Neuroinflammation, microglia and mast cells in the pathophysiology of neurocognitive disorders: A review

CNS and Neurological Disorders - Drug Targets

Volumn 13, Issue 10, 2014, Pages 1654-1666

  Skaper, Stephen D ^a   Facci, Laura ^a   Giusti, Pietro ^a  

^a UNIVERSITY OF PADOVA   (Italy)

Author keywords

Alzheimer disease; Astrocytes; Cognition; Lipid signaling molecules; Mast cells; Microglia; Mood disorders; Neuroinflammation

Indexed keywords

ACID HYDROLASE; ADENOSINE TRIPHOSPHATE; AMYLOID BETA PROTEIN; CD40 LIGAND; CELL ADHESION MOLECULE; COMPLEMENT COMPONENT C3 RECEPTOR; GAMMA INTERFERON; GRANULOCYTE MACROPHAGE COLONY STIMULATING FACTOR; HEPARIN; INTERLEUKIN 1BETA; INTERLEUKIN 4; INTERLEUKIN 6; LEUKEMIA INHIBITORY FACTOR; LEUKOTRIENE C4; LIPOPOLYSACCHARIDE; MACROPHAGE INFLAMMATORY PROTEIN 3BETA; NERVE GROWTH FACTOR; NEUROPEPTIDE; NITRIC OXIDE; OX40 LIGAND; PALMIDROL; PHOSPHOLIPASE; PROSTAGLANDIN D2; SERINE PROTEINASE; THROMBOCYTE ACTIVATING FACTOR; THROMBOXANE; TRANSFORMING GROWTH FACTOR BETA; TUMOR NECROSIS FACTOR ALPHA; UNINDEXED DRUG; CYTOKINE;

AGING; ALZHEIMER DISEASE; ANXIETY; ASTROCYTE; BLOOD BRAIN BARRIER; CELL INTERACTION; CEREBROVASCULAR ACCIDENT; COGNITION; DEPRESSION; HUMAN; INNATE IMMUNITY; MACROPHAGE; MAST CELL; MICROGLIA; NERVOUS SYSTEM INFLAMMATION; NONHUMAN; PATHOPHYSIOLOGY; POSTOPERATIVE COGNITIVE DYSFUNCTION; REVIEW; SIGNAL TRANSDUCTION; SPINAL CORD INJURY; SYNAPSE; ANIMAL; CENTRAL NERVOUS SYSTEM DISEASE; COGNITIVE DEFECT; COMPLICATION; ENCEPHALITIS; IMMUNOLOGY; METABOLISM; PATHOLOGY;

ANIMALS; CENTRAL NERVOUS SYSTEM DISEASES; COGNITION DISORDERS; CYTOKINES; ENCEPHALITIS; HUMANS; MAST CELLS; MICROGLIA;

EID: 84924191380     PISSN: 18715273     EISSN: 19963181     Source Type: Journal    
DOI: 10.2174/1871527313666141130224206     Document Type: Review

References (164)

1. Wrona D. Neural-immune interactions: an integrative view of the bidirectional relationship between the brain and immune systems. J Neuroimmunol 2006; 172: 38-58.
2. Ellis A, Bennett DLH. Neuroinflammation and the generation of neuropathic pain. Br J Anesthesiol 2013; 111: 26-37.
3. Iadecola C, Anrather J. The immunology of stroke: from mechanisms to translation. Nat Med 2011; 17: 796-808.
4. McGeer PL, McGeer EG. The amyloid cascade-inflammatory hypothesis of Alzheimer disease: implications for therapy. Acta Neuropathol 2013; 126: 479-97.
5. Karalija A, Novikova LN, Kingham PJ, Wiberg M, Novikov LN. The Effects of N-acetyl-cysteine and acetyl-L-carnitine on neural survival, neuroinflammation and regeneration following spinal cord injury. Neuroscience 2014; 269: 143-51.
6. Miller AH, Maletic V, Raison CL. Inflammation and its discontents: the role of cytokines in the pathophysiology of major depression. Biol Psychiatry 2009; 65: 732-41.
7. Noriega DB, Savelkoul HF. Immune dysregulation in autism spectrum disorder. Eur J Pediatr 2014; 173: 33-43.
8. Rivat C, Becker C, Blugeot A, et al. Chronic stress induces transient spinal neuroinflammation, triggering sensory hypersensitivity and long-lasting anxiety-induced hyperalgesia. Pain 2010; 150: 358-68.
9. Ridker PM. Inflammatory biomarkers and risks of myocardial infarction, stroke, diabetes, and total mortality: Implications for longevity. Nutr Rev 2007; 65: S253-9.
10. Gold SM, Irwin MR. Depression and immunity: inflammation and depressive symptoms in multiple sclerosis. Neurol Clin 2006; 24: 507-19.
11. Zautra AJ, Yocum DC, Villanueva I, et al. Immune activation and depression in women with rheumatoid arthritis. J Rheumatol 2004; 3: 457-63.
12. Mossner R, Mikova O, Koutsilieri E, et al. Consensus paper of the WFSBP Task Force on Biological Markers: Biological markers in depression. World J Biol Psychiatry 2007; 8: 141-74.
13. Raison CL, Capuron L, Miller AH. Cytokines sing the blues: inflammation and the pathogenesis of depression. Trends Immunol 2006; 27: 24-31.
14. Dantzer R, O'Connor JC, Freund GG, Johnson RW, Kelley KK. From inflammation to sickness and depression: When the immune system subjugates the brain. Nat Rev Neurosci 2008; 9: 46-56.
15. Musselman DL, Lawson DH, Gumnick JF, et al. Paroxetine for the prevention of depression induced by high-dose interferon alpha. N Engl J Med 2001; 344: 961-6.
16. Schaefer M, Ertgelbrecht MA, Gut O, et al. Interferon alpha (IFNα) and psychiatric syndromes: a review. Prog Neuropsychopharmacol Biol Psychiatry 2002; 26: 731-46.
17. Raison CL, Borisov AS, Broadwell SD, et al. Depression during pegylated interferon-alpha plus ribavirin therapy: prevalence and prediction. J Clin Psychiatry 2005; 66: 41-8.
18. Raison CL, Borisov AS, Majer M, et al. Activation of central nervous system inflammatory pathways by interferon-alpha: Relationship to monoamines and depression. Biol Psychiatry 2008; 65: 296-303.
19. Himmerich H, Fischer J, Bauer K, et al. Stress-induced cytokine changes in rats. Eur Cytokine Netw 2013; 24: 97-103.
20. Chourbaji S, Urani A, Inta I, et al. IL-6 knockout mice exhibit resistance to stress-induced development of depression-like behaviors. Neurobiol Dis 2006; 23: 587-94.
21. Sukoff Rizzo SJ, Neal SJ, Hughes ZA, et al. Evidence for sustained elevation of IL-6 in the CNS as a key contributor of depressive-like phenotypes. Transl Psychiatry 2012; 2: e199.
22. Hamer M, Batty GD, Kivimaki M. Risk of future depression in people who are obese but metabolically healthy: the English longitudinal study of ageing. Mol Psychiatry 2012; 17: 940-5.
23. Godha D, Shi L, Mavronicolas H. Association between tendency towards depression and severity of rheumatoid arthritis from a national representative sample: the Medical Expenditure Panel Survey. Curr Med Res Opin 2010; 26: 1685-90.
24. Hellmann-Regen J, Piber D, Hinkelmann K, et al. Depressive syndromes in neurological disorders. Eur Arch Psychiatry Clin Neurosci 2013; 263(Suppl 2): S123-36.
25. Daulatzai MA. Chronic functional bowel syndrome enhances gutbrain axis dysfunction, neuroinflammation, cognitive impairment, and vulnerability to dementia. Neurochem Res 2014; 39: 624-44.
26. Beutler B, Hoebe K, Du X, Ulevitch RJ. How we detect microbes and respond to them: the Toll-like receptors and their transducers. J Leukoc Biol 2003; 74: 479-85.
27. Rummel C, Inoue W, Sachot C, et al. Selective contribution of interleukin-6 and leptin to brain inflammatory signals induced by systemic LPS injection in mice. J Comp Neurol 2008; 511: 373-95.
28. Lin YL, Wang S. Prenatal lipopolysaccharide exposure increases depression-like behaviors and reduces hippocampal neurogenesis in adult rats. Behav Brain Res 2014; 259: 24-34.
29. Ji WW, Wang SY, Ma ZQ. Effects of perillaldehyde on alternations in serum cytokines and depressive-like behavior in mice after lipopolysaccharide administration. Pharmacol Biochem Behav 2014; 116: 1-8.
30. Konsman JP, Luheshi GN, Bluthe RM, Dantzer R. The vagus nerve mediates behavioural depression, but not fever, in response to peripheral immune signals; a functional anatomical analysis. Eur J Neurosci 2000; 12: 4434-46.
31. Ching S, Zhang H, Belevych N, et al. Endothelial-specific knockdown of interleukin-1 (IL-1) type 1 receptor differentially alters CNS responses to IL-1 depending on its route of administration. J Neurosci 2007; 27: 10476-86.
32. McCusker RH, Kelley KW. Immune-neural connections: how the immune system's response to infectious agents influences behaviour. J Exp Biol 2013; 216: 84-98.
33. Barrientos RM, Higgins EA, et al. Peripheral infection and aging interact to impair hippocampal memory consolidation. Neurobiol Aging 2006; 27: 723-32.
34. Chen J, Buchanan JB, Sparkman NL, et al. Neuroinflammation and disruption in working memory in aged mice after acute stimulation of the peripheral innate immune system. Brain Behav Immun 2008; 22: 301-11.
35. Müller N. Immunology of major depression. Neuroimmunomodulation 2014; 21: 123-30.
36. André C, Dinel AL, Ferreira G, Layé S, Castanon N. Diet-induced obesity progressively alters cognition, anxiety-like behavior and lipopolysaccharide-induced depressive-like behavior: Focus on brain indoleamine 2, 3-dioxygenase activation. Brain Behav Immun 2014; 41: 10-21.
37. Dobos N, de Vries EF, Kema IP, et al. The role of indoleamine 2, 3-dioxygenase in a mouse model of neuroinflammation-induced depression. J Alzheimers Dis 2012; 28: 905-15.
38. Shelton RC, Miller AH. Eating ourselves to death (and despair): the contribution of adiposity and inflammation to depression. Prog Neurobiol 2010; 91: 275-99.
39. Sullivan-Singh SJ, Sawyer K, Ehde DM, et al. Comorbidity of pain and depression among persons with traumatic brain injury. Arch Phys Med Rehabil 2014; 95(6): 1100-5.
40. Fenn AM, Gensel JC, Huang Y, et al. Immune activation promotes depression 1 month after diffuse brain injury: a role for primed microglia. Biol Psychiatry 2014; 76(7): 575-84.
41. Frick LR, Williams K, Pittenger C. Microglial dysregulation in psychiatric disease. Clin Dev Immunol 2013; 2013: 608654.
42. Aguliar-Valles A, Kim J, Jung S, Woodside B, Luheshi GN. Role of brain transmigrating neutrophils in depression-like behavior during systemic infection. Mol Psychiatry 2014; 19: 599-606.
43. Chen CC, Grimbaldeston MA, Tsai M, Weissman IL, Galli SJ. Identification of mast cell progenitors in adult mice. Proc Natl Acad Sci USA 2005; 102: 11408-13.
44. Gilfillan AM, Austin SJ, Metcalfe DD. Mast cell biology: introduction and overview. Adv Exp Med Biol 2011; 716: 2-12.
45. Lambracht-Hall M, Dimitriadou V, Theoharides TC. Migration of mast cells in the developing rat brain. Dev Brain Res 1990; 56: 151-9.
46. Silverman AJ, Sutherland AK, Wilhelm M, Silver R. Mast cells migrate from blood to brain. J Neurosci 2000; 20: 401-8.
47. Johnson D, Krenger W. Interactions of mast cells with the nervous system-recent advances. Neurochem Res 1992; 17: 939-51.
48. Gauchat JF, Henchoz S, Mazzei G, et al. Induction of human IgE synthesis in B cells by mast cells and basophils. Nature 1993; 365: 340-3.
49. Wardlaw AJ, Moqbel R, Cromwell O, Kay AB. Platelet-activating factor. A potent chemotactic and chemokinetic factor for human eosinophils. J Clin Invest 1986; 78: 1701-6.
50. Perry VH, Andersson PB, Gordon G. Macrophages and inflammation in the central nervous system. Trends Neurosci 1993; 16: 268-73.
51. Brenner T, Soffer D, Shalit M, Levi-Schaffer F. Mast cells in experimental allergic encephalomyelitis: characterization, distribution in the CNS and in vitro activation by myelin basic protein and neuropeptides. J Neurol Sci 1994; 122: 210-3.
52. Theoharides TC, Baloyannis SJ, Manolidis LS. Activated rat peritoneal mast cells can cause syngeneic brain demyelination in vitro. Int J Immunopathol Pharmacol 1991; 4: 137-44.
53. Medic N, Lorenzon P, Vita F, Trevisan E, et al. Mast cell adhesion induces cytoskeletal modifications and programmed cell death in oligodendrocytes. J Neuroimmunol 2010; 218: 57-66.
54. Nautiyal KM, Ribeiro AC, Pfaff DW, Silver R. Brain mast cells link the immune system to anxiety-like behavior. Proc Natl Acad Sci USA 2008; 105: 18053-7.
55. Valent P, Horny HP, Escribano L, et al. Diagnostic criteria and classification of mastocytosis: a consensus proposal. Leuk Res 2001; 25: 603-25.
56. Hermine O, Lortholary O, Leventhal PS, et al. Case-control cohort study of patients' perceptions of disability in mastocytosis. PLoS One 2008; 3: 5.
57. Rogers MP, Bloomingdale K, Murawski BJ, et al. Mixed organic brain syndrome as a manifestation of systemic mastocytosis. Psychosom Med 1986; m48: 437-47.
58. Brintzenhofe-Szoc KM, Levin TT, Li Y, Kissane DW, Zabora JR. Mixed anxiety/depression symptoms in a large cancer cohort: prevalence by cancer type. Psychosomatics 2009; 50: 383-91.
59. Dubreuil P, Letard S, Ciufolini M, et al. Masitinib (AB1010), a potent and selective tyrosine kinase inhibitor targeting KIT. PLoS One 2009; 4: 9.
60. Paul C, Sans B, Suarez F, et al. Masitinib for the treatment of systemic and cutaneous mastocytosis with handicap: a phase 2a study. Am J Hematol 2010; 85: 921-5.
61. Moura DS, Sultan S, Georgin-Lavialle S, et al. Depression in patients with mastocytosis: prevalence, features and effects of masitinib therapy. PLoS One 2011; 6: 10.
62. Schaie KW. Intellectual Development in Adulthood: The Seattle Longitudinal Study. Cambridge: Cambridge University Press; 1996.
63. Dumitriu D, Hao J, Hara Y, et al. Selective changes in thin spine density and morphology in monkey prefrontal cortex correlate with aging-related cognitive impairment. J Neurosci 2010; 30: 7507-15.
64. Gómez-Isla T, Price JL, McKeel DW Jr, et al. Profound loss of layer II entorhinal cortex neurons occurs in very mild Alzheimer's disease. J Neurosci 1996; 16: 4491-500.
65. Blazer D. Neurocognitive disorders in DSM-5. Am J Psychiatry 2013; 170: 585-7.
66. Buchanan JB, Sparkman NL, Chen J, Johnson RW. Cognitive and neuroinflammatory consequences of mild repeated stress are exacerbated in aged mice. Psychoneuroendocrinology 2008; 33: 755-65.
67. Hein AM, Stasko MR, Matousek SB, et al. Sustained hippocampal IL-1β overexpression impairs contextual and spatial memory in transgenic mice. Brain Behav Immun 2010; 24: 243-53.
68. Sloane JA, Hollander W, Moss MB, Rosene DL, Abraham CR. Increased microglial activation and protein nitration in white matter of the aging monkey. Neurobiol Aging 1999; 20: 395-405.
69. Peters O, Schipke CG, Philipps A, et al. Astrocyte function is modified by Alzheimer's disease-like pathology in aged mice. J Alzheimers Dis 2009; 18: 177-89.
70. Wilson CJ, Finch CE, Cohen HJ. Cytokines and cognition-the case for a head-to-toe inflammatory paradigm. J Am Geriatr Soc 2002; 50: 2041-56.
71. Godbout JP, Chen J, Abraham J, et al. Exaggerated neuroinflammation and sickness behavior in aged mice following activation of the peripheral innate immune system. FASEB J 2005; 19: 1329-31.
72. Counts SE, Nadeem M, Lad SP, Wuu J, Mufson EJ. Differential expression of synaptic proteins in the frontal and temporal cortex of elderly subjects with mild cognitive impairment. J Neuropathol Exp Neurol 2006; 65: 592-601.
73. Kojima N, Shirao T. Synaptic dysfunction and disruption of postsynaptic drebrin-actin complex: a study of neurological disorders accompanied by cognitive deficits. Neurosci Res 2007; 58: 1-5.
74. Paolicelli RC, Bolasco G, Pagani F, et al. Synaptic pruning by microglia is necessary for normal brain development. Science 2011; 333: 1456-8.
75. Schafer DP, Lehrman EK, Stevens B. The "quad-partite" synapse: microglia-synapse interactions in the developing and mature CNS. Glia 2013; 61: 24-36.
76. Stevens B, Allen NJ, Vazquez LE, et al. The classical complement cascade mediates CNS synapse elimination. Cell 2007; 131: 1164-78.
77. Schafer DP, Lehrman EK, Kautzman AG, et al. Microglia sculpt postnatal neural circuits in an activity and complement-dependent manner. Neuron 2012; 74: 691-705.
78. Zlokovic BV. Neurovascular pathways to neurodegeneration in Alzheimer's disease and other disorders. Nat Rev Neurosci 2011; 12: 723-38.
79. Nizet V, Johnson RS. Interdependence of hypoxic and innate immune responses. Nat Rev Immunol 2009; 9: 609-17.
80. Zhang J, Malik A, Choi HB, et al. Microglial CR3 activation triggers long-term synaptic depression in the hippocampus via NADPH oxidase. Neuron 2014; 82: 195-207.
81. Selkoe D, Mandelkow E, Holtzman D. Deciphering Alzheimer disease. Cold Spring Harb Perspect Med 2012; 2: a011460.
82. Wyss-Coray T. Inflammation in Alzheimer disease: driving force, bystander or beneficial response? Nat Med 2006; 12: 1005-15.
83. Medeiros R, LaFerla FM. Astrocytes: conductors of the Alzheimer disease neuroinflammatory symphony. Exp Neurol 2013; 239: 133-8.
84. Rivest S. Regulation of innate immune responses in the brain. Nat Rev Immunol 2009; 9: 429-39.
85. Biscaro B, Lindvall O, Tesco G, Ekdahl CT, Nitsch RM. Inhibition of microglial activation protects hippocampal heurogenesis and improves cognitive deficits in a transgenic mouse model for Alzheimer's disease. Neurodegener Dis 2012; 9: 187-98.
86. Cleary JP, Walsh DM, Hofmeister JJ, et al. Natural oligomers of the amyloid-beta protein specifically disrupt cognitive function. Nat Neurosci 2005; 8: 79-84.
87. Bachstetter AD, Norris CM, Sompol P, et al. Early stage drug treatment that normalizes proinflammatory cytokine production attenuates synaptic dysfunction in a mouse model that exhibits agedependent progression of Alzheimer's disease-related pathology. J Neurosci 2012; 32: 10201-10.
88. Newman S, Stygall J, Hirani S, Shaefi S, Maze M. Postoperative cognitive dysfunction after noncardiac surgery: a systematic review. Anesthesiology 2007; 106: 572-90.
89. Rasmussen LS. Postoperative cognitive dysfunction: incidence and prevention. Best Pract Res Anaesthesiol 2006; 20: 315-30.
90. Krenk L, Rasmussen LS, Kehlet H. New insights into the pathophysiology of postoperative cognitive dysfunction. Acta Anaesthesiol Scand 2010; 54: 951-6.
91. Shapira-Lichter I, Beilin B, Ofek K, et al. Cytokines and cholinergic signals co-modulate surgical stress-induced changes in mood and memory. Brain Behav Immun 2008; 22: 388-98.
92. Dilger RN, Johnson RW. Aging, microglial cell priming, and the discordant central inflammatory response to signals from the peripheral immune system. J Leukoc Biol 2008; 84: 932-9.
93. Barrientos RM, Higgins EA, Biedenkapp JC, et al. Peripheral infection and aging interact to impair hippocampal memory consolidation. Neurobiol Aging 2006; 27: 723-32.
94. Warrington JP, Ashpole N, Csiszar A, et al. Whole brain radiationinduced vascular cognitive impairment: mechanisms and implications. J Vasc Res 2013; 50: 445-57.
95. Jenrow KA, Brown SL, Lapanowski K, et al. Selective inhibition of microglia-mediated neuroinflammation mitigates radiationinduced cognitive impairment. Radiat Res 2013; 179: 549-56.
96. Skaper SD, Giusti P, Facci L. Microglia and mast cells: two tracks on the road to neuroinflammation. FASEB J 2012; 26: 3103-17.
97. Osipchuk Y, Cahalan M. Cell-to-cell spread of calcium signals mediated by ATP receptors in mast cells. Nature 1992; 359: 241-4.
98. Chakraborty S, Kaushik DK, Gupta M, Basu A. Inflammasome signaling at the heart of central nervous system pathology. J Neurosci Res 2010; 88: 1615-31.
99. Trang T, Beggs S, Wan X, Salter MW. P2X4-receptor-mediated synthesis and release of brain-derived neurotrophic factor in microglia is dependent on calcium and p38-mitogen-activated protein kinase activation. J Neurosci 2009; 29: 3518-28.
100. Zhang H, Yang H, He S. TNF increases expression of IL-4 and PARs in mast cells. Cell Physiol Biochem 2010; 26: 327-36.
101. Gasque P, Singhrao SK, Neal JW, Götze O, Morgan BP. Expression of the receptor for complement C5a (CD88) is upregulated on reactive astrocytes, microglia, and endothelial cells in the inflamed human central nervous system. Am J Pathol 1997; 150: 31-41.
102. Griffin RS, Costigan M, Brenner GJ, et al. Complement induction in spinal cord microglia results in anaphylatoxin C5a-mediated pain hypersensitivity. J Neurosci 2007; 27: 8699-708.
103. Dong Y, Benveniste EN. Immune function of astrocytes. Glia 2001; 36: 180-90.
104. Kim DY, Hong GU, Ro JY. Signal pathways in astrocytes activated by cross-talk between of astrocytes and mast cells through CD40-CD40L. J Neuroinflammation 2011; 8: 25.
105. Wang M, Wang X, Zhao L, et al. Macroglia-microglia interactions via TSPO signaling regulates microglial activation in the mouse retina. J Neurosci 2014; 34: 3793-806.
106. Buckley CD, Gilroy DW, Serhan CN, Stockinger B, Tak PP. The resolution of inflammation. Nat Rev Immunol 2013; 13: 59-66.
107. Zhu C, Solorzano C, Sahar S, et al. Proinflammatory stimuli control N-acylphosphatidylethanolamine-specific phospholipase D expression in macrophages. Mol Pharmacol 2011; 79: 786-92.
108. Tabas I, Glass CK. Anti-inflammatory therapy in chronic disease: challenges and opportunities. Science 2013; 339: 166-72.
109. Pacher P, Bátkai S, Kunos G. The endocannabinoid system as an emerging target of pharmacotherapy. Pharmacol Rev 2006; 58: 389-462.
110. Ueda N, Tsuboi K, Uyama T. Metabolism of endocannabinoids and related N-acylethanolamines: Canonical and alternative pathways. FEBS J 2013; 280: 1874-94.
111. Leung D, Saghatelian A, Simon GM, Cravatt BF. Inactivation of N-acyl phosphatidylethanolamine phospholipase D reveals multiple mechanisms for the biosynthesis of endocannabinoids. Biochemistry 2006; 45: 4720-6.
112. Cravatt BF, Giang DK, Mayfield SP, et al. Molecular characterization of an enzyme that degrades neuromodulatory fattyacid amides. Nature 1996; 384: 83-7.
113. Tsuboi K, Takezaki N, Ueda N. The N-acylethanolaminehydrolyzing acid amidase (NAAA). Chem Biodivers 2007; 4: 1914-25.
114. Skaper SD, Facci L. Mast cell-glia axis in neuroinflammation and therapeutic potential of the anandamide congener palmitoylethanolamide. Philos Trans R Soc Lond B Biol Sci 2012; 367: 3312-25.
115. Piomelli D, Sasso O. Peripheral gating of pain signals by endogenous lipid mediators. Nat Neurosci 2014; 17: 164-74.
116. Bisogno T, Maurelli S, Melck D, De Petrocellis L, Di Marzo V. Biosynthesis, uptake, and degradation of anandamide and palmitoylethanolamide in leukocytes. J Biol Chem 1997; 272: 3315-23.
117. Muccioli GG, Stella N. Microglia produce and hydrolyze palmitoylethanolamide. Neuropharmacology 2008; 54: 16-22.
118. Facci L, Dal Toso R, Romanello S, et al. Mast cells express a peripheral cannabinoid receptor with differential sensitivity to anandamide and palmitoylethanolamide. Proc Natl Acad Sci USA 1995; 92: 3376-80.
119. Franklin A, Parmentier-Batteur S, Walter L, Greenberg DA, Stella N. Palmitoylethanolamide increases after focal cerebral ischemia and potentiates microglial cell motility. J Neurosci 2003; 23: 7767-75.
120. Luongo L, Guida F, Boccella S, et al. Palmitoylethanolamide reduces formalin-induced neuropathic-like behaviour through spinal glial/microglial phenotypical changes in mice. CNS Neurol Disord Drug Targets 2013; 12: 45-54.
121. Petrosino S, Palazzo E, de Novellis V, et al. Changes in spinal and supraspinal endocannabinoid levels in neuropathic rats. Neuropharmacology 2007; 52: 415-22.
122. Jhaveri MD, Richardson D, Robinson I, et al. Inhibition of fatty acid amide hydrolase and cyclooxygenase-2 increases levels of endocannabinoid related molecules and produces analgesia via peroxisome proliferator-activated receptor-alpha in a model of inflammatory pain. Neuropharmacology 2008; 55: 85-93.
123. Ghafouri N, Ghafouri B, Larsson B, et al. Palmitoylethanolamide and stearoylethanolamide levels in the interstitium of the trapezius muscle of women with chronic widespread pain and chronic neckshoulder pain correlate with pain intensity and sensitivity. Pain 2013; 154: 1649-58.
124. Skaper SD, Facci L, Giusti P. Glia and mast cells as targets for palmitoylethanolamide, an anti-inflammatory and neuroprotective lipid mediator. Mol Neurobiol 2013; 48: 340-52.
125. Skaper SD, Facci L, Fusco M, et al. Palmitoylethanolamide, a naturally occurring disease-modifying agent in neuropathic pain. Inflammopharmacology 2014; 22: 79-94.
126. Solorzano C, Zhu C, Battista N, et al. Selective Nacylethanolamine-hydrolyzing acid amidase inhibition reveals a key role for endogenous palmitoylethanolamide in inflammation. Proc Natl Acad Sci USA 2009; 106: 20966-71.
127. Solorzano C, Antonietti F, Duranti A, et al. Synthesis and structure-activity relationships of N-(2-oxo-3-oxetanyl)amides as N-acylethanolamine-hydrolyzing acid amidase inhibitors. J Med Chem 2010; 53: 5770-81.
128. Saturnino C, Petrosino S, Ligresti A, et al. Synthesis and biological evaluation of new potential inhibitors of N-acylethanolamine hydrolyzing acid amidase. Bioorg Med Chem Lett 2010; 20: 1210-3.
129. Yamano Y, Tsuboi K, Hozaki Y, et al. Lipophilic amines as potent inhibitors of N-acylethanolamine-hydrolyzing acid amidase. Bioorg Med Chem 2012; 20: 3658-65.
130. Duranti A, Tontini A, Antonietti F, et al. 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 2012; 55: 4824-36.
131. Li Y, Yang L, Chen L, et al. Design and synthesis of potent Nacylethanolamine-hydrolyzing acid amidase (NAAA) inhibitor as anti-inflammatory compounds. PLoS One 2012; 7: 8.
132. Sasso O, Moreno-Sanz G, Martucci C, et al. Antinociceptive effects of the N-acylethanolamine acid amidase inhibitor ARN077 in rodent pain models. Pain 2013; 154: 350-60.
133. Ponzano S, Bertozzi F, Mengatto L, et al. Synthesis and structureactivity relationship (SAR) of 2-methyl-4-oxo-3-oxetanylcarbamic acid esters, a class of potent N-acylethanolamine acid amidase (NAAA) inhibitors. J Med Chem 2013; 56: 6917-34.
134. Vitale R, Ottonello G, Petracca R, et al. Synthesis, structureactivity, and structure-stability relationships of 2-substituted-N-(4-oxo-3-oxetanyl) N-acylethanolamine acid amidase (NAAA) inhibitors. ChemMedChem 2014; 9: 323-36.
135. D'Agostino G, Russo R, Avagliano C, et al. Palmitoylethanolamide protects against the amyloid-β25-35-induced learning and memory impairment in mice, an experimental model of Alzheimer disease. Neuropsychopharmacology 2012; 37: 1784-92.
136. Scuderi C, Valenza M, Stecca C, et al. Palmitoylethanolamide exerts neuroprotective effects in mixed neuroglial cultures and organotypic hippocampal slices via peroxisome proliferatoractivated receptor-α. J Neuroinflammation 2012; 9: 49.
137. 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: 8.
138. Cervellati C, Cremonini E, Bosi C, et al. Systemic oxidative stress in older patients with mild cognitive impairment or late onset Alzheimer's disease. Curr Alzheimer Res 2013; 10: 365-72.
139. Schrag M, Mueller C, Zabel M, et al. Oxidative stress in blood in Alzheimer's disease and mild cognitive impairment: a metaanalysis. Neurobiol Dis 2013; 59: 100-10.
140. Salim S. Oxidative stress and psychological disorders. Curr Neuropharmacol 2014; 12: 140-7.
141. Gutierrez-Merino C, Lopez-Sanchez C, Lagoa R, et al. Neuroprotective actions of flavonoids. Curr Med Chem 2011; 18(8): 1195-212.
142. Grosso C, Valentão P, Ferreres F, Andrade PB. The use of flavonoids in central nervous system disorders. Curr Med Chem 2013; 20(37): 4694-719.
143. Xu B, Li XX, He GR, et al. Luteolin promotes long-term potentiation and improves cognitive functions in chronic cerebral hypoperfused rats. Eur J Pharmacol 2010; 627: 99-105.
144. Coleta M, Campos MG, Cotrim MD, Lima TC, Cunha AP. Assessment of luteolin (3', 4', 5, 7-tetrahydroxyflavone) neuropharmacological activity. Behav Brain Res 2008; 189: 75-82.
145. Crupi R, Paterniti I, Ahmad A, et al. Effects of palmitoylethanolamide and luteolin in an animal model of anxiety/depression. CNS Neurol Disord Drug Targets 2013; 12: 989-1001.
146. Esposito M, Paterniti I, Cuzzocrea S, et al. Neuroprotection by association of palmitoylethanolamide with luteolin in experimental Alzheimer's disease models: the control of neuroinflammation. CNS Neurol Disord Drug Targets 2014; 13(9): 1530-41.
147. Paterniti I, Impellizzeri D, Di Paola R, et al. A new coultramicronized composite including palmitoylethanolamide and luteolin to prevent neuroinflammation in spinal cord injury. J Neuroinflammation 2013; 10: 91.
148. Bossers K, Wirz KT, Meerhoff GF, et al. Concerted changes in transcripts in the prefrontal cortex precede neuropathology in Alzheimer's disease. Brain 2010; 133: 3699-723.
149. Parra-Damas A, Valero J, Chen M, et al. Crtc1 activates a transcriptional program deregulated at early Alzheimer's diseaserelated stages. J Neurosci 2014; 34: 5776-87.
150. Kang HJ, Voleti B, Hajszan T, et al. Decreased expression of synapse-related genes and loss of synapses in major depressive disorder. Nat Med 2012; 18: 1413-7.
151. Lo Verme J, Fu J, Astarita G, et al. The nuclear receptor peroxisome proliferator-activated receptor-alpha mediates the antiinflammatory actions of palmitoylethanolamide. Mol Pharmacol 2005; 67: 15-9.
152. Raso GM, Esposito E, Vitiello S, et al. Palmitoylethanolamide stimulation induces allopregnanolone synthesis in C6 cells and primary astrocytes: involvement of peroxisome-proliferator activated receptor-α. J Neuroendocrinol 2011; 23: 591-600.
153. Scuderi C, Esposito G, Blasio A, et al. Palmitoylethanolamide counteracts reactive astrogliosis induced by β-amyloid peptide. J Cell Mol Med 2011; 15: 2664-74.
154. Fidaleo M, Fanelli F, Ceru MP, Moreno S. Neuroprotective properties of peroxisome proliferator-activated receptor alpha (PPARα) and its lipid ligands. Curr Med Chem 2014; 21(24): 2803-21.
155. Moura DS, Sultan S, Georgin-Lavialle S, et al. Evidence for cognitive impairment in mastocytosis: prevalence, features and correlations to depression. PLoS One 2012; 7: 6.
156. Felger JC, Lotrich FE. Inflammatory cytokines in depression: neurobiological mechanisms and therapeutic implications. Neuroscience 2013; 246: 199-229.
157. Cunningham C. Microglia and neurodegeneration: the role of systemic inflammation. Glia 2013; 61: 71-90.
158. Nelson RB, Siman R, Iqbal MA, Potter H. Identification of a chymotrypsin-like mast cell protease in rat brain capable of generating the N-terminus of the Alzheimer amyloid beta-protein. J Neurochem 1993; 61: 567-77.
159. Norden DM, Godbout JP. Review: microglia of the aged brain: primed to be activated and resistant to regulation. Neuropathol Appl Neurobiol 2013; 39: 19-34.
160. Salminen A, Ojala J, Kaarniranta K, et al. Astrocytes in the aging brain express characteristics of senescence-associated secretory phenotype. Eur J Neurosci 2011; 34: 3-11.
161. Harrison NA, Doeller CF, Voon V, Burgess N, Critchley HD. Peripheral inflammation acutely impairs human spatial memory via actions on medial temporal lobe glucose metabolism. Biol Psychiatry 2014; 76(7): 585-93.
162. Weaver JD, Huang MH, Albert M, et al. Interleukin-6 and risk of cognitive decline: MacArthur studies of successful aging. Neurology 2002; 59: 371-8.
163. Furuno T, Hagiyama M, Sekimura M, et al. Cell adhesion molecule 1 (CADM1) on mast cells promotes interaction with dorsal root ganglion neurites by heterophilic binding to nectin-3. J Neuroimmunol 2012; 250: 50-8.
164. Choudhuri K, Llodrá J, Roth EW, et al. Polarized release of T-cellreceptor-enriched microvesicles at the immunological synapse. Nature 2014; 507: 118-23.