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Oral Palmitoylethanolamide Treatment Is Associated with Reduced Cutaneous Adverse Effects of Interferon-β1a and Circulating Proinflammatory Cytokines in Relapsing–Remitting Multiple Sclerosis

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Orefice, Nicola S. Al Houayek, Mireille [UCL] Carotenuto, Antonio Montella, Silvana Barbato, Franscesco Muccioli, Giulio [UCL] Orefice, Giuseppe

Palmitoylethanolamide (PEA) is an endogenous lipid mediator known to reduce pain and inflammation. However, only limited clinical studies have evaluated the effects of PEA in neuroinflammatory and neurodegenerative diseases. Multiple sclerosis (MS) is a chronic autoimmune and inflammatory disease of the central nervous system. Although subcutaneous administration of interferon (IFN)-β1a is approved as first-line therapy for the treatment of relapsing-remitting MS (RR-MS), its commonly reported adverse events (AEs) such as pain, myalgia, and erythema at the injection site, deeply affect the quality of life (QoL) of patients with MS. In this randomized, double-blind, placebo-controlled study, we tested the effect of ultramicronized PEA (um-PEA) added to IFN-β1a in the treatment of clinically defined RR-MS. The primary objectives were to estimate whether, with um-PEA treatment, patients with MS perceived an improvement in pain and a decrease of the erythema width at the IFN-β1a injection site in addition to an improvement in their QoL. The secondary objectives were to evaluate the effects of um-PEA on circulating interferon-γ, tumor necrosis factor-α, and interleukin-17 serum levels, N-acylethanolamine plasma levels, Expanded Disability Status Scale (EDSS) progression, and safety and tolerability after 1 year of treatment. Patients with MS receiving um-PEA perceived an improvement in pain sensation without a reduction of the erythema at the injection site. A significant improvement in QoL was observed. No significant difference was reported in EDSS score, and um-PEA was well tolerated. We found a significant increase of palmitoylethanolamide, anandamide and oleoylethanolamide plasma levels, and a significant reduction of interferon-γ, tumor necrosis factor-α, and interleukin-17 serum profile compared with the placebo group. Our results suggest that um-PEA may be considered as an appropriate add-on therapy for the treatment of IFN-β1a-related adverse effects in RR-MS.

Document type Article de périodique (Journal article) – Article de recherche
Access type Accès restreint
Publication date 2016
Language Anglais
Journal information "Neurotherapeutics" - Vol. 13, no. 2, p. 428-438 (2016)
Peer reviewed yes
Publisher Springer New York LLC ((United States) New York, NY)
issn 1933-7213
e-issn 1878-7479
Publication status Publié
Affiliation UCL - SSS/LDRI - Louvain Drug Research Institute
Links
  1. Cadas Hugues, Schinelli Sergio, Piomelli Daniele, Membrane localization of N-acylphosphatidylethanolamine in central neurons: Studies with exogenous phospholipases, 10.1016/0929-7855(96)00510-x
  2. Alhouayek Mireille, Muccioli Giulio G., Harnessing the anti-inflammatory potential of palmitoylethanolamide, 10.1016/j.drudis.2014.06.007
  3. Calignano Antonio, Rana Giovanna La, Giuffrida Andrea, Piomelli Daniele, Control of pain initiation by endogenous cannabinoids, 10.1038/28393
  4. Calignano Antonio, La Rana Giovanna, Piomelli Daniele, Antinociceptive activity of the endogenous fatty acid amide, palmitylethanolamide, 10.1016/s0014-2999(01)00988-8
  5. LoVerme J., Russo R., La Rana G., Fu J., Farthing J., Mattace-Raso G., Meli R., Hohmann A., Calignano A., Piomelli D., Rapid Broad-Spectrum Analgesia through Activation of Peroxisome Proliferator-Activated Receptor- , 10.1124/jpet.106.111385
  6. Lambert Didier M., Vandevoorde Séverine, Diependaele Gérald, Govaerts Sophie J., Robert Annie R., Anticonvulsant Activity of N-Palmitoylethanolamide, a Putative Endocannabinoid, in Mice, 10.1046/j.1528-1157.2001.41499.x
  7. Esposito E, Impellizzeri D, Mazzon E, Paterniti I, Cuzzocrea S. Neuroprotective activities of palmitoylethanolamide in an animal model of parkinson’s disease. Plos One 2012;7:e41880.
  8. D'Agostino Giuseppe, Russo Roberto, Avagliano Carmen, Cristiano Claudia, Meli Rosaria, Calignano Antonio, Palmitoylethanolamide Protects Against the Amyloid-β25-35-Induced Learning and Memory Impairment in Mice, an Experimental Model of Alzheimer Disease, 10.1038/npp.2012.25
  9. Mazzari Silvio, Canella Roberto, Petrelli Lucia, Marcolongo Gabriele, Leon Alberta, N-(2-Hydroxyethyl)hexadecanamide is orally active in reducing edema formation and inflammatory hyperalgesia by down-modulating mast cell activation, 10.1016/0014-2999(96)00015-5
  10. Esposito Emanuela, Paterniti Irene, Mazzon Emanuela, Genovese Tiziana, Di Paola Rosanna, Galuppo Maria, Cuzzocrea Salvatore, Effects of palmitoylethanolamide on release of mast cell peptidases and neurotrophic factors after spinal cord injury, 10.1016/j.bbi.2011.02.006
  11. Verme J. L., The Nuclear Receptor Peroxisome Proliferator-Activated Receptor-  Mediates the Anti-Inflammatory Actions of Palmitoylethanolamide, 10.1124/mol.104.006353
  12. D'Agostino G., La Rana G., Russo R., Sasso O., Iacono A., Esposito E., Raso G. M., Cuzzocrea S., Lo Verme J., Piomelli D., Meli R., Calignano A., Acute Intracerebroventricular Administration of Palmitoylethanolamide, an Endogenous Peroxisome Proliferator-Activated Receptor-  Agonist, Modulates Carrageenan-Induced Paw Edema in Mice, 10.1124/jpet.107.123265
  13. D'Agostino Giuseppe, La Rana Giovanna, Russo Roberto, Sasso Oscar, Iacono Anna, Esposito Emanuela, Mattace Raso Giuseppina, Cuzzocrea Salvatore, LoVerme Jesse, Piomelli Daniele, Meli Rosaria, Calignano Antonio, Central administration of palmitoylethanolamide reduces hyperalgesia in mice via inhibition of NF-κB nuclear signalling in dorsal root ganglia, 10.1016/j.ejphar.2009.04.022
  14. LoVerme Jesse, La Rana Giovanna, Russo Roberto, Calignano Antonio, Piomelli Daniele, The search for the palmitoylethanolamide receptor, 10.1016/j.lfs.2005.05.012
  15. Solorzano C., Zhu C., Battista N., Astarita G., Lodola A., Rivara S., Mor M., Russo R., Maccarrone M., Antonietti F., Duranti A., Tontini A., Cuzzocrea S., Tarzia G., Piomelli D., Selective N-acylethanolamine-hydrolyzing acid amidase inhibition reveals a key role for endogenous palmitoylethanolamide in inflammation, 10.1073/pnas.0907417106
  16. Noseworthy John H., Lucchinetti Claudia, Rodriguez Moses, Weinshenker Brian G., Multiple Sclerosis, 10.1056/nejm200009283431307
  17. Chard Declan, Miller David, Grey matter pathology in clinically early multiple sclerosis: Evidence from magnetic resonance imaging, 10.1016/j.jns.2009.01.012
  18. Calabrese Massimiliano, Filippi Massimo, Rovaris Marco, Mattisi Irene, Bernardi Valentina, Atzori Matteo, Favaretto Alice, Barachino Luigi, Rinaldi Luciano, Romualdi Chiara, Perini Paola, Gallo Paolo, Morphology and evolution of cortical lesions in multiple sclerosis. A longitudinal MRI study, 10.1016/j.neuroimage.2008.06.028
  19. Bornstein Murray B., Miller Aaron, Slagle Susan, Weitzman Muriel, Crystal Howard, Drexler Ellen, Keilson Marshall, Merriam Arnold, Wassertheil-Smoller Sylvia, Spada Vincent, Weiss William, Arnon Ruth, Jacobsohn Israel, Teitelbaum Dvora, Sela Michael, A Pilot Trial of Cop 1 in Exacerbating–Remitting Multiple Sclerosis, 10.1056/nejm198708133170703
  20. , Interferon beta-1b is effective in relapsing-remitting multiple sclerosis: I. Clinical results of a multicenter, randomized, double-blind, placebo-controlled trial, 10.1212/wnl.43.4.655
  21. Jacobs Lawrence D., Cookfair Diane L., Rudick Richard A., Herndon Robert M., Richert John R., Salazar Andres M., Fischer Jill S., Goodkin Donald E., Granger Carl V., Simon Jack H., Alam John J., Bartoszak David M., Bourdette Dennis N., Braiman Jonathan, Brownscheidle Carol M., Coats Michael E., Cohan Stanley L., Dougherty David S., Kinkel Revere P., Mass Michele K., Munschauer Frederick E., Priore Roger L., Pullicino Patrick M., Scherokman Barbara J., Weinstock-Guttman Bianca, Whitham Ruth H., , Intramuscular interferon beta-1a for disease progression in relapsing multiple sclerosis, 10.1002/ana.410390304
  22. Ebers George C, Randomised double-blind placebo-controlled study of interferon β-1a in relapsing/remitting multiple sclerosis, 10.1016/s0140-6736(98)03334-0
  23. Johnson Kenneth P., Baringer J. Richard, Current Therapy of Multiple Sclerosis : Commentary, 10.1080/21548331.2001.11444101
  24. Walther E. U., Hohlfeld R., Multiple sclerosis: Side effects of interferon beta therapy and their management, 10.1212/wnl.53.8.1622
  25. Panitch H., Goodin D.S., Francis G., Chang P., Coyle P.K., O'Connor P., Monaghan E., Li D., Weinshenker B., Randomized, comparative study of interferon  -1a treatment regimens in MS: The EVIDENCE Trial, 10.1212/01.wnl.0000034080.43681.da
  26. Carotenuto Antonio, Iodice Rosa, Barbato Francesco, Orefice Nicola Salvatore, Orefice Giuseppe, Necrotizing skin lesion and radial nerve palsy in a patient treated with glatiramer acetate, 10.1016/j.jns.2013.05.031
  27. Loría Frida, Petrosino Stefania, Mestre Leyre, Spagnolo Alessandra, Correa Fernando, Hernangómez Miriam, Guaza Carmen, Di Marzo Vincenzo, Docagne Fabian, Study of the regulation of the endocannabinoid system in a virus model of multiple sclerosis reveals a therapeutic effect of palmitoylethanolamide, 10.1111/j.1460-9568.2008.06377.x
  28. Polman Chris H., Reingold Stephen C., Banwell Brenda, Clanet Michel, Cohen Jeffrey A., Filippi Massimo, Fujihara Kazuo, Havrdova Eva, Hutchinson Michael, Kappos Ludwig, Lublin Fred D., Montalban Xavier, O'Connor Paul, Sandberg-Wollheim Magnhild, Thompson Alan J., Waubant Emmanuelle, Weinshenker Brian, Wolinsky Jerry S., Diagnostic criteria for multiple sclerosis: 2010 Revisions to the McDonald criteria, 10.1002/ana.22366
  29. Kurtzke J. F., Rating neurologic impairment in multiple sclerosis: An expanded disability status scale (EDSS), 10.1212/wnl.33.11.1444
  30. Vickrey B. G., Hays R. D., Harooni R., Myers L. W., Ellison G. W., A health-related quality of life measure for multiple sclerosis, 10.1007/bf02260859
  31. Forn C., Belenguer A., Parcet-Ibars M. A., Ávila C., Information-processing speed is the primary deficit underlying the poor performance of multiple sclerosis patients in the Paced Auditory Serial Addition Test (PASAT), 10.1080/13803390701779560
  32. Fos LA, Greve KW, South MB, Mathias C, Benefield H. Paced visual serial addition test: an alternative measure of information processing speed. Neuropsychology. 2000;7:140-146.
  33. Grau-López L., Sierra S., Martínez-Cáceres E., Ramo-Tello C., Análisis del dolor en pacientes con esclerosis múltiple, 10.1016/j.nrl.2010.07.014
  34. Alhouayek M., Masquelier J., Cani P. D., Lambert D. M., Muccioli G. G., Implication of the anti-inflammatory bioactive lipid prostaglandin D2-glycerol ester in the control of macrophage activation and inflammation by ABHD6, 10.1073/pnas.1314017110
  35. Muccioli Giulio G., Endocannabinoid biosynthesis and inactivation, from simple to complex, 10.1016/j.drudis.2010.03.007
  36. Cravatt B. F., Demarest K., Patricelli M. P., Bracey M. H., Giang D. K., Martin B. R., Lichtman A. H., Supersensitivity to anandamide and enhanced endogenous cannabinoid signaling in mice lacking fatty acid amide hydrolase, 10.1073/pnas.161191698
  37. Ahn Kay, Johnson Douglas S., Mileni Mauro, Beidler David, Long Jonathan Z., McKinney Michele K., Weerapana Eranthie, Sadagopan Nalini, Liimatta Marya, Smith Sarah E., Lazerwith Scott, Stiff Cory, Kamtekar Satwik, Bhattacharya Keshab, Zhang Yanhua, Swaney Stephen, Van Becelaere Keri, Stevens Raymond C., Cravatt Benjamin F., Discovery and Characterization of a Highly Selective FAAH Inhibitor that Reduces Inflammatory Pain, 10.1016/j.chembiol.2009.02.013
  38. Sun Yong-Xin, Tsuboi Kazuhito, Zhao Li-Ying, Okamoto Yasuo, Lambert Didier M., Ueda Natsuo, Involvement of N-acylethanolamine-hydrolyzing acid amidase in the degradation of anandamide and other N-acylethanolamines in macrophages, 10.1016/j.bbalip.2005.08.010
  39. Ueda N, Tsuboi K, Uyama T. Enzymological studies on the biosynthesis of N-acylethanolamines. Biochim. Biophys. Acta 2010;1801:1274-1285.
  40. Centonze Diego, Battistini Luca, Maccarrone Mauro, The Endocannabinoid System in Peripheral Lymphocytes as a Mirror of Neuroinflammatory Diseases, 10.2174/138161208785740018
  41. O’Connor Alec B., Schwid Steven R., Herrmann David N., Markman John D., Dworkin Robert H., Pain associated with multiple sclerosis: Systematic review and proposed classification : , 10.1016/j.pain.2007.08.024
  42. Foley Peter L., Vesterinen Hanna M., Laird Barry J., Sena Emily S., Colvin Lesley A., Chandran Siddharthan, MacLeod Malcolm R., Fallon Marie T., Prevalence and natural history of pain in adults with multiple sclerosis: Systematic review and meta-analysis : , 10.1016/j.pain.2012.12.002
  43. Guida G, de Martino M, de Fabiani A, et al. La palmitoiletanolamida (Normast) en el dolor neuropatico cronico por lumbociatalgia de tipo compresivo: estudio clinico multicentrico. [Palmitoylethanolamide treatment of sciatic pain: results form a multicenter study]. Dolor. 2010; 25:35-42.
  44. Keppel Hesselink Jan, Hekker, Therapeutic utility of palmitoylethanolamide in the treatment of neuropathic pain associated with various pathological conditions: a case series, 10.2147/jpr.s32143
  45. Hao Shuzhen, Avraham Yosefa, Mechoulam Raphael, Berry Elliot M, Low dose anandamide affects food intake, cognitive function, neurotransmitter and corticosterone levels in diet-restricted mice, 10.1016/s0014-2999(00)00059-5
  46. Barbierato Massimo, Facci Laura, Marinelli Carla, Zusso Morena, Argentini Carla, Skaper Stephen D., Giusti Pietro, Co-ultramicronized Palmitoylethanolamide/Luteolin Promotes the Maturation of Oligodendrocyte Precursor Cells, 10.1038/srep16676
  47. Yang Li-chao, Guo Han, Zhou Hao, Suo Da-qin, Li Wen-jun, Zhou Yu, Zhao Yun, Yang Wu-shuang, Jin Xin, Chronic oleoylethanolamide treatment improves spatial cognitive deficits through enhancing hippocampal neurogenesis after transient focal cerebral ischemia, 10.1016/j.bcp.2015.02.012
  48. Zepp Jarod, Wu Ling, Li Xiaoxia, IL-17 receptor signaling and T helper 17-mediated autoimmune demyelinating disease, 10.1016/j.it.2011.02.007
  49. Zhu Shu, Pan Wen, Song Xinyang, Liu Yan, Shao Xinrui, Tang Yuanjia, Liang Dong, He Dongyi, Wang Honglin, Liu Wenjun, Shi Yufang, Harley John B, Shen Nan, Qian Youcun, The microRNA miR-23b suppresses IL-17-associated autoimmune inflammation by targeting TAB2, TAB3 and IKK-α, 10.1038/nm.2815
  50. Meares Gordon P., Ma Xiangyu, Qin Hongwei, Benveniste Etty N., Regulation of CCL20 expression in astrocytes by IL-6 and IL-17, 10.1002/glia.22307
  51. Kolls Jay K., Lindén Anders, Interleukin-17 Family Members and Inflammation, 10.1016/j.immuni.2004.08.018
  52. Chen Meiyue, Chen Guangjie, Nie Hong, Zhang Xin, Niu Xiaoyin, Zang Ying C. Q., Skinner Sheri M., Zhang Jingwu Z., Killian James M., Hong Jian, Regulatory effects of IFN-β on production of osteopontin and IL-17 by CD4+ T Cells in MS, 10.1002/eji.200838879
  53. Christophi George P., Panos Michael, Hudson Chad A., Tsikkou Chriso, Mihai Cornelia, Mejico Luis J., Jubelt Burk, Massa Paul T., Interferon-β treatment in multiple sclerosis attenuates inflammatory gene expression through inducible activity of the phosphatase SHP-1, 10.1016/j.clim.2009.05.019
  54. Guarda Greta, Braun Marion, Staehli Francesco, Tardivel Aubry, Mattmann Chantal, Förster Irmgard, Farlik Matthias, Decker Thomas, Du Pasquier Renaud A., Romero Pedro, Tschopp Jürg, Type I Interferon Inhibits Interleukin-1 Production and Inflammasome Activation, 10.1016/j.immuni.2011.02.006
  55. Lucchinetti Claudia F., Parisi Joseph, Bruck Wolfgang, The pathology of multiple sclerosis, 10.1016/j.ncl.2004.09.002
  56. Lassmann Hans, Multiple Sclerosis Pathology: Evolution of Pathogenetic Concepts, 10.1111/j.1750-3639.2005.tb00523.x
  57. Lassmann Hans, Brück Wolfgang, Lucchinetti Claudia F., The Immunopathology of Multiple Sclerosis: An Overview, 10.1111/j.1750-3639.2007.00064.x
  58. Lassmann Hans, Mechanisms of inflammation induced tissue injury in multiple sclerosis, 10.1016/j.jns.2008.04.003
  59. D'Addario Claudio, Di Francesco Andrea, Arosio Beatrice, Gussago Cristina, Dell'Osso Bernardo, Bari Monica, Galimberti Daniela, Scarpini Elio, Altamura A. Carlo, Mari Daniela, Maccarrone Mauro, Epigenetic Regulation of Fatty Acid Amide Hydrolase in Alzheimer Disease, 10.1371/journal.pone.0039186
  60. Wolfson Manuel L., Aisemberg Julieta, Salazar Ana I., Domínguez Rubio Ana P., Vercelli Claudia A., Franchi Ana M., Progesterone reverts LPS-reduced FAAH activity in murine peripheral blood mononuclear cells by a receptor-mediated fashion, 10.1016/j.mce.2013.07.020
  61. Scuderi Caterina, Steardo Luca, Neuroglial Roots of Neurodegenerative Diseases: Therapeutic Potential of Palmitoylethanolamide in Models of Alzheimer’s Disease, 10.2174/1871527311312010011
  62. Eljaschewitsch Eva, Witting Anke, Mawrin Christian, Lee Thomas, Schmidt Peter M., Wolf Susanne, Hoertnagl Heide, Raine Cedric S., Schneider-Stock Regine, Nitsch Robert, Ullrich Oliver, The Endocannabinoid Anandamide Protects Neurons during CNS Inflammation by Induction of MKP-1 in Microglial Cells, 10.1016/j.neuron.2005.11.027
  63. Correa Fernando, Docagne Fabian, Mestre Leyre, Clemente Diego, Hernangómez Miriam, Loría Frida, Guaza Carmen, A role for CB2 receptors in anandamide signalling pathways involved in the regulation of IL-12 and IL-23 in microglial cells, 10.1016/j.bcp.2008.09.014
  64. De Petrocellis Luciano, Davis John B, Di Marzo Vincenzo, Palmitoylethanolamide enhances anandamide stimulation of human vanilloid VR1 receptors, 10.1016/s0014-5793(01)02934-9
  65. Di Marzo V, Endovanilloid signaling in pain, 10.1016/s0959-4388(02)00340-9
  66. Ross Ruth A, Anandamide and vanilloid TRPV1 receptors, 10.1038/sj.bjp.0705467
  67. Fu Jin, Gaetani Silvana, Oveisi Fariba, Lo Verme Jesse, Serrano Antonia, Rodríguez de Fonseca Fernando, Rosengarth Anja, Luecke Hartmut, Di Giacomo Barbara, Tarzia Giorgio, Piomelli Daniele, Oleylethanolamide regulates feeding and body weight through activation of the nuclear receptor PPAR-α, 10.1038/nature01921
  68. Overton Hilary A., Babbs Adam J., Doel Sheila M., Fyfe Matthew C.T., Gardner Lisa S., Griffin Graeme, Jackson Helen C., Procter Martin J., Rasamison Chrystelle M., Tang-Christensen Mads, Widdowson Peter S., Williams Geoffery M., Reynet Christine, Deorphanization of a G protein-coupled receptor for oleoylethanolamide and its use in the discovery of small-molecule hypophagic agents, 10.1016/j.cmet.2006.02.004
  69. Baker D, Pryce G, Croxford JL, et al. Endocannabinoids control spasticity in a multiple sclerosis model. FASEB J. 2001;15:300-302.
  70. Gubellini P, Picconi B, Bari M et al. Experimental Parkinsonism alters endocannabinoid degradation: implications for striatal glutamatergic transmission. J. Neurosci. 2002;22: 6900-6907.
  71. Bisogno Tiziana, Martire Alberto, Petrosino Stefania, Popoli Patrizia, Di Marzo Vincenzo, Symptom-related changes of endocannabinoid and palmitoylethanolamide levels in brain areas of R6/2 mice, a transgenic model of Huntington's disease, 10.1016/j.neuint.2007.06.031
  72. Zhou Yu, Yang Lichao, Ma Ang, Zhang Xuemei, Li Weijie, Yang Wushuang, Chen Caixia, Jin Xin, Orally administered oleoylethanolamide protects mice from focal cerebral ischemic injury by activating peroxisome proliferator-activated receptor α, 10.1016/j.neuropharm.2012.03.008
  73. Gonzalez-Aparicio Ramiro, Blanco Eduardo, Serrano Antonia, Pavon Francisco Javier, Parsons Loren H., Maldonado Rafael, Robledo Patricia, Fernandez-Espejo Emilio, de Fonseca Fernando Rodriguez, The systemic administration of oleoylethanolamide exerts neuroprotection of the nigrostriatal system in experimental Parkinsonism, 10.1017/s1461145713001259
Bibliographic reference Orefice, Nicola S. ; Al Houayek, Mireille ; Carotenuto, Antonio ; Montella, Silvana ; Barbato, Franscesco ; et. al. Oral Palmitoylethanolamide Treatment Is Associated with Reduced Cutaneous Adverse Effects of Interferon-β1a and Circulating Proinflammatory Cytokines in Relapsing–Remitting Multiple Sclerosis. In: Neurotherapeutics, Vol. 13, no. 2, p. 428-438 (2016)
Permanent URL http://hdl.handle.net/2078.1/175321