Bridge between neuroimmunity and traumatic brain injury

Current Pharmaceutical Design

Volumn 20, Issue 26, 2014, Pages 4284-4298

  Kelso, Matthew L ^a   Gendelman, Howard E ^b  

^a UNIVERSITY OF NEBRASKA MEDICAL CENTER   (United States)

^b UNIVERSITY OF NEBRASKA MEDICAL CENTER   (United States)

Author keywords

Astrocytes; Inflammation; Mononuclear phagocytes; Neurodegeneration; Neuroimmunity; Traumatic brain injury

Indexed keywords

ARACHIDONIC ACID; GRANULOCYTE MACROPHAGE COLONY STIMULATING FACTOR; INTERLEUKIN 10; NEUROPROTECTIVE AGENT;

ADAPTIVE IMMUNITY; ASTROCYTE; B LYMPHOCYTE; CYTOKINE RELEASE; HUMAN; IMMUNE RESPONSE; IMMUNE SYSTEM; IMMUNITY; INNATE IMMUNITY; MACROPHAGE; MICROGLIA; NERVE REGENERATION; NEUROIMMUNITY; NEUROIMMUNOLOGY; NEUROPROTECTION; NEUTROPHIL; NONHUMAN; PRIORITY JOURNAL; REVIEW; T LYMPHOCYTE; TRAUMATIC BRAIN INJURY; BRAIN INJURY; IMMUNOLOGY; IMMUNOMODULATION;

BRAIN INJURIES; HUMANS; NEUROIMMUNOMODULATION; NEUROPROTECTIVE AGENTS;

EID: 84904737894     PISSN: 13816128     EISSN: 18734286     Source Type: Journal    
DOI: None     Document Type: Review

References (185)

1. Frank-Cannon TC, Alto LT, McAlpine FE, Tansey MG. Does neuroinflammation fan the flame in neurodegenerative diseases? Molecular Neurodegenerat 2009; 4: 47.
2. Hellewell SC, Morganti-Kossmann MC. Guilty molecules, guilty minds? The conflicting roles of the innate immune response to traumatic brain injury. Mediators Inflammat 2012; 2012: 356494.
3. Hoge CW, McGurk D, Thomas JL, et al. Mild traumatic brain injury in U.S. Soldiers returning from Iraq. New Eng J Med 2008; 358(5): 453-63.
4. NFL Concussion Lawsuits. [Internet]: The Washington Times; [updated 3/20/2013; cited 2013 3/21/2013]; Available from: http: //www.washingtontimes.com/footballinjuries/.
5. Faul M, Xu L, Wald MM, Coronado VG. Traumatic Brain Injury in the United States: Emergency Department Visits, Hospitalizations and Deaths 2002-2006. Atlanta, GA: Centers for Disease Control and Prevention, National Center for Injury Prevention and Control; 2010.
6. Das M, Mohapatra S, Mohapatra SS. New perspectives on central and peripheral immune responses to acute traumatic brain injury. J Neuroinflammat 2012; 9: 236.
7. Anderson KJ, Miller KM, Fugaccia I, Scheff SW. Regional distribution of fluoro-jade B staining in the hippocampus following traumatic brain injury. Exp Neurol 2005; 193(1): 125-30.
8. Hall ED, Sullivan PG, Gibson TR, et al. Spatial and temporal characteristics of neurodegeneration after controlled cortical impact in mice: more than a focal brain injury. J Neurotrauma 2005; 22(2): 252-65.
9. Hall ED, Bryant YD, Cho W, Sullivan PG. Evolution of posttraumatic neurodegeneration after controlled cortical impact traumatic brain injury in mice and rats as assessed by the de olmos silver and fluorojade staining methods. J Neurotrauma 2008; 25(3): 235-47.
10. Xiong Y, Mahmood A, Chopp M. Animal models of traumatic brain injury. Nature Rev 2013; 14(2): 128-42.
11. Narayan RK, Michel ME, Ansell B, et al. Clinical trials in head injury. J Neurotrauma 2002; 19(5): 503-57.
12. Marklund N, Bakshi A, Castelbuono DJ, Conte V, McIntosh TK. Evaluation of pharmacological treatment strategies in traumatic brain injury. Curr Pharm Des 2006; 12(13): 1645-80.
13. Landis SC, Amara SG, Asadullah K, et al. A call for transparent reporting to optimize the predictive value of preclinical research. Nature 2012; 490(7419): 187-91.
14. Nimmerjahn A, Kirchhoff F, Helmchen F. Resting microglial cells are highly dynamic surveillants of brain parenchyma in vivo. Science 2005; 308(5726): 1314-8.
15. Davalos D, Grutzendler J, Yang G, et al. ATP mediates rapid microglial response to local brain injury in vivo. Nat Neurosci 2005; 8(6): 752-8.
16. Lagraoui M, Latoche JR, Cartwright NG, et al. Controlled cortical impact and craniotomy induce strikingly similar profiles of inflammatory gene expression, but with distinct kinetics. Frontiers Neurol 2012; 3: 155.
17. Borregaard N. Neutrophils, from marrow to microbes. Immunity 2010; 33(5): 657-70.
18. Carlos TM, Clark RS, Franicola-Higgins D, Schiding JK, Kochanek PM. Expression of endothelial adhesion molecules and recruitment of neutrophils after traumatic brain injury in rats. J leukocyte Biol 1997; 61(3): 279-85.
19. Clark RS, Carlos TM, Schiding JK, et al. Antibodies against Mac-1 attenuate neutrophil accumulation after traumatic brain injury in rats. J Neurotrauma 1996; 13(6): 333-41.
20. Kenne E, Erlandsson A, Lindbom L, Hillered L, Clausen F. Neutrophil depletion reduces edema formation and tissue loss following traumatic brain injury in mice. J Neuroinflammat 2012; 9: 17.
21. Schwarzmaier SM, Kim SW, Trabold R, Plesnila N. Temporal profile of thrombogenesis in the cerebral microcirculation after traumatic brain injury in mice. J Neurotrauma 2010; 27(1): 121-30.
22. Soares HD, Hicks RR, Smith D, McIntosh TK. Inflammatory leukocytic recruitment and diffuse neuronal degeneration are separate pathological processes resulting from traumatic brain injury. J Neurosci 1995; 15(12): 8223-33.
23. Royo NC, Wahl F, Stutzmann JM. Kinetics of polymorphonuclear neutrophil infiltration after a traumatic brain injury in rat. Neuroreport 1999; 10(6): 1363-7.
24. Clausen F, Hanell A, Bjork M, et al. Neutralization of interleukin-1beta modifies the inflammatory response and improves histological and cognitive outcome following traumatic brain injury in mice. Eur J Neurosci 2009; 30(3): 385-96.
25. Clark RS, Schiding JK, Kaczorowski SL, Marion DW, Kochanek PM. Neutrophil accumulation after traumatic brain injury in rats: comparison of weight drop and controlled cortical impact models. J Neurotrauma 1994; 11(5): 499-506.
26. Jin X, Ishii H, Bai Z, Itokazu T, Yamashita T. Temporal changes in cell marker expression and cellular infiltration in a controlled cortical impact model in adult male C57BL/6 mice. PLoS One 2012; 7(7): e41892.
27. Chodobski A, Chung I, Kozniewska E, et al. Early neutrophilic expression of vascular endothelial growth factor after traumatic brain injury. Neuroscience 2003; 122(4): 853-67.
28. Whalen MJ, Carlos TM, Kochanek PM, et al. Neutrophils do not mediate blood-brain barrier permeability early after controlled cortical impact in rats. J Neurotrauma 1999; 16(7): 583-94.
29. Dressler J, Hanisch U, Kuhlisch E, Geiger KD. Neuronal and glial apoptosis in human traumatic brain injury. Int J legal Med 2007; 121(5): 365-75.
30. Oehmichen M, Walter T, Meissner C, Friedrich HJ. Time course of cortical hemorrhages after closed traumatic brain injury: statistical analysis of posttraumatic histomorphological alterations. J Neurotrauma 2003; 20(1): 87-103.
31. Ginhoux F, Greter M, Leboeuf M, et al. Fate mapping analysis reveals that adult microglia derive from primitive macrophages. Science 2010; 330(6005): 841-5.
32. Aguzzi A, Barres BA, Bennett ML. Microglia: scapegoat, saboteur, or something else? Science 2013; 339(6116): 156-61.
33. Ghorpade A, Gendelman HE, Kipnis J. Macrophages, Microglia, and Dendritic Cells. In: Ikezu T, Gendelman HE, editors. Neuroimmune Pharmacology. New York, NY: Springer; 2008. p. 89-104.
34. Gao TL, Yuan XT, Yang D, et al. Expression of HMGB1 and RAGE in rat and human brains after traumatic brain injury. The J trauma and acute care surgery 2012; 72(3): 643-9.
35. Okuma Y, Liu K, Wake H, et al. Anti-high mobility group box-1 antibody therapy for traumatic brain injury. Ann Neurol 2012; 72(3): 373-84.
36. Zhang Z, Zhang ZY, Wu Y, Schluesener HJ. Immunolocalization of Toll-like receptors 2 and 4 as well as their endogenous ligand, heat shock protein 70, in rat traumatic brain injury. Neuroimmunomodulation 2012; 19(1): 10-9.
37. Kleindienst A, Hesse F, Bullock MR, Buchfelder M. The neurotrophic protein S100B: value as a marker of brain damage and possible therapeutic implications. Prog Brain Res 2007; 161: 317-25.
38. Honda M, Tsuruta R, Kaneko T, et al. Serum glial fibrillary acidic protein is a highly specific biomarker for traumatic brain injury in humans compared with S-100B and neuron-specific enolase. J Trauma 2010; 69(1): 104-9.
39. Metting Z, Wilczak N, Rodiger LA, Schaaf JM, van der Naalt J. GFAP and S100B in the acute phase of mild traumatic brain injury. Neurology 2012; 78(18): 1428-33.
40. Kong Y, Le Y. Toll-like receptors in inflammation of the central nervous system. Int Immunopharmacol 2011; 11(10): 1407-14.
41. Faden AI, Demediuk P, Panter SS, Vink R. The role of excitatory amino acids and NMDA receptors in traumatic brain injury. Science 1989; 244(4906): 798-800.
42. Palmer AM, Marion DW, Botscheller ML, et al. Traumatic brain injury-induced excitotoxicity assessed in a controlled cortical impact model. J Neurochem 1993; 61(6): 2015-24.
43. Shytle RD, Mori T, Townsend K, et al. Cholinergic modulation of microglial activation by alpha 7 nicotinic receptors. J Neurochem 2004; 89(2): 337-43.
44. De Simone R, Ajmone-Cat M, Carnevale D, Minghetti L. Activation of alpha7 nicotinic acetylcholine receptor by nicotine selectively up-regulates cyclooxygenase-2 and prostaglandin E2 in rat microglial cultures. J Neuroinflammat 2005; 2(1): 4.
45. Kaindl AM, Degos V, Peineau S, et al. Activation of microglial Nmethyl-D-aspartate receptors triggers inflammation and neuronal cell death in the developing and mature brain. Ann Neurol 2012; 72(4): 536-49.
46. Verbois SL, Scheff SW, Pauly JR. Time-dependent changes in rat brain cholinergic receptor expression after experimental brain injury. J Neurotrauma 2002; 19(12): 1569-85.
47. Verbois SL, Sullivan PG, Scheff SW, Pauly JR. Traumatic brain injury reduces hippocampal alpha7 nicotinic cholinergic receptor binding. J Neurotrauma 2000; 17(11): 1001-11.
48. Biegon A, Fry PA, Paden CM, et al. Dynamic changes in Nmethyl-D-aspartate receptors after closed head injury in mice: Implications for treatment of neurological and cognitive deficits. Proc Natl Acad Sci USA 2004; 101(14): 5117-22.
49. Wang H, Yu M, Ochani M, et al. Nicotinic acetylcholine receptor alpha7 subunit is an essential regulator of inflammation. Nature 2003; 421(6921): 384-8.
50. Kox M, Pompe JC, Pickkers P, et al. Increased vagal tone accounts for the observed immune paralysis in patients with traumatic brain injury. Neurology 2008; 70(6): 480-5.
51. Cao T, Thomas TC, Ziebell JM, Pauly JR, Lifshitz J. Morphological and genetic activation of microglia after diffuse traumatic brain injury in the rat. Neuroscience 2012; 225: 65-75.
52. Chen S, Pickard JD, Harris NG. Time course of cellular pathology after controlled cortical impact injury. Exp Neurol 2003; 182(1): 87-102.
53. Raghavendra Rao VL, Dogan A, Bowen KK, Dempsey RJ. Traumatic brain injury leads to increased expression of peripheraltype benzodiazepine receptors, neuronal death, and activation of astrocytes and microglia in rat thalamus. Exp Neurol 2000 Jan; 161(1): 102-14.
54. Loane DJ, Byrnes KR. Role of microglia in neurotrauma. Neurotherapeutics 2010; 7(4): 366-77.
55. Ramlackhansingh AF, Brooks DJ, Greenwood RJ, et al. Inflammation after trauma: Microglial activation and traumatic brain injury. Ann Neurol 2011; 70(3): 374-83.
56. Kigerl KA, Gensel JC, Ankeny DP, et al. Identification of two distinct macrophage subsets with divergent effects causing either neurotoxicity or regeneration in the injured mouse spinal cord. J Neurosci 2009; 29(43): 13435-44.
57. Yrjanheikki J, Keinanen R, Pellikka M, Hokfelt T, Koistinaho J. Tetracyclines inhibit microglial activation and are neuroprotective in global brain ischemia. Proc Natl Acad Sci USA 1998; 95(26): 15769-74.
58. Yrjanheikki J, Tikka T, Keinanen R, et al. A tetracycline derivative, minocycline, reduces inflammation and protects against focal cerebral ischemia with a wide therapeutic window. Proc Natl Acad Sci USA 1999; 96(23): 13496-500.
59. Lampl Y, Boaz M, Gilad R, et al. Minocycline treatment in acute stroke: an open-label, evaluator-blinded study. Neurology 2007; 69(14): 1404-10.
60. Padma Srivastava MV, Bhasin A, Bhatia R, et al. Efficacy of minocycline in acute ischemic stroke: a single-blinded, placebocontrolled trial. Neurology India 2012; 60(1): 23-8.
61. Wu DC, Jackson-Lewis V, Vila M, et al. Blockade of microglial activation is neuroprotective in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine mouse model of Parkinson disease. J Neurosci 2002; 22(5): 1763-71.
62. Choi Y, Kim HS, Shin KY, et al. Minocycline attenuates neuronal cell death and improves cognitive impairment in Alzheimer's disease models. Neuropsychopharmacology 2007; 32(11): 2393-404.
63. Ferretti MT, Allard S, Partridge V, Ducatenzeiler A, Cuello AC. Minocycline corrects early, pre-plaque neuroinflammation and inhibits BACE-1 in a transgenic model of Alzheimer's disease-like amyloid pathology. J Neuroinflammat 2012; 9: 62.
64. Menalled LB, Patry M, Ragland N, et al. Comprehensive behavioral testing in the R6/2 mouse model of Huntington's disease shows no benefit from CoQ10 or minocycline. PLoS One 2010; 5(3): e9793.
65. Festoff BW, Ameenuddin S, Arnold PM, et al. Minocycline neuroprotects, reduces microgliosis, and inhibits caspase protease expression early after spinal cord injury. J Neurochem 2006; 97(5): 1314-26.
66. Diguet E, Gross CE, Tison F, Bezard E. Rise and fall of minocycline in neuroprotection: need to promote publication of negative results. Exp Neurol 2004; 189(1): 1-4.
67. Fagan SC, Waller JL, Nichols FT, et al. Minocycline to improve neurologic outcome in stroke (MINOS): a dose-finding study. Stroke 2010; 41(10): 2283-7.
68. Huntington Study Group DI. A futility study of minocycline in Huntington's disease. Mov Disord 2010; 25(13): 2219-24.
69. Gordon PH, Moore DH, Miller RG, et al. Efficacy of minocycline in patients with amyotrophic lateral sclerosis: a phase III randomised trial. Lancet Neurol 2007; 6(12): 1045-53.
70. NCT01058395. Safety and Feasibility of Minocycline in the Treatment of Traumatic Brain Injury. [accessed 23 March 2013]; Available from: http://clinicaltrials.gov/ct2/show/NCT01058395.
71. Bushong EA, Martone ME, Jones YZ, Ellisman MH. Protoplasmic astrocytes in CA1 stratum radiatum occupy separate anatomical domains. J Neurosci 2002; 22(1): 183-92.
72. Oberheim NA, Takano T, Han X, et al. Uniquely hominid features of adult human astrocytes. J Neurosci 2009; 29(10): 3276-87.
73. DeFelipe J, Alonso-Nanclares L, Arellano JI. Microstructure of the neocortex: comparative aspects. J Neurocytol 2002; 31(3-5): 299-316.
74. Laird MD, Vender JR, Dhandapani KM. Opposing roles for reactive astrocytes following traumatic brain injury. Neuro-Signals 2008; 16(2-3): 154-64.
75. Myer DJ, Gurkoff GG, Lee SM, Hovda DA, Sofroniew MV. Essential protective roles of reactive astrocytes in traumatic brain injury. Brain 2006; 129(Pt 10): 2761-72.
76. Danbolt NC. Glutamate uptake. Progress Neurobiol 2001; 65(1): 1-105.
77. Rothstein JD, Martin L, Levey AI, et al. Localization of neuronal and glial glutamate transporters. Neuron 1994; 13(3): 713-25.
78. Lehre KP, Levy LM, Ottersen OP, Storm-Mathisen J, Danbolt NC. Differential expression of two glial glutamate transporters in the rat brain: quantitative and immunocytochemical observations. J Neurosci 1995; 15(3 Pt 1): 1835-53.
79. Lehre KP, Danbolt NC. The number of glutamate transporter subtype molecules at glutamatergic synapses: chemical and stereological quantification in young adult rat brain. J Neurosci 1998; 18(21): 8751-7.
80. Haugeto O, Ullensvang K, Levy LM, et al. Brain glutamate transporter proteins form homomultimers. J Biological Chem 1996; 271(44): 27715-22.
81. Rothstein JD, Dykes-Hoberg M, Pardo CA, et al. Knockout of glutamate transporters reveals a major role for astroglial transport in excitotoxicity and clearance of glutamate. Neuron 1996; 16(3): 675-86.
82. Hu WH, Walters WM, Xia XM, Karmally SA, Bethea JR. Neuronal glutamate transporter EAAT4 is expressed in astrocytes. Glia 2003; 44(1): 13-25.
83. Yi JH, Herrero R, Chen G, Hazell AS. Glutamate transporter EAAT4 is increased in hippocampal astrocytes following lateral fluid-percussion injury in the rat. Brain Res 2007; 1154: 200-5.
84. Floyd CL, Lyeth BG. Astroglia: important mediators of traumatic brain injury. Prog Brain Res 2007; 161: 61-79.
85. van Landeghem FK, Stover JF, Bechmann I, et al. Early expression of glutamate transporter proteins in ramified microglia after controlled cortical impact injury in the rat. Glia 2001; 35(3): 167-79.
86. Rao VL, Baskaya MK, Dogan A, Rothstein JD, Dempsey RJ. Traumatic brain injury down-regulates glial glutamate transporter (GLT-1 and GLAST) proteins in rat brain. J Neurochem 1998; 70(5): 2020-7.
87. Rao VL, Dogan A, Bowen KK, Todd KG, Dempsey RJ. Antisense knockdown of the glial glutamate transporter GLT-1 exacerbates hippocampal neuronal damage following traumatic injury to rat brain. Eur J Neurosci 2001; 13(1): 119-28.
88. Rothstein JD, Patel S, Regan MR, et al. Beta-lactam antibiotics offer neuroprotection by increasing glutamate transporter expression. Nature 2005; 433(7021): 73-7.
89. Lipski J, Wan CK, Bai JZ, et al. Neuroprotective potential of ceftriaxone in in vitromodels of stroke. Neuroscience 2007; 146(2): 617-29.
90. Ouyang YB, Voloboueva LA, Xu LJ, Giffard RG. Selective dysfunction of hippocampal CA1 astrocytes contributes to delayed neuronal damage after transient forebrain ischemia. J Neurosci 2007; 27(16): 4253-60.
91. Chu K, Lee ST, Sinn DI, et al. Pharmacological Induction of Ischemic Tolerance by Glutamate Transporter-1 (EAAT2) Upregulation. Stroke 2007; 38(1): 177-82.
92. Rumbaugh JA, Li G, Rothstein J, Nath A. Ceftriaxone protects against the neurotoxicity of human immunodeficiency virus proteins. J Neurovirol 2007; 13(2): 168-72.
93. Berry JD, Shefner JM, Conwit R, et al. Design and initial results of a multi-phase randomized trial of ceftriaxone in amyotrophic lateral sclerosis. PLoS One 2013; 8(4): e61177
94. Montiel T, Camacho A, Estrada-Sanchez AM, Massieu L. Differential effects of the substrate inhibitor l-trans-pyrrolidine-2,4-dicarboxylate (PDC) and the non-substrate inhibitor DL-threo-betabenzyloxyaspartate (DL-TBOA) of glutamate transporters on neuronal damage and extracellular amino acid levels in rat brain in vivo. Neuroscience 2005; 133(3): 667-78.
95. Wei J, Pan X, Pei Z, et al. The beta-lactam antibiotic, ceftriaxone, provides neuroprotective potential via anti-excitotoxicity and antiinflammation response in a rat model of traumatic brain injury. J Trauma Acute Care Surgery 2012; 73(3): 654-60.
96. Goodrich GS, Kabakov AY, Hameed MQ, et al. Ceftriaxone treatment after traumatic brain injury restores expression of the glutamate transporter GLT-1, reduces regional gliosis, and reduces posttraumatic seizures in the rat. J Neurotrauma 2013; 30(16): 1434-41.
97. Liu Y, Teige I, Birnir B, Issazadeh-Navikas S. Neuron-mediated generation of regulatory T cells from encephalitogenic T cells suppresses EAE. Nat Med 2006; 12(5): 518-25.
98. Huang Y, Erdmann N, Hexum TD, Zheng J. Cytokines and Chemokines. In: Ikezu T, Gendelman HE, editors. Neuroimmune Pharmacology. New York, NY: Springer; 2008. p. 183-206.
99. Woodcock T, Morganti-Kossmann MC. The role of markers of inflammation in traumatic brain injury. Frontiers Neurol 2013; 4: 18.
100. Knoblach SM, Faden AI. Interleukin-10 improves outcome and alters proinflammatory cytokine expression after experimental traumatic brain injury. Exp Neurol 1998; 153(1): 143-51.
101. Kline AE, Bolinger BD, Kochanek PM, et al. Acute systemic administration of interleukin-10 suppresses the beneficial effects of moderate hypothermia following traumatic brain injury in rats. Brain Res 2002; 937(1-2): 22-31.
102. Hercus TR, Broughton SE, Ekert PG, et al. The GM-CSF receptor family: mechanism of activation and implications for disease. Growth Factors 2012; 30(2): 63-75.
103. Ridwan S, Bauer H, Frauenknecht K, von Pein H, Sommer CJ. Distribution of granulocyte-monocyte colony-stimulating factor and its receptor alpha-subunit in the adult human brain with specific reference to Alzheimer's disease. J Neural Transmission 2012; 119(11): 1389-406.
104. Zou T, Satake A, Ojha P, Kambayashi T. Cellular therapies supplement: the role of granulocyte macrophage colony-stimulating factor and dendritic cells in regulatory T-cell homeostasis and expansion. Transfusion 2011; 51 Suppl 4: 160S-8S.
105. Sheng JR, Muthusamy T, Prabhakar BS, Meriggioli MN. GM-CSFinduced regulatory T cells selectively inhibit anti-acetylcholine receptor-specific immune responses in experimental myasthenia gravis. J Neuroimmunol 2011; 240-241: 65-73.
106. Schabitz WR, Kruger C, Pitzer C, et al. A neuroprotective function for the hematopoietic protein granulocyte-macrophage colony stimulating factor (GM-CSF). J Cereb Blood Flow Metab 2008; 28(1): 29-43.
107. Nishihara T, Ochi M, Sugimoto K, et al. Subcutaneous injection containing IL-3 and GM-CSF ameliorates stab wound-induced brain injury in rats. Exp Neurol 2011; 229(2): 507-16.
108. Yamagata K, Andreasson KI, Kaufmann WE, Barnes CA, Worley PF. Expression of a mitogen-inducible cyclooxygenase in brain neurons: regulation by synaptic activity and glucocorticoids. Neuron 1993; 11(2): 371-86.
109. Kaufmann WE, Worley PF, Pegg J, Bremer M, Isakson P. COX-2, a synaptically induced enzyme, is expressed by excitatory neurons at postsynaptic sites in rat cerebral cortex. Proc Natl Acad Sci USA 1996; 93(6): 2317-21.
110. Breder CD, Dewitt D, Kraig RP. Characterization of inducible cyclooxygenase in rat brain. J Comp Neurol 1995; 355(2): 296-315.
111. Chen C, Bazan NG. Endogenous PGE2 regulates membrane excitability and synaptic transmission in hippocampal CA1 pyramidal neurons. J Neurophysiol 2005; 93(2): 929-41.
112. Chen C, Magee JC, Bazan NG. Cyclooxygenase-2 regulates prostaglandin E2 signaling in hippocampal long-term synaptic plasticity. J Neurophysiol 2002; 87(6): 2851-7.
113. Dash PK, Mach SA, Moore AN. Regional expression and role of cyclooxygenase-2 following experimental traumatic brain injury. J Neurotrauma 2000; 17(1): 69-81.
114. Hickey RW, Adelson PD, Johnnides MJ, et al. Cyclooxygenase-2 Activity Following Traumatic Brain Injury in the Developing Rat. Pediatr Res 2007 Jul 6.
115. Strauss KI, Barbe MF, Marshall RM, et al. Prolonged cyclooxygenase-2 induction in neurons and glia following traumatic brain injury in the rat. J Neurotrauma 2000; 17(8): 695-711.
116. Cernak I, O'Connor C, Vink R. Inhibition of cyclooxygenase 2 by nimesulide improves cognitive outcome more than motor outcome following diffuse traumatic brain injury in rats. Exp Brain Res 2002; 147(2): 193-9.
117. Schwab JM, Beschorner R, Meyermann R, Gozalan F, Schluesener HJ. Persistent accumulation of cyclooxygenase-1-expressing microglial cells and macrophages and transient upregulation by endothelium in human brain injury. J Neurosurg 2002; 96(5): 892-9.
118. Schwab JM, Seid K, Schluesener HJ. Traumatic brain injury induces prolonged accumulation of cyclooxygenase-1 expressing microglia/brain macrophages in rats. J Neurotrauma 2001; 18(9): 881-90.
119. Choi SH, Aid S, Choi U, Bosetti F. Cyclooxygenases-1 and-2 differentially modulate leukocyte recruitment into the inflamed brain. Pharmacogenomics J 2010; 10(5): 448-57.
120. Koyfman L, Kaplanski J, Artru AA, et al. Inhibition of cyclooxygenase 2 by nimesulide decreases prostaglandin E2 formation but does not alter brain edema or clinical recovery after closed head injury in rats. J Neurosurg Anesthesiol 2000; 12(1): 44-50.
121. Gopez JJ, Yue H, Vasudevan R, et al. Cyclooxygenase-2-specific inhibitor improves functional outcomes, provides neuroprotection, and reduces inflammation in a rat model of traumatic brain injury. Neurosurgery 2005; 56(3): 590-604.
122. Kunz T, Marklund N, Hillered L, Oliw EH. Effects of the selective cyclooxygenase-2 inhibitor rofecoxib on cell death following traumatic brain injury in the rat. Restorative Neurol Neurosci 2006; 24(1): 55-63.
123. Kelso ML, Scheff SW, Pauly JR, Loftin CD. Effects of genetic deficiency of cyclooxygenase-1 or cyclooxygenase-2 on functional and histological outcomes following traumatic brain injury in mice. BMC Neurosci 2009; 10(1): 108.
124. Ahmad M, Rose ME, Vagni V, et al. Genetic disruption of cyclooxygenase-2 does not improve histological or behavioral outcome after traumatic brain injury in mice. J Neurosci Res 2008; 86(16): 3605-12.
125. Bresalier RS, Sandler RS, Quan H, et al. Cardiovascular events associated with rofecoxib in a colorectal adenoma chemoprevention trial. New Eng J Med 2005; 352(11): 1092-102.
126. Nussmeier NA, Whelton AA, Brown MT, et al. Complications of the COX-2 inhibitors parecoxib and valdecoxib after cardiac surgery. New Eng J Med 2005; 352(11): 1081-91.
127. Girgis H, Palmier B, Croci N, et al. Effects of selective and nonselective cyclooxygenase inhibition against neurological deficit and brain oedema following closed head injury in mice. Brain Res 2013; 1491: 78-87.
128. Thau-Zuchman O, Shohami E, Alexandrovich AG, Trembovler V, Leker RR. The anti-inflammatory drug carprofen improves longterm outcome and induces gliogenesis after traumatic brain injury. J Neurotrauma 2012; 29(2): 375-84.
129. Dewitt DS, Kong DL, Lyeth BG, et al. Experimental traumatic brain injury elevates brain prostaglandin E2 and thromboxane B2 levels in rats. J Neurotrauma 1988; 5(4): 303-13.
130. Shohami E, Shapira Y, Cotev S. Experimental closed head injury in rats: prostaglandin production in a noninjured zone. Neurosurgery 1988; 22(5): 859-63.
131. Olivecrona M, Rodling-Wahlstrom M, Naredi S, Koskinen LO. Prostacyclin treatment and clinical outcome in severe traumatic brain injury patients managed with an ICP-targeted therapy: a prospective study. Brain Inj 2012; 26(1): 67-75.
132. Olivecrona M, Rodling-Wahlstrom M, Naredi S, Koskinen LO. Prostacyclin treatment in severe traumatic brain injury: a microdialysis and outcome study. J Neurotrauma 2009; 26(8): 1251-62.
133. Kawano T, Anrather J, Zhou P, et al. Prostaglandin E2 EP1 receptors: downstream effectors of COX-2 neurotoxicity. Nat Med 2006; 12(2): 225-9.
134. Khatibi NH, Jadhav V, Matus B, et al. Prostaglandin E2 EP1 receptor inhibition fails to provide neuroprotection in surgically induced brain-injured mice. Acta Neurochir Suppl 2011; 111: 277-81.
135. Ansari MA, Roberts KN, Scheff SW. Oxidative stress and modification of synaptic proteins in hippocampus after traumatic brain injury. Free Radical Biol Med 2008; 45(4): 443-52.
136. Ansari MA, Roberts KN, Scheff SW. A time course of contusioninduced oxidative stress and synaptic proteins in cortex in a rat model of TBI. J Neurotrauma 2008; 25(5): 513-26.
137. Holmin S, Mathiesen T, Shetye J, Biberfeld P. Intracerebral inflammatory response to experimental brain contusion. Acta Neurochirurgica 1995; 132(1-3): 110-9.
138. Meissner A, Zilles O, Varona R, et al. CC chemokine ligand 20 partially controls adhesion of naive B cells to activated endothelial cells under shear stress. Blood 2003; 102(8): 2724-7.
139. Dalgard CL, Cole JT, Kean WS, et al. The cytokine temporal profile in rat cortex after controlled cortical impact. Frontiers Mol Neurosci 2012; 5: 6.
140. Weckbach S, Neher M, Losacco JT, et al. Challenging the role of adaptive immunity in neurotrauma: Rag1(-/-) mice lacking mature B and T cells do not show neuroprotection after closed head injury. J Neurotrauma 2012; 29(6): 1233-42.
141. Fee D, Crumbaugh A, Jacques T, et al. Activated/effector CD4+ T cells exacerbate acute damage in the central nervous system following traumatic injury. J Neuroimmunol 2003; 136(1-2): 54-66.
142. Rudehill S, Muhallab S, Wennersten A, et al. Autoreactive antibodies against neurons and basal lamina found in serum following experimental brain contusion in rats. Acta Neurochirurgica 2006; 148(2): 199-205; discussion
143. Mrakovcic-Sutic I, Tokmadzic VS, Laskarin G, et al. Early changes in frequency of peripheral blood lymphocyte subpopulations in severe traumatic brain-injured patients. Scandinavian J Immunol 2010; 72(1): 57-65.
144. Clausen F, Lorant T, Lewen A, Hillered L. T lymphocyte trafficking: a novel target for neuroprotection in traumatic brain injury. J Neurotrauma 2007; 24(8): 1295-307.
145. Zhang Z, Artelt M, Burnet M, Trautmann K, Schluesener HJ. Early infiltration of CD8+ macrophages/microglia to lesions of rat traumatic brain injury. Neuroscience 2006; 141(2): 637-44.
146. Hori S, Nomura T, Sakaguchi S. Control of regulatory T cell development by the transcription factor Foxp3. Science 2003; 299(5609): 1057-61.
147. Reynolds AD, Stone DK, Hutter JA, et al. Regulatory T cells attenuate Th17 cell-mediated nigrostriatal dopaminergic neurodegeneration in a model of Parkinson's disease. J Immunol 2010; 184(5): 2261-71.
148. Kebir H, Kreymborg K, Ifergan I, et al. Human TH17 lymphocytes promote blood-brain barrier disruption and central nervous system inflammation. Nat Med 2007; 13(10): 1173-5.
149. Chaudhry A, Samstein RM, Treuting P, et al. Interleukin-10 signaling in regulatory T cells is required for suppression of Th17 cell-mediated inflammation. Immunity 2011; 34(4): 566-78.
150. Huber S, Gagliani N, Esplugues E, et al. Th17 cells express interleukin-10 receptor and are controlled by Foxp3(-) and Foxp3+ regulatory CD4+ T cells in an interleukin-10-dependent manner. Immunity 2011; 34(4): 554-65.
151. Logan TT, Villapol S, Symes AJ. TGF-beta superfamily gene expression and induction of the Runx1 transcription factor in adult neurogenic regions after brain injury. PLoS One 2013; 8(3): e59250.
152. Morganti-Kossmann MC, Hans VH, Lenzlinger PM, et al. TGFbeta is elevated in the CSF of patients with severe traumatic brain injuries and parallels blood-brain barrier function. J Neurotrauma 1999; 16(7): 617-28.
153. Trajkovic V, Vuckovic O, Stosic-Grujicic S, et al. Astrocyteinduced regulatory T cells mitigate CNS autoimmunity. Glia 2004; 47(2): 168-79.
154. Holmin S, Soderlund J, Biberfeld P, Mathiesen T. Intracerebral inflammation after human brain contusion. Neurosurgery 1998; 42(2): 291-8; discussion 8-9.
155. Reynolds AD, Banerjee R, Liu J, Gendelman HE, Mosley RL. Neuroprotective activities of CD4+CD25+ regulatory T cells in an animal model of Parkinson's disease. J leukocyte Biol 2007; 82(5): 1083-94.
156. Liu J, Gong N, Huang X, et al. Neuromodulatory activities of CD4+CD25+ regulatory T cells in a murine model of HIV-1-associated neurodegeneration. J Immunol 2009; 182(6): 3855-65.
157. Sheng JR, Li LC, Ganesh BB, Prabhakar BS, Meriggioli MN. Regulatory T cells induced by GM-CSF suppress ongoing experimental myasthenia gravis. Clin Immunol 2008; 128(2): 172-80.
158. Mosley RL, Benner EJ, Kadiu I, et al. Neuroinflammation, Oxidative Stress and the Pathogenesis of Parkinson's Disease. Clin Neurosci Res 2006; 6(5): 261-81.
159. Kong T, Choi JK, Park H, et al. Reduction in programmed cell death and improvement in functional outcome of transient focal cerebral ischemia after administration of granulocyte-macrophage colony-stimulating factor in rats. Laboratory investigation. J Neurosurg 2009; 111(1): 155-63.
160. Liesz A, Suri-Payer E, Veltkamp C, et al. Regulatory T cells are key cerebroprotective immunomodulators in acute experimental stroke. Nat Med 2009; 15(2): 192-9.
161. Cosentino M, Gendelman HE. The first Insubria autumn school on neuroimmunopharmacology: challenging paradigms beyond boundaries. J Neuroimmune Pharmacol 2013; 8(1): 1-3.
162. Galea I, Bechmann I, Perry VH. What is immune privilege (not)? Trends Immunol 2007; 28(1): 12-8.
163. Matyszak MK, Perry VH. The potential role of dendritic cells in immune-mediated inflammatory diseases in the central nervous system. Neuroscience 1996 Sep; 74(2): 599-608.
164. Bechmann I, Galea I, Perry VH. What is the blood-brain barrier (not)? Trends Immunol 2007; 28(1): 5-11.
165. Klyachko NL, Manickam DS, Brynskikh AM, et al. Cross-linked antioxidant nanozymes for improved delivery to CNS. Nanomedicine 2012; 8(1): 119-29.
166. Rosenbaugh EG, Roat JW, Gao L, et al. The attenuation of central angiotensin II-dependent pressor response and intra-neuronal signaling by intracarotid injection of nanoformulated copper/zinc superoxide dismutase. Biomaterials 2010; 31(19): 5218-26.
167. Zhao Y, Haney MJ, Mahajan V, et al. Active Targeted Macrophage-mediated Delivery of Catalase to Affected Brain Regions in Models of Parkinson's Disease. J Nanomed Nanotechnol. Sep 10; S4.
168. Brynskikh AM, Zhao Y, Mosley RL, et al. Macrophage delivery of therapeutic nanozymes in a murine model of Parkinson's disease. Nanomedicine (Lond).; 5(3): 379-96.
169. Gong N, Liu J, Reynolds AD, et al. Brain ingress of regulatory T cells in a murine model of HIV-1 encephalitis. J Neuroimmunol; 230(1-2): 33-41.
170. Banerjee R, Mosley RL, Reynolds AD, et al. Adaptive immune neuroprotection in G93A-SOD1 amyotrophic lateral sclerosis mice. PLoS One 2008; 3(7): e2740.
171. Kelso ML, Scheff NN, Scheff SW, Pauly JR. Melatonin and minocycline for combinatorial therapy to improve functional and histopathological deficits following traumatic brain injury. Neurosci Lett 2011; 488(1): 60-4.
172. Kovesdi E, Kamnaksh A, Wingo D, et al. Acute minocycline treatment mitigates the symptoms of mild blast-induced traumatic brain injury. Frontiers Neurol 2012; 3: 111.
173. Siopi E, Llufriu-Daben G, Fanucchi F, et al. Evaluation of late cognitive impairment and anxiety states following traumatic brain injury in mice: the effect of minocycline. Neurosci Lett 2012; 511(2): 110-5.
174. Ng SY, Semple BD, Morganti-Kossmann MC, Bye N. Attenuation of microglial activation with minocycline is not associated with changes in neurogenesis after focal traumatic brain injury in adult mice. J Neurotrauma 2012; 29(7): 1410-25.
175. Lu DC, Zador Z, Yao J, Fazlollahi F, Manley GT. Aquaporin-4 Reduces Post-Traumatic Seizure Susceptibility by Promoting Astrocytic Glial Scar Formation in Mice. J Neurotrauma 2011 Sep 22.
176. Siopi E, Calabria S, Plotkine M, Marchand-Leroux C, JafarianTehrani M. Minocycline restores olfactory bulb volume and olfactory behavior after traumatic brain injury in mice. J Neurotrauma 2012; 29(2): 354-61.
177. Siopi E, Cho AH, Homsi S, et al. Minocycline restores sAPPalpha levels and reduces the late histopathological consequences of traumatic brain injury in mice. J Neurotrauma 2011; 28(10): 2135-43.
178. Abdel Baki SG, Schwab B, Haber M, Fenton AA, Bergold PJ. Minocycline synergizes with N-acetylcysteine and improves cognition and memory following traumatic brain injury in rats. PLoS One 2010; 5(8): e12490.
179. Homsi S, Piaggio T, Croci N, et al. Blockade of acute microglial activation by minocycline promotes neuroprotection and reduces locomotor hyperactivity after closed head injury in mice: a twelveweek follow-up study. J Neurotrauma 2010; 27(5): 911-21.
180. Homsi S, Federico F, Croci N, et al. Minocycline effects on cerebral edema: relations with inflammatory and oxidative stress markers following traumatic brain injury in mice. Brain Res 2009; 1291: 122-32.
181. Ding JY, Kreipke CW, Speirs SL, et al. Hypoxia-inducible factor-1alpha signaling in aquaporin upregulation after traumatic brain injury. Neurosci Lett 2009; 453(1): 68-72.
182. Crack PJ, Gould J, Bye N, et al. The genomic profile of the cerebral cortex after closed head injury in mice: effects of minocycline. J Neural Transmission 2009; 116(1): 1-12.
183. Bye N, Habgood MD, Callaway JK, et al. Transient neuroprotection by minocycline following traumatic brain injury is associated with attenuated microglial activation but no changes in cell apoptosis or neutrophil infiltration. Exp Neurol 2007; 204(1): 220-33.
184. Sanchez Mejia RO, Ona VO, Li M, Friedlander RM. Minocycline reduces traumatic brain injury-mediated caspase-1 activation, tissue damage, and neurological dysfunction. Neurosurgery 2001; 48(6): 1393-9; discussion 9-401.
185. Higashida T, Kreipke CW, Rafols, JA, et al. The role of hypoxiainducible factor-1alpha, aquaporin-4, and matrix metalloproteinase-9 in blood-brain barrier disruption and brain edema after traumatic brain injury. J Neurosurg 2011; 114(1): 92-101