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N-Palmitoylethanolamine and Neuroinflammation: a Novel Therapeutic Strategy of Resolution

Abstract

Inflammation is fundamentally a protective cellular response aimed at removing injurious stimuli and initiating the healing process. However, when prolonged, it can override the bounds of physiological control and becomes destructive. Inflammation is a key element in the pathobiology of chronic pain, neurodegenerative diseases, stroke, spinal cord injury, and neuropsychiatric disorders. Glia, key players in such nervous system disorders, are not only capable of expressing a pro-inflammatory phenotype but respond also to inflammatory signals released from cells of immune origin such as mast cells. Chronic inflammatory processes may be counteracted by a program of resolution that includes the production of lipid mediators endowed with the capacity to switch off inflammation. These naturally occurring lipid signaling molecules include the N-acylethanolamines, N-arachidonoylethanolamine (an endocannabinoid), and its congener N-palmitoylethanolamine (palmitoylethanolamide or PEA). PEA may play a role in maintaining cellular homeostasis when faced with external stressors provoking, for example, inflammation. PEA is efficacious in mast cell-mediated models of neurogenic inflammation and neuropathic pain and is neuroprotective in models of stroke, spinal cord injury, traumatic brain injury, and Parkinson disease. PEA in micronized/ultramicronized form shows superior oral efficacy in inflammatory pain models when compared to naïve PEA. Intriguingly, while PEA has no antioxidant effects per se, its co-ultramicronization with the flavonoid luteolin is more efficacious than either molecule alone. Inhibiting or modulating the enzymatic breakdown of PEA represents a complementary therapeutic approach to treat neuroinflammation. This review is intended to discuss the role of mast cells and glia in neuroinflammation and strategies to modulate their activation based on leveraging natural mechanisms with the capacity for self-defense against inflammation.

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References

  1. Nathan C, Ding A (2010) Nonresolving inflammation. Cell 140:871–882. doi:10.1016/j.cell.2010.02.029

    CAS  Article  PubMed  Google Scholar 

  2. Castellheim A, Brekke OL, Espevik T, Harboe M, Mollnes TE (2009) Innate immune responses to danger signals in systemic inflammatory response syndrome and sepsis. Scand J Immunol 69:479–491. doi:10.1111/j.1365-3083.2009.02255.x

    CAS  Article  PubMed  Google Scholar 

  3. Myers RR, Campana WM, Shubayev VI (2006) The role of neuroinflammation in neuropathic pain: mechanisms and therapeutic targets. Drug Discov Today 11:8–20. doi:10.1016/S1359-6446(05)03637-8

    CAS  Article  PubMed  Google Scholar 

  4. Amor S, Peferoen LA, Vogel DY, Breur M, van der Valk P, Baker D, van Noort JM (2014) Innate and adaptive immune responses in neurodegeneration and repair. Immunology 141:287–291. doi:10.1111/imm.12233

    PubMed Central  CAS  Article  PubMed  Google Scholar 

  5. Iadecola C, Anrather J (2011) The immunology of stroke: from mechanisms to translation. Nat Med 17:796–808. doi:10.1038/nm.2399

    PubMed Central  CAS  Article  PubMed  Google Scholar 

  6. McGeer PL, McGeer EG (2013) The amyloid cascade-inflammatory hypothesis of Alzheimer disease: implications for therapy. Acta Neuropathol 126:479–497. doi:10.1007/s00401-013-1177-7

    CAS  Article  PubMed  Google Scholar 

  7. Najjar S, Pearlman DM, Alper K, Najjar A, Devinsky O (2013) Neuroinflammation and psychiatric illness. J Neuroinflammation 10:43. doi:10.1186/1742-2094-10-43

    PubMed Central  CAS  Article  PubMed  Google Scholar 

  8. Noriega DB, Savelkoul HF (2014) Immune dysregulation in autism spectrum disorder. Eur J Pediatr 173:33–43. doi:10.1007/s00431-013-2183-4

    CAS  Article  PubMed  Google Scholar 

  9. Rivat C, Becker C, Blugeot A, Zeau B, Mauborgne A, Pohl M, Benoliel JJ (2010) Chronic stress induces transient spinal neuroinflammation, triggering sensory hypersensitivity and long-lasting anxiety-induced hyperalgesia. Pain 150:358–368. doi:10.1016/j.pain.2010.05.031

    Article  PubMed  Google Scholar 

  10. Peferoen LA, Vogel DY, Ummenthum K, Breur M, Heijnen PD, Gerritsen WH, Peferoen-Baert RM, van der Valk P, Dijkstra CD, Amor S (2015) Activation status of human microglia is dependent on lesion formation stage and remyelination in multiple sclerosis. J Neuropathol Exp Neurol 74:48–63. doi:10.1097/NEN.0000000000000149

    CAS  Article  PubMed  Google Scholar 

  11. Morales I, Guzmán-Martínez L, Cerda-Troncoso C, Farías GA, Maccioni RB (2014) Neuroinflammation in the pathogenesis of Alzheimer's disease. A rational framework for the search of novel therapeutic approaches. Front Cell Neurosci 8:112. doi:10.3389/fncel.2014.00112

    PubMed Central  PubMed  Google Scholar 

  12. Frakes AE, Ferraiuolo L, Haidet-Phillips AM, Schmelzer L, Braun L, Miranda CJ, Ladner KJ, Bevan AK, Foust KD, Godbout JP, Popovich PG, Guttridge DC, Kaspar BK (2014) Microglia induce motor neuron death via the classical NF-κB pathway in amyotrophic lateral sclerosis. Neuron 81:1009–1023. doi:10.1016/j.neuron.2014.01.013

    PubMed Central  CAS  Article  PubMed  Google Scholar 

  13. Prinz M, Priller J (2014) Microglia and brain macrophages in the molecular age: from origin to neuropsychiatric disease. Nat Rev Neurosci 15:300–312. doi:10.1038/nrn3722, 10:43

    CAS  Article  PubMed  Google Scholar 

  14. Carson MJ (2002) Microglia as liaisons between the immune and central nervous systems. Functional implications for multiple sclerosis. Glia 40:218–231. doi:10.1002/glia.10145

    PubMed Central  Article  PubMed  Google Scholar 

  15. Gao YJ, Ji RR (2010) Chemokines, neuronal-glial interactions, and central processing of neuropathic pain. Pharmacol Ther 126:56–68. doi:10.1016/j.pharmthera.2010.01.002

    PubMed Central  CAS  Article  PubMed  Google Scholar 

  16. Engler H, Doenlen R, Engler A, Riether C, Prager G, Niemi MB, Pacheco-López G, Krügel U, Schedlowski M (2011) Acute amygdaloid response to systemic inflammation. Brain Behav Immun 25:1384–1392. doi:10.1016/j.bbi.2011.04.005

    CAS  Article  PubMed  Google Scholar 

  17. Perry VH, Holmes C (2014) Microglial priming in neurodegenerative disease. Nat Rev Neurol 10:217–224. doi:10.1038/nrneurol.2014.38

    CAS  Article  PubMed  Google Scholar 

  18. Chen CC, Grimbaldeston MA, Tsai M, Weissman IL, Galli SJ (2005) Identification of mast cell progenitors in adult mice. Proc Natl Acad Sci U S A 102:11408–11413. doi:10.1073/pnas.0504197102

    PubMed Central  CAS  Article  PubMed  Google Scholar 

  19. Gilfillan AM, Austin SJ, Metcalfe DD (2011) Mast cell biology: introduction and overview. Adv Exp Med Biol 716:2–12. doi:10.1038/ni1158

    PubMed Central  CAS  Article  PubMed  Google Scholar 

  20. Lambracht-Hall M, Dimitriadou V, Theoharides TC (1990) Migration of mast cells in the developing rat brain. Dev Brain Res 56:151–159. doi:10.1016/0165-3806(90)90077-C

    CAS  Article  Google Scholar 

  21. Silverman AJ, Sutherland AK, Wilhelm M, Silver R (2000) Mast cells migrate from blood to brain. J Neurosci 20:401–408

    CAS  PubMed  Google Scholar 

  22. Silver R, Curley JP (2013) Mast cells on the mind: new insights and opportunities. Trends Neurosci 36:513–521. doi:10.1016/tins.2013.06.001

    CAS  Article  PubMed  Google Scholar 

  23. Gauchat JF, Henchoz S, Mazzei G, Aubry JP, Brunner T, Blasey H, Life P, Talabot D, Flores-Romo L, Thompson J, Kishi K, Butterfield J, Dahinden C, Bonnefoy J-Y (1993) Induction of human IgE synthesis in B cells by mast cells and basophils. Nature 365:340–343. doi:10.1038/365340a0

    CAS  Article  PubMed  Google Scholar 

  24. Wardlaw AJ, Moqbel R, Cromwell O, Kay AB (1986) Platelet-activating factor. A potent chemotactic and chemokinetic factor for human eosinophils. J Clin Invest 78:1701–1706. doi:10.1172/JCI112765

    PubMed Central  CAS  Article  PubMed  Google Scholar 

  25. Brenner T, Soffer D, Shalit M, Levi-Schaffer F (1994) Mast cells in experimental allergic encephalomyelitis: characterization, distribution in the CNS and in vitro activation by myelin basic protein and neuropeptides. J Neurol Sci 122:210–213. doi:10.1016/0022-510X(94)90300-X

    CAS  Article  PubMed  Google Scholar 

  26. Costanza M, Colombo MP, Pedotti R (2012) Mast cells in the pathogenesis of multiple sclerosis and experimental autoimmune encephalomyelitis. Int J Mol Sci 13:15107–15125. doi:10.3390/ijms131115107

    PubMed Central  CAS  Article  PubMed  Google Scholar 

  27. Xanthos DN, Gaderer S, Drdla R, Nuro E, Abramova A, Ellmeier W, Sandkühler J (2011) Central nervous system mast cells in peripheral inflammatory nociception. Mol Pain 7:42. doi:10.1186/1744-8069-7-42

    PubMed Central  Article  PubMed  Google Scholar 

  28. Leal-Berumen I, Conlon P, Marshall JS (1994) IL-6 production by rat peritoneal mast cells is not necessarily preceded by histamine release and can be induced by bacterial lipopolysaccharide. J Immunol 152:5468–5476

    CAS  PubMed  Google Scholar 

  29. Lindsberg PJ, Strbian D, Karjalainen-Lindsberg ML (2010) Mast cells as early responders in the regulation of acute blood-brain barrier changes after cerebral ischemia and hemorrhage. J Cereb Blood Flow Metab 30:689–702. doi:10.1038/jcbfm.2009.282

    PubMed Central  Article  PubMed  Google Scholar 

  30. Esposito E, Paterniti I, Mazzon E, Genovese T, Di Paola R, Galuppo M, Cuzzocrea S (2011) Effects of palmitoylethanolamide on release of mast cell peptidases and neurotrophic factors after spinal cord injury. Brain Behav Immun 25:1099–1112. doi:10.1016/j.bbi.2011.02.006

    CAS  Article  PubMed  Google Scholar 

  31. Graves MC, Fiala M, Dinglasan LA, Liu NQ, Sayre J, Chiappelli F, van Kooten C, Vinters HV (2004) Inflammation in amyotrophic lateral sclerosis spinal cord and brain is mediated by activated macrophages, mast cells and T cells. Amyotroph Lateral Scler Other Motor Neuron Disord 5:213–219

    CAS  Article  PubMed  Google Scholar 

  32. Fiala M, Chattopadhay M, La Cava A, Tse E, Liu G, Lourenco E, Eskin A, Liu PT, Magpantay L, Tse S, Mahanian M, Weitzman R, Tong J, Nguyen C, Cho T, Koo P, Sayre J, Martinez-Maza O, Rosenthal MJ, Wiedau-Pazos M (2010) IL-17A is increased in the serum and in spinal cord CD8 and mast cells of ALS patients. J Neuroinflammation 7:76. doi:10.1186/1742-2094-7-76

    PubMed Central  Article  PubMed  Google Scholar 

  33. Skaper SD, Facci, Giusti P (2014) Mast cells, glia and neuroinflammation: partners in crime? Immunology 141:314–327. doi:10.1111/imm.12170

    PubMed Central  CAS  Article  PubMed  Google Scholar 

  34. Skaper SD, Giusti P, Facci L (2012) Microglia and mast cells: two tracks on the road to neuroinflammation. FASEB J 26:3103–3117. doi:10.1096/fj.11-197194

    CAS  Article  PubMed  Google Scholar 

  35. Pietrzak A, Wierzbicki M, Wiktorska M, Brzezińska-Błaszczyk E (2011) Surface TLR2 and TLR4 expression on mature rat mast cells can be affected by some bacterial components and proinflammatory cytokines. Mediators Inflamm 427473. doi:10.1155/2011/427473

  36. Gasque P, Singhrao SK, Neal JW, Götze O, Morgan BP (1997) Expression of the receptor for complement C5a (CD88) is up-regulated on reactive astrocytes, microglia, and endothelial cells in the inflamed human central nervous system. Am J Pathol 150:31–41

    PubMed Central  CAS  PubMed  Google Scholar 

  37. Kim DY, Hong GU, Ro JY (2011) Signal pathways in astrocytes activated by cross-talk between of astrocytes and mast cells through CD40-CD40L. J Neuroinflammation 8:25. doi:10.1186/1742-2094-8-25

    PubMed Central  CAS  Article  PubMed  Google Scholar 

  38. Wang M, Wang X, Zhao L, Ma W, Rodriguez IR, Fariss RN, Wong WT (2014) Macroglia-microglia interactions via TSPO signaling regulates microglial activation in the mouse retina. J Neurosci 34:3793–3806. doi:10.1523/JNEUROSCI.3153-13.2014

    PubMed Central  CAS  Article  PubMed  Google Scholar 

  39. Tabas I, Glass CK (2013) Anti-inflammatory therapy in chronic disease: challenges and opportunities. Science 166:166–172. doi:10.1126/science.1230720

    Article  Google Scholar 

  40. Buckley CD, Gilroy DW, Serhan CN, Stockinger B, Tak PP (2013) The resolution of inflammation. Nat Rev Immunol 13:59–66. doi:10.1038/nri3362

    CAS  Article  PubMed  Google Scholar 

  41. Piomelli D, Sasso O (2014) Peripheral gating of pain signals by endogenous lipid mediators. Nat Neurosci 17:164–174. doi:10.1038/nn.3612

    PubMed Central  CAS  Article  PubMed  Google Scholar 

  42. Pacher P, Bátkai S, Kunos G (2006) The endocannabinoid system as an emerging target of pharmacotherapy. Pharmacol Rev 58:389–462. doi:10.1124/pr.58.3.2

    PubMed Central  CAS  Article  PubMed  Google Scholar 

  43. Ueda N, Tsuboi K, Uyama T (2013) Metabolism of endocannabinoids and related N-acylethanolamines: canonical and alternative pathways. FEBS J 280:1874–1894. doi:10.1111/febs.12152

    CAS  Article  PubMed  Google Scholar 

  44. Leung D, Saghatelian A, Simon GM, Cravatt BF (2006) Inactivation of N-acyl phosphatidylethanolamine phospholipase D reveals multiple mechanisms for the biosynthesis of endocannabinoids. Biochemistry 45:4720–4726. doi:10.1021/bi060163l

    PubMed Central  CAS  Article  PubMed  Google Scholar 

  45. Olusanmi D, Jayawickrama D, Bu D, McGeorge G, Sailes H, Kelleher J, Gamble JF, Shahd UV, Tobyn M (2014) A control strategy for bioavailability enhancement by size reduction: effect of micronisation conditions on the bulk, surface and blending characteristics of an active pharmaceutical ingredient. Powder Technol. doi:10.1016/j.powtec.2014.03.032

    Google Scholar 

  46. Rasenack N, Müller BW (2004) Micron-size drug particles: common and novel micronization techniques. Pharm Dev Technol 9:1–13

    CAS  Article  PubMed  Google Scholar 

  47. Joshi JT (2011) A review on micronization techniques. J Pharmaceutical Sci Technol 3:651–681

    CAS  Google Scholar 

  48. Bisrat M, Nyström C (1988) Physicochemical aspects of drug release. VIII. The relation between particle size and surface specific dissolution rate in agitated suspensions. Int J Pharm 47:223–231

    CAS  Article  Google Scholar 

  49. Oh DM, Curl RL, Yong CS, Amidon GL (1995) Effect of micronization on the extent of drug absorption from suspensions in humans. Arch Pharm Res 18:427–433

    CAS  Article  Google Scholar 

  50. Impellizzeri D, Bruschetta G, Cordaro M, Crupi R, Siracusa R, Esposito E, Cuzzocrea S (2014) Micronized/ultramicronized palmitoylethanolamide displays superior oral efficacy compared to non-micronized palmitoylethanolamide in a rat model of inflammatory pain. J Neuroinflammation 11:136. doi:10.1186/s12974-014-0136-0

    PubMed Central  Article  PubMed  Google Scholar 

  51. Winter CA, Risley EA, Nuss GW (1962) Carrageenan-induced oedema in hind paw of the rat as an assay for anti-inflammatory drugs. Proc Soc Exp Biol Med 111:544–547

    CAS  Article  PubMed  Google Scholar 

  52. Radi E, Formichi P, Battisti C, Federico A (2014) Apoptosis and oxidative stress in neurodegenerative diseases. J Alzheimers Dis. doi:10.3233/JAD-132738

    PubMed  Google Scholar 

  53. Cervellati C, Cremonini E, Bosi C, Magon S, Zurlo A, Bergamini CM, Zuliani G (2013) Systemic oxidative stress in older patients with mild cognitive impairment or late onset Alzheimer's disease. Curr Alzheimer Res 10:365–372. doi:10.2174/1567205011310040003

    CAS  Article  PubMed  Google Scholar 

  54. Salim S (2014) Oxidative stress and psychological disorders. Curr Neuropharmacol 12:140–147. doi:10.2174/1570159X11666131120230309

    PubMed Central  CAS  Article  PubMed  Google Scholar 

  55. Grosso C, Valentão P, Ferreres F, Andrade PB (2013) The use of flavonoids in central nervous system disorders. Curr Med Chem 20:4694–4719. doi:10.2174/09298673113209990155

    CAS  Article  PubMed  Google Scholar 

  56. Xu B, Li XX, He GR, Hu JJ, Mu X, Tian S, Du GH (2010) Luteolin promotes long-term potentiation and improves cognitive functions in chronic cerebral hypoperfused rats. Eur J Pharmacol 627:99–105. doi:10.1016/j.ejphar.2009.10.038

    CAS  Article  PubMed  Google Scholar 

  57. Coleta M, Campos MG, Cotrim MD, Lima TC, Cunha AP (2008) Assessment of luteolin (3',4',5,7-tetrahydroxyflavone) neuropharmacological activity. Behav Brain Res 189:75–82. doi:10.1016/j.bbr.2007.12.010

    CAS  Article  PubMed  Google Scholar 

  58. Paterniti I, Impellizzeri D, Di Paola R, Navarra M, Cuzzocrea S, Esposito E (2013) A new co-ultramicronized composite including palmitoylethanolamide and luteolin to prevent neuroinflammation in spinal cord injury. J Neuroinflammation 10:91. doi:10.1186/1742-2094-10-91

    PubMed Central  CAS  Article  PubMed  Google Scholar 

  59. Crupi R, Paterniti I, Ahmad A, Campolo M, Esposito E, Cuzzocrea S (2013) Effects of palmitoylethanolamide and luteolin in an animal model of anxiety/depression. CNS Neurol Disord Drug Targets 12:989–1001. doi:10.2174/18715273113129990084

    CAS  Article  PubMed  Google Scholar 

  60. Paterniti I, Cordaro M, Campolo M, Siracusa R, Cornelius C, Navarra M, Cuzzocrea S, Esposito E (2014) Neuroprotection by association of palmitoylethanolamide with luteolin in experimental Alzheimer's disease models: the control of neuroinflammation. CNS Neurol Disord Drug Targets. doi:10.2174/1871527313666140806124322

    PubMed  Google Scholar 

  61. Cordaro M, Impellizzeri D, Paterniti I, Bruschetta G, Siracusa R, De Stefano D, Cuzzocrea S, Esposito E (2014) Neuroprotective effects of Co-ultraPEALut on secondary inflammatory process and autophagy involved in traumatic brain injury. J Neurotrauma. doi:10.1089/neu.2014.3460

    Google Scholar 

  62. Bossers K, Wirz KT, Meerhoff GF, Essing AH, van Dongen JW, Houba P, Kruse CG, Verhaagen J, Swaab DF (2010) Concerted changes in transcripts in the prefrontal cortex precede neuropathology in Alzheimer’s disease. Brain 133:3699–3723. doi:10.1093/brain/awq258

    Article  PubMed  Google Scholar 

  63. Parra-Damas A, Valero J, Chen M, España J, Martín E, Ferrer I, Rodríguez-Alvarez J, Saura CA (2014) Crtc1 activates a transcriptional program deregulated at early Alzheimer's disease-related stages. J Neurosci 34:5776–5787. doi:10.1523/JNEUROSCI.5288-13.2014

    Article  PubMed  Google Scholar 

  64. Kang HJ, Voleti B, Hajszan T, Rajkowska G, Stockmeier CA, Licznerski P, Lepack A, Majik MS, Jeong LS, Banasr M, Son H, Duman RS (2012) Decreased expression of synapse-related genes and loss of synapses in major depressive disorder. Nat Med 18:1413–1417. doi:10.1038/nm.2886

    PubMed Central  CAS  Article  PubMed  Google Scholar 

  65. 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 (2009) Selective N-acylethanolamine-hydrolyzing acid amidase inhibition reveals a key role for endogenous palmitoylethanolamide in inflammation. Proc Natl Acad Sci U S A 106:20966–20971. doi:10.1073/pnas.0907417106

    PubMed Central  CAS  Article  PubMed  Google Scholar 

  66. Saturnino C, Petrosino S, Ligresti A, Palladino C, De Martino G, Bisogno T, Di Marzo V (2010) Synthesis and biological evaluation of new potential inhibitors of N-acylethanolamine hydrolyzing acid amidase. Bioorg Med Chem Lett 20:1210–1213. doi:10.1016/j.bmcl.2009.11.134

    CAS  Article  PubMed  Google Scholar 

  67. Yamano Y, Tsuboi K, Hozaki Y, Takahashi K, Jin XH, Ueda N, Wada A (2012) Lipophilic amines as potent inhibitors of N-acylethanolamine-hydrolyzing acid amidase. Bioorg Med Chem 20:3658–3665. doi:10.1016/j.bmc.2012.03.065

    CAS  Article  PubMed  Google Scholar 

  68. Duranti A, Tontini A, Antonietti F, Vacondio F, Fioni A, Silva C, Lodola A, Rivara S, Solorzano C, Piomelli D, Tarzia G, Mor M (2012) N-(2-oxo-3-oxetanyl)carbamic acid esters as N-acylethanolamine acid amidase inhibitors: synthesis and structure-activity and structure-property relationships. J Med Chem 55:4824–4836. doi:10.1021/jm300349j

    CAS  Article  PubMed  Google Scholar 

  69. Li Y, Yang L, Chen L, Zhu C, Huang R, Zheng X, Qiu Y, Fu J (2012) Design and synthesis of potent N-acylethanolamine-hydrolyzing acid amidase (NAAA) inhibitor as anti-inflammatory compounds. PLoS One 7:8. doi:10.1371/journal.pone.0043023

    Google Scholar 

  70. Sasso O, Moreno-Sanz G, Martucci C, Realini N, Dionisi M, Mengatto L, Duranti A, Tarozzo G, Tarzia G, Mor M, Bertorelli R, Reggiani A, Piomelli D (2013) Antinociceptive effects of the N-acylethanolamine acid amidase inhibitor ARN077 in rodent pain models. Pain 154:350–360. doi:10.1016/j.pain.2012.10.018

    PubMed Central  CAS  Article  PubMed  Google Scholar 

  71. Vitale R, Ottonello G, Petracca R, Bertozzi SM, Ponzano S, Armirotti A, Berteotti A, Dionisi M, Cavalli A, Piomelli D, Bandiera T, Bertozzi F (2014) Synthesis, structure-activity, and structure-stability relationships of 2-substituted-N-(4-oxo-3-oxetanyl) N-acylethanolamine acid amidase (NAAA) inhibitors. ChemMedChem 9:323–336. doi:10.1002/cmdc.201300416

    CAS  Article  PubMed  Google Scholar 

  72. Siegmund SV, Wojtalla A, Schlosser M, Zimmer A, Singer MV (2013) Fatty acid amide hydrolase but not monoacyl glycerol lipase controls cell death induced by the endocannabinoid 2-arachidonoyl glycerol in hepatic cell populations. Biochem Biophys Res Commun 437:48–54. doi:10.1016/j.bbrc.2013.06.033

    CAS  Article  PubMed  Google Scholar 

  73. Hoyer FF, Khoury M, Slomka H, Kebschull M, Lerner R, Lutz B, Schott H, Lütjohann D, Wojtalla A, Becker A, Zimmer A, Nickenig G (2014) Inhibition of endocannabinoid-degrading enzyme fatty acid amide hydrolase increases atherosclerotic plaque vulnerability in mice. J Mol Cell Cardiol 66:126–132. doi: 10.1016/j.yjmcc.2013.11.013

  74. Skaper SD, Facci L (2012) Mast cell-glia axis in neuroinflammation and therapeutic potential of the anandamide congener palmitoylethanolamide. Philos Trans R Soc Lond B Biol Sci 367:3312–3325. doi:10.1098/rstb.2011.0391

    PubMed Central  CAS  Article  PubMed  Google Scholar 

  75. Patent application WO 2013121449 A1 (2013) Compositions and methods for the modulation of specific amidases for n-acylethanolamines for use in the therapy of inflammatory diseases. Published August 22

  76. Schäfer T, Starkl P, Allard C, Wolf RM, Schweighoffer T (2010) A granular variant of CD63 is a regulator of repeated human mast cell degranulation. Allergy 65:1242–1255. doi:10.1111/j.1398-9995.2010.02350.x

    Article  PubMed  Google Scholar 

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Acknowledgments

This study was supported in part by MIUR, PON “Ricerca e Competitività 2007–2013” project PON01_02512.

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The authors declare that they have no conflicts of interest.

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Skaper, S.D., Facci, L., Barbierato, M. et al. N-Palmitoylethanolamine and Neuroinflammation: a Novel Therapeutic Strategy of Resolution. Mol Neurobiol 52, 1034–1042 (2015). https://doi.org/10.1007/s12035-015-9253-8

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Keywords

  • Microglia
  • Mast cells
  • Neuroinflammation
  • Neuropathic pain
  • Neurodegeneration
  • Palmitoylethanolamide
  • Luteolin
  • Ultramicronization
  • Neuroprotection