recently found that FTY720, a S1P analogue, and SEW2871, a selective S1P receptor 1 (S1P1) agonist, provide protection against neural damage and memory deficit in amyloid beta (Aβ)-injected animals. This study aimed to evaluate the effects of these two analogues on the expression of SMEs as well as their anti-inflammatory roles. Methods: Rats were treated with intracerebral lipopolysaccharide (LPS) or Aβ. Memory impairment was assessed by Morris water maze and the effects of drugs on SMEs as well as inflammatory markers, TNF- α and COX-II, were determined by immunoblotting. Results: Aβ and LPS differentially altered the expression profile of SMEs. In Aβ-injected animals, FTY720 and SEW2871 treatments exerted anti-inflammatory effects and restored the expression profile of SMEs, in parallel to our previous findings. In LPS animals however, in spite of anti-inflammatory effects of the two analogues, only FTY720 restored the levels of SMEs and prevented memory deficit. Conclusion: The observed ameliorating effects of FTY720 and SEW7821 can be partly attributed to the interruption of the vicious cycle of abnormal S1P metabolism and neuro-inflammation. The close imitation of the FTY720 effects by SW2871 in Aβ-induced neuro-inflammation may highlight the attractive role of S1P1 as a potential target to restore S1P metabolism and inhibit inflammatory processes.

Le récepteur 1 de la sphingosine-1-phosphate : une cible potentielle pour inhiber la neuroinflammation et rétablir le métabolisme de S1P. Contexte: Selon des données récentes, un changement très important pourrait survenir dans le métabolisme de la sphingosine dans le contexte de la neuroinflammation. Les enzymes qui métabolisent la sphingosine-1-phosphate (S1P) régulent le niveau de S1P. Nous avons observé récemment que FTY720, un analogue de S1P, et SEW2871, un agoniste sélectif du récepteur 1 de S1P, protègent contre le dommage neuronal et le déficit mnésique chez des animaux à qui on a injecté de l’amyloïde bêta (Aß). Le but de cette étude était d’évaluer les effets de ces deux analogues sur l’expression d’enzymes qui métabolisent S1P (SMes ainsi que leur rôle antiinflammatoire. Méthode: Des rats ont été traités au moyen de lipopolysaccarides (LPS) ou d’Aß intracérébral. Le déficit mnésique a été évalué au moyen du labyrinthe aquatique de Morris et les effets de médicaments sur les SMEs ainsi que les marqueurs de l’inflammation, TNF-α et COX-II, ont été déterminés par technique de buvardage. Résultats: L’Aß et les LPS modifiaient de façon différente le profil d’expression des SMEs. Chez les animaux à qui l’Aß avait été injectée, le traitement par FTY720 et par SEW2871 avait des effets antiinflammatoires et restauraient le profil d’expression des SMEs, en parallèle à nos observations antérieures. Cependant, chez les animaux ayant reçu des LPS, seul FTY720 restaurait les niveaux de SMEs et prévenait le déficit mnésique, malgré les effets antiinflammatoires des deux analogues. Conclusion: Les effets bénéfiques de FTY720 et de SEW7821 observés peuvent être partiellement attribués à l’interruption du cycle infernal du métabolisme anormal de S1P et de la neuroinflammation. Les effets très semblables de FTY720 et de SEW2871 sur la neuroinflammation induite par l’Aß pourraient mettre en lumière le rôle important de S1P1 comme cible potentielle pour restaurer le métabolisme de S1P et inhiber le processus inflammatoire.

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Corresponding author

Correspondence to: Leila Dargahi, NeuroBiology Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran. Email:


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1. Spiegel, S, Milstien, S. Sphingosine-1-phosphate: an enigmatic signalling lipid. Nature Rev Mol Cell Biology. 2003;4:397-407.
2. Ogretmen, B, Hannun, YA. Biologically active sphingolipids in cancer pathogenesis and treatment. Nature Rev Cancer. 2004;4:604-616.
3. Cuvillier, O, Pirianov, G, Kleuser, B, Vanek, PG, Coso, OA, Gutkind, JS, Spiegel, S. Suppression of ceramide-mediated programmed cell death by sphingosine-1-phosphate. Nature. 1996;381:800-803.
4. Kim, S, Steelman, AJ, Zhang, Y, Kinney, HC, Li, J. Aberrant upregulation of astroglial ceramide potentiates oligodendrocyte injury. Brain Pathol. 2012;22:41-57.
5. Maceyka, M, Harikumar, KB, Milstien, S, Spiegel, S. Sphingosine-1-phosphate signaling and its role in disease. Trends Cell Biol. 2012;22:50-60.
6. Alessenko, A. The potential role for sphingolipids in neuropathogenesis of Alzheimer’s disease. Biochemistry (Moscow) Supplement Series B: Biomed Chem. 2013;7:108-123.
7. Malaplate-Armand, C, Florent-Béchard, S, Youssef, I, et al. Soluble oligomers of amyloid-β peptide induce neuronal apoptosis by activating a cPLA-2 dependent sphingomyelinase-ceramide pathway. Neurobiol Dis. 2006;23:178-189.
8. Zeng, C, Lee, J, Chen, H, Chen, S, Hsu, C, Xu, J. Amyloid-β peptide enhances tumor necrosis factor-α-induced iNOS through neutral sphingomyelinase/ceramide pathway in oligodendrocytes. J Neurochem. 2005;94:703-712.
9. Ayasolla, K, Khan, M, Singh, AK, Singh, I. Inflammatory mediator and β-amyloid (25–35)-induced ceramide generation and iNOS expression are inhibited by vitamin E. Free Radic Biol Med. 2004;37:325-338.
10. Della Valle, G, Costantini, C, Weindruch, R, Puglielli, L. A TrkA-to-p75NTR molecular switch activates amyloid beta-peptide generation during aging. Biochem J. 2005;391:59-67.
11. He, X, Huang, Y, Li, B, Gong, C-X, Schuchman, EH. Deregulation of sphingolipid metabolism in Alzheimer’s disease. Neurobiol Aging. 2010;31:398-408.
12. Cutler, RG, Kelly, J, Storie, K. Involvement of oxidative stress-induced abnormalities in ceramide and cholesterol metabolism in brain aging and Alzheimer’s disease. Proc Natl Acad Sci USA. 2004;101:2070-2075.
13. Bandaru, VV, Troncoso, J, Det, W. ApoE4 disrupts sterol and sphingolipid metabolism in Alzheimer’s but not normal brain. Neurobiol Aging. 2009;30:591-599.
14. Pettegrew, JW, Panchalingam, K, Hamilton, RL, McClure, RJ. Brain membrane phospholipid alterations in Alzheimer’s disease. Neurochem Res. 2001;26:771-782.
15. Swan, DJ, Kirby, JA, Ali, S. Vascular biology: the role of sphingosine 1‐phosphate in both the resting state and inflammation. J Cell Mol Med. 2010;14:2211-2212.
16. Colton, CA. Heterogeneity of microglial activation in the innate immune response in the brain. J Neuroimmune Pharmacol. 2009;4:399-418.
17. Fischer, I, Alliod, C, Martinier, N, Newcombe, J, Brana, C, Pouly, S. Sphingosine kinase 1 and sphingosine 1-phosphate receptor 3 are functionally upregulated on astrocytes under pro-inflammatory conditions. PloS one. 2011;6:e23905.
18. Nayak, D, Huo, Y, Kwang, W, Pushparaj, P, Kumar, S, Ling, E-A, Dheen, S. Sphingosine kinase 1 regulates the expression of proinflammatory cytokines and nitric oxide in activated microglia. Neuroscience. 2010;166:132-144.
19. Van Doorn, R, Lopes Pinheiro, MA, Kooij, G, et al. Sphingosine 1-phosphate receptor 5 mediates the immune quiescence of the human brain endothelial barrier. J Neuroinflam. 2012;9:133.
20. Choi, JW, Gardell, SE, Herr, DR, et al. FTY720 (fingolimod) efficacy in an animal model of multiple sclerosis requires astrocyte sphingosine 1-phosphate receptor 1 (S1P1) modulation. Proc Natl Acad Sci USA. 2011;108:751-756.
21. Di Menna, L, Molinaro, G, Di Nuzzo, L, et al. Fingolimod protects cultured cortical neurons against excitotoxic death. Pharmacol Res. 2012;67:1-9.
22. Asle-Rousta, M, Oryan, S, Ahmadiani, A, Rahnema, M. Activation of sphingosine 1-phosphate receptor-1 by sew2871 improves cognitive function in Alzheimer΄ s disease model rats. EXCLI J. 2013;12:449-461.
23. Asle-Rousta, M, Kolahdooz, Z, Oryan, S, Ahmadiani, A, Dargahi, L. FTY720 (Fingolimod) Attenuates Beta-amyloid Peptide (Aβ42)-Induced Impairment of Spatial Learning and Memory in Rats. J Mol Neurosci. 2013;50:524-532.
24. Paxinos, G, Watson, C. The rat brain in stereotaxic coordinates: hard cover edition: Access Online via Elsevier; 2006.
25. Vorhees, CV, Williams, MT. Morris water maze: procedures for assessing spatial and related forms of learning and memory. Nat Protoc. 2006;1:848-858.
26. Matloubian, M, Lo, CG, Cinamon, G, et al. Lymphocyte egress from thymus and peripheral lymphoid organs is dependent on S1P receptor 1. Nature. 2004;427:355-360.
27. Kharel, Y, Lee, S, Snyder, AH, et al. Sphingosine kinase 2 is required for modulation of lymphocyte traffic by FTY720. J Biol Chem. 2005;280:36865-36872.
28. Omidbakhsh, R, Rajabli, B, Nasoohi, S, et al. Fingolimod affects gene expression profile associated with LPS-induced memory impairment. Exp Brain Res. 2014:1-10.
29. Cutler, RG, Pedersen, WA, Camandola, S, Rothstein, JD, Mattson, MP. Evidence that accumulation of ceramides and cholesterol esters mediates oxidative stress–induced death of motor neurons in amyotrophic lateral sclerosis. Annals Neurol. 2002;52:448-457.
30. Haughey, NJ, Cutler, RG, Tamara, A, et al. Perturbation of sphingolipid metabolism and ceramide production in HIV-dementia. Annals Neurol. 2004;55:257-267.
31. Katsel, P, Li, C, Haroutunian, V. Gene expression alterations in the sphingolipid athways during progression of dementia and Alzheimer’s disease: a shift toward ceramide accumulation at the earliest recognizable stages of Alzheimer’s disease? Neuroch Res. 2007;32:845-856.
32. Couttas, TA, Kain, N, Daniels, B, et al. Loss of the neuroprotective factor Sphingosine 1-phosphate early in Alzheimer’s disease pathogenesis. Acta Neuropathol Commun. 2014;2:9. doi: 10.1186/2051-5960-2-9.
33. Ceccom, J, Loukh, N, Lauwers-Cances, V, et al. Reduced sphingosine kinase-1 and enhanced sphingosine 1-phosphate lyase expression demonstrate deregulated sphingosine 1-phosphate signaling in Alzheimer’s disease. Acta Neuropathol Commun. 2014;2:12. doi: 10.1186/2051-5960-2-12.
34. Leong, WI, Saba, JD. S1P metabolism in cancer and other pathological conditions. Biochimie. 2010;92:716-723.
35. Lépine, S, Allegood, J, Park, M, Dent, P, Milstien, S, Spiegel, S. Sphingosine-1-phosphate phosphohydrolase-1 regulates ER stress-induced autophagy. Cell Death Differ. 2010;18:350-361.
36. Mandala, SM. Sphingosine-1-phosphate phosphatases. Prostaglandins Other Lipid Mediat. 2001;64:143-156.
37. Serra, M, Saba, JD. Sphingosine 1-phosphate lyase, a key regulator of sphingosine 1-phosphate signaling and function. Adv Enzyme Regul. 2010;50:349-362.
38. Pyne, NJ, Pyne, S. Sphingosine 1-phosphate and cancer. Nature Rev Cancer. 2010;10:489-503.
39. Toman, RE, Payne, SG, Watterson, KR, et al. Differential transactivation of sphingosine-1-phosphate receptors modulates NGF-induced neurite extension. J Cell Biol. 2004;166:381-392.
40. Hobson, JP, Rosenfeldt, HM, Barak, LS, et al. Role of the sphingosine-1-phosphate receptor EDG-1 in PDGF-induced cell motility. Science. 2001;291:1800-1803.
41. Allende, ML, Sasaki, T, Kawai, H, et al. Mice deficient in sphingosine kinase 1 are rendered lymphopenic by FTY720. J. Biol. Chem. 2004;279:52487-52492.
42. Blondeau, N, Lai, Y, Tyndall, S, et al. Distribution of sphingosine kinase activity and mRNA in rodent brain. J Neurochem. 2007;103:509-517.
43. Pitman, MR, Pitson, SM. Inhibitors of the sphingosine kinase pathway as potential therapeutics. Curr. Cancer Drug Targets. 2010;10:354-367.
44. Mizugishi, K, Yamashita, T, Olivera, A, Miller, GF, Spiegel, S, Proia, RL. Essential role for sphingosine kinases in neural and vascular development. Mol. Cell Biol. 2005;25:11113-11121.
45. Takasugi, N, Sasaki, T, Suzuki, K, et al. BACE1 activity is modulated by cell-associated sphingosine-1-phosphate. J Neurosci. 2011;31:6850-6857.
46. Bandhuvula, P, Tam, YY, Oskouian, B, Saba, JD. Sphingosine-1-phosphate lyase activity the immune modulator FTY720 inhibits. J Biol Chem. 2005;280:697-33700.
47. Berdyshev, EV, Goya, J, Gorshkova, I, et al. Characterization of sphingosine-1-phosphate lyase activity by electrospray ionization-liquid chromatography/tandem mass spectrometry quantitation of (2E)-hexadecenal. Anal Biochem. 2011;408:2-18.
48. Kaneider, NC, Lindner, J, Feistritzer, C, et al. The immune modulator FTY720 targets sphingosine–kinase-dependent migration of human monocytes in response to amyloid beta-protein and its precursor. FASEB J. 2004;18:1309-1311.
49. Hammad, SM, Crellin, HG, Wu, BX, Melton, J, Anelli, V, Obeid, LM. Dual and distinct roles for sphingosine kinase 1 and sphingosine 1 phosphate in the response to inflammatory stimuli in RAW macrophages. Prostaglandins Other Lipid Mediat. 2008;85:107-114.
50. Wu, W, Mosteller, RD, Broek, D. Sphingosine kinase protects lipopolysaccharide-activated macrophages from apoptosis. Mol Cellular Biol. 2004;24:7359-7369.
51. Bachmaier, K, Guzman, E, Kawamura, T, Gao, X, Malik, AB. Sphingosine kinase 1 mediation of expression of the anaphylatoxin receptor C5L2 dampens the inflammatory response to endotoxin. PloS one. 2012;7:e30742.
52. Grin’kina, NM, Karnabi, EE, Damania, D, Wadgaonkar, S, Muslimov, IA, Wadgaonkar, R. Sphingosine kinase 1 deficiency exacerbates LPS-induced neuroinflammation. PloS one. 2012;7:e36475.
53. Sanna, MG, Liao, J, Jo, E, et al. Sphingosine 1-phosphate (S1P) receptor subtypes S1P1 and S1P3, respectively, regulate lymphocyte recirculation and heart rate. J Biol Chem. 2004;279:13839-13848.
54. Wei, SH, Rosen, H, Matheu, MP, et al. Sphingosine 1-phosphate type 1 receptor agonism inhibits transendothelial migration of medullary T cells to lymphatic sinuses. Nature Immunol. 2005;6:1228-1235.
55. Jo, E, Sanna, MG, Gonzalez-Cabrera, PJ, et al. S1P1-Selective In Vivo-Active Agonists from High-Throughput Screening: Off-the-Shelf Chemical Probes of Receptor Interactions, Signaling, and Fate. Chem Biol. 2005;12:703-715.
56. Wu, C, Leong, SY, Moore, CS, et al. Dual effects of daily FTY720 on human astrocytes in vitro: relevance for neuroinflammation. J Neuroinflam. 2013;10:41.
57. Ponnusamy, S, Meyers-Needham, M, Senkal, CE, et al. Sphingolipids and cancer: ceramide and sphingosine-1-phosphate in the regulation of cell death and drug resistance. Future Oncol. 2010;6:1603-1624.
58. Kajimoto, T, Okada, T, Yu, H, Goparaju, SK, Jahangeer, S, Nakamura, S. Involvement of sphingosine-1-phosphate in glutamate secretion in hippocampal neurons. Mol Cell Biol. 2007;27:3429-3440.
59. Kanno, T, Nishizaki, T, Proia, RL, et al. Regulation of synaptic strength by sphingosine 1-phosphate in the hippocampus. Neuroscience. 2010;171:973-980.
60. Zhang, Y, Yu, Q, Lai, T-B, Yang, Y, Li, G, Sun, S. Effects of small interfering RNA targeting sphingosine kinase-1 gene on the animal model of Alzheimer’s disease. J Huazhong Univ Sci Tech. 2013;33:427-432.
61. Takasugi, N, Sasaki, T, Ebinuma, I, et al. FTY720/fingolimod, a sphingosine analogue, reduces amyloid-β production in neurons. PloS One. 2013;8:e64050.
62. Alessenko, A, Bugrova, A, Dudnik, L. Connection of lipid peroxide oxidation with the sphingomyelin pathway in the development of Alzheimer’s disease. Biochem Soc Trans. 2004;32:144-146.
63. Fukumoto, K, Mizoguchi, H, Takeuchi, H, et al. Fingolimod increases brain-derived neurotrophic factor levels and ameliorates amyloid β-induced memory impairment. Behav Brain Res. 2014;268:88-93.


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Sphingosin-1-phosphate Receptor 1: a Potential Target to Inhibit Neuroinflammation and Restore the Sphingosin-1-phosphate Metabolism

  • Zeynab Kolahdooz (a1), Sanaz Nasoohi (a2), Masoumeh Asle-Rousta (a3), Abolhassan Ahmadiani (a1) (a4) and Leila Dargahi (a5)...


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