, Volume 7, Issue 1, pp 22–30 | Cite as

Involvement of pro- and anti-inflammatory cytokines and chemokines in the pathophysiology of traumatic brain injury

  • Jenna M. Ziebell
  • Maria Cristina Morganti-Kossmann
Review Article


Despite dramatic improvements in the management of traumatic brain injury (TBI), to date there is no effective treatment available to patients, and morbidity and mortality remain high. The damage to the brain occurs in two phases, the initial primary phase being the injury itself, which is irreversible and amenable only to preventive measures to minimize the extent of damage, followed by an ongoing secondary phase, which begins at the time of injury and continues in the ensuing days to weeks. This delayed phase leads to a variety of physiological, cellular, and molecular responses aimed at restoring the homeostasis of the damaged tissue, which, if not controlled, will lead to secondary insults. The development of secondary brain injury represents a window of opportunity in which pharmaceutical compounds with neuroprotective properties could be administered. To establish effective treatments for TBI victims, it is imperative that the complex molecular cascades contributing to secondary injury be fully elucidated. One pathway known to be activated in response to TBI is cellular and humoral inflammation. Neuroinflammation within the injured brain has long been considered to intensify the damage sustained following TBI. However, the accumulated findings from years of clinical and experimental research support the notion that the action of inflammation may differ in the acute and delayed phase after TBI, and that maintaining limited inflammation is essential for repair. This review addresses the role of several cytokines and chemokines following focal and diffuse TBI, as well as the controversies around the use of therapeutic anti-inflammatory treatments versus genetic deletion of cytokine expression.

Key Words

Inflammation traumatic brain injury cytokines chemokines human TBI 


  1. 1.
    Raghupathi R. Cell death mechanisms following traumatic brain injury. Brain Pathol 2004;14: 215–222.PubMedCrossRefGoogle Scholar
  2. 2.
    Morganti-Kossmann MC, Rancan M, Otto VI, Stahel PF, Kossmann T. Role of cerebral inflammation after traumatic brain injury: a revisited concept. Shock 2001;16: 165–177.PubMedCrossRefGoogle Scholar
  3. 3.
    Correale J, Villa A. The neuroprotective role of inflammation in nervous system injuries. J Neurol 2004;251: 1304–1316.PubMedCrossRefGoogle Scholar
  4. 4.
    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: 220–233.PubMedCrossRefGoogle Scholar
  5. 5.
    McIntosh TK, Saatman KE, Raghupathi R, et al. The Dorothy Russell Memorial Lecture. The molecular and cellular sequelae of experimental traumatic brain injury: pathogenetic mechanisms. Neuropathol Appl Neurobiol 1998;24: 251–267.PubMedCrossRefGoogle Scholar
  6. 6.
    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: 499–506.PubMedCrossRefGoogle Scholar
  7. 7.
    Kato H, Walz W. The initiation of the microglial response. Brain Pathol 2000;10: 137–143.PubMedCrossRefGoogle Scholar
  8. 8.
    Kubes P, Ward PA. Leukocyte recruitment and the acute inflammatory response. Brain Pathol 2000;10: 127–135.PubMedCrossRefGoogle Scholar
  9. 9.
    Perry RT, Collins JS, Wiener H, Acton R, Go RC. The role of TNF and its receptors in Alzheimer’s disease. Neurobiol Aging 2001;22: 873–883.PubMedCrossRefGoogle Scholar
  10. 10.
    Werner C, Engelhard K. Pathophysiology of traumatic brain injury. Br J Anaesth 2007;99: 4–9.PubMedCrossRefGoogle Scholar
  11. 11.
    Lucas SM, Rothwell NJ, Gibson RM. The role of inflammation in CNS injury and disease. Br J Pharmacol 2006; 147 Suppl 1: S232-S240.PubMedGoogle Scholar
  12. 12.
    Kreutzberg GW. Microglia: a sensor for pathological events in the CNS. Trends Neurosci 1996;19: 312–318.PubMedCrossRefGoogle Scholar
  13. 13.
    Bush TG, Puvanachandra N, Homer CH, et al. Leukocyte infiltration, neuronal degeneration, and neurite outgrowth after ablation of scar-forming, reactive astrocytes in adult transgenic mice. Neuron 1999;23: 297–308.PubMedCrossRefGoogle Scholar
  14. 14.
    Tanno H, Nockels RP, Pitts LH, Noble LJ. Breakdown of the blood-brain barrier after fluid percussive brain injury in the rat. Part 1: Distribution and time course of protein extravasation. J Neurotrauma 1992;9: 21–32.PubMedCrossRefGoogle Scholar
  15. 15.
    Habgood MD, Bye N, Dziegielewska KM, et al. Changes in blood-brain barrier permeability to large and small molecules following traumatic brain injury in mice. Eur J Neurosci 2007; 25: 231–238.PubMedCrossRefGoogle Scholar
  16. 16.
    Rothwell NJ. Annual review prize lecture. Cytokines: killers in the brain? J Physiol 1999;514: 3–17.PubMedCrossRefGoogle Scholar
  17. 17.
    Wang CX, Shuaib A. Involvement of inflammatory cytokines in central nervous system injury. Prog Neurobiol 2002;67: 161–172.PubMedCrossRefGoogle Scholar
  18. 18.
    Lu W, Gersting JA, Maheshwari A, Christensen RD, Calhoun DA. Developmental expression of chemokine receptor genes in the human fetus. Early Hum Dev 2005;81: 489–496.PubMedCrossRefGoogle Scholar
  19. 19.
    Kielian T, Hickey WF. Proinflammatory cytokine, chemokine, and cellular adhesion molecule expression during the acute phase of experimental brain abscess development. Am J Pathol 2000; 157: 647–658.PubMedCrossRefGoogle Scholar
  20. 20.
    Semple BD, Kossmann T, Morganti-Kossmann MC. Role of chemokines in CNS health and pathology: a focus on the CCL2/ CCR2 and CXCL8/CXCR2 networks. J Cereb Blood Flow Metab 2009 Nov 11. [Epub ahead of print].Google Scholar
  21. 21.
    Fan L, Young PR, Barone FC, Feuerstein GZ, Smith DH, McIntosh TK. Experimental brain injury induces expression of interleukin-1β mRNA in the rat brain. Brain Res Mol Brain Res 1995;30: 125–130.PubMedCrossRefGoogle Scholar
  22. 22.
    Boraschi D, Bossù P, Ruggiero P, et al. Mapping of receptor binding sites on IL-1β by reconstruction of IL-1ra-like domains. J Immunol 1995;155: 4719–4725.PubMedGoogle Scholar
  23. 23.
    Winter CD, Iannotti F, Ringle AK, Trikkas C, Clough GF, Church MK. A microdialysis method for the recovery of IL-1β, IL-6 and nerve growth factor from human brain in vivo. J Neurosci Methods 2002;119: 45–50.PubMedCrossRefGoogle Scholar
  24. 24.
    Woodroofe MN, Sarna GS, Wadhwa M, et al. Detection of interleukin-1 and interleukin-6 in adult rat brain, following mechanical injury, by in vivo microdialysis: evidence of a role for microglia in cytokine production. J Neuroimmunol 1991;33: 227–236.PubMedCrossRefGoogle Scholar
  25. 25.
    Knoblach SM, Faden AI. Cortical interleukin-1β elevation after traumatic brain injury in the rat: no effect of two selective antagonists on motor recovery. Neurosci Lett 2000;289: 5–8.PubMedCrossRefGoogle Scholar
  26. 26.
    Loddick SA, Rothwell NJ. Neuroprotective effects of human recombinant interleukin-1 receptor antagonist in focal cerebral ischaemia in the rat. J Cereb Blood Flow Metab 1996; 16: 932–940.PubMedCrossRefGoogle Scholar
  27. 27.
    Relton JK, Rothwell NJ. Interleukin-1 receptor antagonist inhibits ischaemic and excitotoxic neuronal damage in the rat. Brain Res Bull 1992;29: 243–246.PubMedCrossRefGoogle Scholar
  28. 28.
    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 Transm 2009;116: 1–12.PubMedCrossRefGoogle Scholar
  29. 29.
    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: 1393–1399; discussion 1399–1401.CrossRefGoogle Scholar
  30. 30.
    Hammacher A, Ward LD, Weinstock J, Treutlein H, Yasukawa K, Simpson RJ. Structure-function analysis of human IL-6: identification of two distinct regions that are important for receptor binding. Protein Sci 1994;3: 2280–2293.PubMedCrossRefGoogle Scholar
  31. 31.
    Raivich G, Bohatschek M, Kloss CU, Werner A, Jones LL, Kreutzberg GW. Neuroglial activation repertoire in the injured brain: graded response, molecular mechanisms and cues to physiological function. Brain Res Brain Res Rev 1999;30: 77–105.PubMedCrossRefGoogle Scholar
  32. 32.
    Hopkins SJ, Rothwell NJ. Cytokines and the nervous system. I: Expression and recognition. Trends Neurosci 1995;18: 83–88.PubMedCrossRefGoogle Scholar
  33. 33.
    Benveniste EN. Cytokine actions in the central nervous system. Cytokine Growth Factor Rev 1998;9: 259–275.PubMedCrossRefGoogle Scholar
  34. 34.
    Kossmann T, Hans VH, Imhof HG, et al. Intrathecal and serum interleukin-6 and the acute-phase response in patients with severe traumatic brain injuries. Shock 1995;4: 311–317.PubMedCrossRefGoogle Scholar
  35. 35.
    Shohami E, Novikov M, Bass R, Yamin A, Gallily R. Closed head injury triggers early production of TNFα and IL-6 by brain tissue. J Cereb Blood Flow Metab 1994;14: 615–619.PubMedCrossRefGoogle Scholar
  36. 36.
    Taupin V, Toulmond S, Serrano A, Benavides J, Zavala F. Increase in IL-6, IL-1 and TNF levels in rat brain following traumatic lesion: influence of pre- and post-traumatic treatment with Ro5 4864, a peripheral-type (p site) benzodiazepine ligand. J Neuroimmunol 1993;42: 177–185.PubMedCrossRefGoogle Scholar
  37. 37.
    Penkowa M, Camats J, Hadberg H, et al. Astrocyte-targeted expression of interleukin-6 protects the central nervous system during neuroglial degeneration induced by 6-aminonicotinamide. J Neurosci Res 2003;73: 481–496.PubMedCrossRefGoogle Scholar
  38. 38.
    Penkowa M, Giralt M, Carrasco J, Hadberg H, Hidalgo J. Impaired inflammatory response and increased oxidative stress and neurodegeneration after brain injury in interleukin-6-deficient mice. Glia 2000;32: 271–285.PubMedCrossRefGoogle Scholar
  39. 39.
    Meager A. The molecular biology of cytokines. New York: Wiley, 1998.Google Scholar
  40. 40.
    Aloisi F, De Simone R, Columba-Cabezas S, Levi G. Opposite effects of interferon-γ and prostaglandin E2 on tumor necrosis factor and interleukin-10 production in microglia: a regulatory loop controlling microglia pro- and anti-inflammatory activities. J Neurosci Res 1999;56: 571–580.PubMedCrossRefGoogle Scholar
  41. 41.
    Mesples B, Plaisant F, Gressens P. Effects of interleukin-10 on neonatal excitotoxic brain lesions in mice. Brain Res Dev Brain Res 2003; 141: 25–32.PubMedCrossRefGoogle Scholar
  42. 42.
    Wu Z, Zhang J, Nakanishi H. Leptomeningeal cells activate microglia and astrocytes to induce IL-10 production by releasing pro-inflammatory cytokines during systemic inflammation. J Neuroimmunol 2005;167: 90–98.PubMedCrossRefGoogle Scholar
  43. 43.
    Knoblach SM, Faden AI. Interleukin-10 improves outcome and alters proinflammatory cytokine expression after experimental traumatic brain injury. Exp Neurol 1998;153: 143–151.PubMedCrossRefGoogle Scholar
  44. 44.
    Kremlev SG, Palmer C. Interleukin-10 inhibits endotoxin-in-duced pro-inflammatory cytokines in microglial cell cultures. J Neuroimmunol 2005;162: 71–80.PubMedCrossRefGoogle Scholar
  45. 45.
    Csuka E, Morganti-Kossmann MC, Lenzlinger PM, Joller H, Trentz O, Kossmann T. IL-10 levels in cerebrospinal fluid and serum of patients with severe traumatic brain injury: relationship to IL-6, TNF-α, TGF-β1 and blood-brain barrier function. J Neuroimmunol 1999; 101: 211–221.PubMedCrossRefGoogle Scholar
  46. 46.
    Lyng K, Munkeby BH, Saugstad OD, Stray-Pedersen B, Frøen JF. Effect of interleukin-10 on newborn piglet brain following hypoxia-ischemia and endotoxin-induced inflammation. Biol Neonate 2005;87: 207–216.PubMedCrossRefGoogle Scholar
  47. 47.
    Bell MJ, Kochanek PM, Doughty LA, et al. Interleukin-6 and interleukin-10 in cerebrospinal fluid after severe traumatic brain injury in children. J Neurotrauma 1997;14: 451–457.PubMedCrossRefGoogle Scholar
  48. 48.
    Bieder CD, Tsujimoto M, Terano Y, Scott DW, Saper CB. Distribution and characterization of tumor necrosis factor-α-like immunoreactivity in the murine central nervous system. J Comp Neurol 1993;337: 543–567.CrossRefGoogle Scholar
  49. 49.
    Allan SM, Rothwell NJ. Cytokines and acute neurodegeneration. Nat Rev Neurosci 2001;2: 734–744.PubMedCrossRefGoogle Scholar
  50. 50.
    Chao CC, Hu S, Ehrlich L, Peterson PK. Interleukin-1 and tumor necrosis factor-α synergistically mediate neurotoxicity: involvement of nitric oxide and of N-methyl-d-aspartate receptors. Brain Behav Immun 1995;9: 355–365.PubMedCrossRefGoogle Scholar
  51. 51.
    Shohami E, Gallily R, Mechoulam R, Bass R, Ben-Hur T. Cytokine production in the brain following closed head injury: dexanabinol (HU-211) is a novel TNF-α inhibitor and an effective neuroprotectant. J Neuroimmunol 1997;72: 169–177.PubMedCrossRefGoogle Scholar
  52. 52.
    Riva-Depaty I, Fardeau C, Mariani J, Bouchaud C, Delhaye-Bouchaud N. Contribution of peripheral macrophages and microglia to the cellular reaction after mechanical or neurotoxin-induced lesions of the rat brain. Exp Neurol 1994;128: 77–87.PubMedCrossRefGoogle Scholar
  53. 53.
    Csuka E, Hans VH, Ammann E, Trentz O, Kossmann T, Morganti-Kossmann MC. Cell activation and inflammatory response following traumatic axonal injury in the rat. Neuroreport 2000; 11: 2587–2590.PubMedCrossRefGoogle Scholar
  54. 54.
    Knoblach SM, Fan L, Faden AI. Early neuronal expression of tumor necrosis factor-α after experimental brain injury contributes to neurological impairment. J Neuroimmunol 1999;95: 115–125.PubMedCrossRefGoogle Scholar
  55. 55.
    Kim KS, Wass CA, Cross AS, Opal SM. Modulation of blood-brain barrier permeability by tumor necrosis factor and antibody to tumor necrosis factor in the rat. Lymphokine Cytokine Res 1992;11: 293–298.PubMedGoogle Scholar
  56. 56.
    Ramilo O, Sáez-Llorens X, Mertsola J, et al. Tumor necrosis factor α/cachectin and interleukin 1 β initiate meningeal inflammation. J Exp Med 1990; 172: 497–507.PubMedCrossRefGoogle Scholar
  57. 57.
    Maas AI, Murray G, Henney H 3rd, et al. Efficacy and safety of dexanabinol in severe traumatic brain injury: results of a phase III randomised, placebo-controlled, clinical trial. Lancet Neurol 2006;5: 38–45.PubMedCrossRefGoogle Scholar
  58. 58.
    Scherbel U, Raghupathi R, Nakamura M, et al. Differential acute and chronic responses of tumor necrosis factor-deficient mice to experimental brain injury. Proc Natl Acad Sci U S A 1999;96: 8721–8726.PubMedCrossRefGoogle Scholar
  59. 59.
    Stahel PF, Shohami E, Younis FM, et al. Experimental closed head injury: analysis of neurological outcome, blood-brain barrier dysfunction, intracranial neutrophil infiltration, and neuronal cell death in mice deficient in genes for pro-inflammatory cytokines. J Cereb Blood Flow Metab 2000;20: 369–380.PubMedCrossRefGoogle Scholar
  60. 60.
    Sullivan PG, Bruce-Keller AJ, Rabchevsky AG, et al. Exacerbation of damage and altered NF-κB activation in mice lacking tumor necrosis factor receptors after traumatic brain injury. J Neurosci 1999;19: 6248–6256.PubMedGoogle Scholar
  61. 61.
    Itoh N, et al. The polypeptide encoded by the cDNA for human cell surface antigen Fas can mediate apoptosis. Cell 1991;66: 233–243.PubMedCrossRefGoogle Scholar
  62. 62.
    Nagata S, Golstein P. The Fas death factor. Science 1995;267: 1449–1456.PubMedCrossRefGoogle Scholar
  63. 63.
    Suda T, Takahashi T, Golstein P, Nagata S. Molecular cloning and expression of the Fas ligand, a novel member of the tumor necrosis factor family. Cell 1993;75: 1169–1178.PubMedCrossRefGoogle Scholar
  64. 64.
    Choi C, Park JY, Lee J, et al. Fas ligand and Fas are expressed constitutively in human astrocytes and the expression increases with IL-1, IL-6, TNF-α, or IFN-γ. J Immunol 1999;162: 1889–1895.PubMedGoogle Scholar
  65. 65.
    Beer R, Franz G, Schöpf M, et al. Expression of Fas and Fas ligand after experimental traumatic brain injury in the rat. J Cereb Blood Flow Metab 2000;20: 669–677.PubMedCrossRefGoogle Scholar
  66. 66.
    Grosjean MB, Lenzlinger PM, Stahel PF, et al. Immunohisto-chemical characterization of Fas (CD95) and Fas ligand (FasL/ CD95L) expression in the injured brain: relationship with neuronal cell death and inflammatory mediators. Histol Histopathol 2007;22: 235–250.PubMedGoogle Scholar
  67. 67.
    Martin-Villalba A, Herr I, Jeremias I, et al. CD95 ligand (Fas-L/ APO-1L) and tumor necrosis factor-related apoptosis-inducing ligand mediate ischemia-induced apoptosis in neurons. J Neurosci 1999;19: 3809–3817.PubMedGoogle Scholar
  68. 68.
    Qiu J, Whalen MJ, Lowenstein P, et al. Upregulation of the Fas receptor death-inducing signaling complex after traumatic brain injury in mice and humans. J Neurosci 2002;22: 3504–3511.PubMedGoogle Scholar
  69. 69.
    Rosenbaum DM, Gupta G, D’Amore J, et al. Fas (CD95/APO-1) plays a role in the pathophysiology of focal cerebral ischemia. J Neurosci Res 2000;61: 686–692.PubMedCrossRefGoogle Scholar
  70. 70.
    Tanaka M, Suda T, Takahashi T, Nagata S. Expression of the functional soluble form of human fas ligand in activated lymphocytes. EMBO J 1995;14: 1129–1135.PubMedGoogle Scholar
  71. 71.
    Ertel W, Keel M, Stocker R, et al. Detectable concentrations of Fas ligand in cerebrospinal fluid after severe head injury. J Neuroimmunol 1997;80: 93–96.PubMedCrossRefGoogle Scholar
  72. 72.
    Lenzlinger PM, Marx A, Trentz O, Kossmann T, Morganti-Kossmann MC. Prolonged intrathecal release of soluble Fas following severe traumatic brain injury in humans. J Neuroimmunol 2002;122: 167–174.PubMedCrossRefGoogle Scholar
  73. 73.
    Park DR, Thomsen AR, Frevert CW, et al. Fas (CD95) induces proinflammatory cytokine responses by human monocytes and monocyte-derived macrophages. J Immunol 2003;170: 6209–6216.PubMedGoogle Scholar
  74. 74.
    Baggiolini M, Walz A, Kunkel SL. Neutrophil-activating peptide-1/interleukin 8, a novel cytokine that activates neutrophils. J Clin Invest 1989;84: 1045–1049.PubMedCrossRefGoogle Scholar
  75. 75.
    Smith WB, Gamble JR, Clark-Lewis I, Vadas MA. Interleukin-8 induces neutrophil transendothelial migration. Immunology 1991; 72: 65–72.PubMedGoogle Scholar
  76. 76.
    Zwijnenburg PJ, Polfliet MM, Florquin S, et al. CXC-chemokines KC and macrophage inflammatory protein-2 (MIP-2) synergistically induce leukocyte recruitment to the central nervous system in rats. Immunol Lett 2003;85: 1–4.PubMedCrossRefGoogle Scholar
  77. 77.
    Aloisi F, Carè A, Borsellino G, et al. Production of hemolym-phopoietic cytokines (IL-6, IL-8, colony-stimulating factors) by normal human astrocytes in response to IL-1β and tumor necrosis factor-α. J Immunol 1992;149: 2358–2366.PubMedGoogle Scholar
  78. 78.
    Whalen MJ, Carlos TM, Kochanek PM, et al. Interleukin-8 is increased in cerebrospinal fluid of children with severe head injury. Crit Care Med 2000;28: 929–934.PubMedCrossRefGoogle Scholar
  79. 79.
    Morganti-Kossmann MC, Lenzlinger PM, Hans V, et al. Production of cytokines following brain injury: beneficial and deleterious for the damaged tissue. Mol Psychiatry 1997;2: 133–136.CrossRefGoogle Scholar
  80. 80.
    Yoshimura T, Robinson EA, Tanaka S, Appella E, Leonard EJ. Purification and amino acid analysis of two human monocyte chemoattractants produced by phytohemagglutinin-stimulated human blood mononuclear leukocytes. J Immunol 1989;142: 1956–1962.PubMedGoogle Scholar
  81. 81.
    Glabinski AR, Balasingam V, Tani M, et al. Chemokine monocyte chemoattractant protein-1 is expressed by astrocytes after mechanical injury to the brain. J Immunol 1996;156: 4363–4368.PubMedGoogle Scholar
  82. 82.
    Banisadr G, et al. Distribution, cellular localization and functional role of CCR2 chemokine receptors in adult rat brain. J Neurochem 2002;81: 257–269.PubMedCrossRefGoogle Scholar
  83. 83.
    Rankine EL, Hughes PM, Botham MS, Perry VH, Felton LM. Brain cytokine synthesis induced by an intraparenchymal injection of LPS is reduced in MCP-1-deficient mice prior to leucocyte recruitment. Eur J Neurosci 2006;24: 77–86.PubMedCrossRefGoogle Scholar
  84. 84.
    Gourmala NG, Buttini M, Limonta S, Sauter A, Boddeke HW. Differential and time-dependent expression of monocyte chemoattractant protein-1 mRNA by astrocytes and macrophages in rat brain: effects of ischemia and peripheral lipopolysaccharide administration. J Neuroimmunol 1997;74: 35–44.PubMedCrossRefGoogle Scholar
  85. 85.
    Galasso JM, Miller MJ, Cowell RM, Harrison JK, Warren JS, Silverstein FS. Acute excitotoxic injury induces expression of monocyte chemoattractant protein-1 and its receptor, CCR2, in neonatal rat brain. Exp Neurol 2000;165: 295–305.PubMedCrossRefGoogle Scholar
  86. 86.
    Hughes PM, Allegrini PR, Rudin M, Perry VH, Mir AK, Wiessner C. Monocyte chemoattractant protein-1 deficiency is protective in a murine stroke model. J Cereb Blood Flow Metab 2002; 22: 308–317.PubMedCrossRefGoogle Scholar
  87. 87.
    Lu B, Rutledge BJ, Gu L, et al. Abnormalities in monocyte recruitment and cytokine expression in monocyte chemoattractant protein 1-deficient mice. J Exp Med 1998;187: 601–608.PubMedCrossRefGoogle Scholar
  88. 88.
    Edwards P, Arango M, Balica L, et al.; CRASH trial collaborators. Final results of MRC CRASH, a randomised placebo-controlled trial of intravenous corticosteroid in adults with head injury: outcomes at 6 months. Lancet 2005;365: 1957–1959.PubMedCrossRefGoogle Scholar
  89. 89.
    Breitner JC, Welsh KA, Helms MJ, Delayed onset of Alzheimer’s disease with nonsteroidal anti-inflammatory and histamine H2 blocking drugs. Neurobiol Aging 1995;16: 523–530.PubMedCrossRefGoogle Scholar
  90. 90.
    Etminan M, Gill S, Samii A. Effect of non-steroidal anti-inflammatory drugs on risk of Alzheimer’s disease: systematic review and meta-analysis of observational studies. BMJ 2003;327: 128.PubMedCrossRefGoogle Scholar
  91. 91.
    Townsend KP, Praticò D. Novel therapeutic opportunities for Alzheimer’s disease: focus on nonsteroidal anti-inflammatory drugs. FASEB J 2005;19: 1592–1601.PubMedCrossRefGoogle Scholar
  92. 92.
    Browne KD, Iwata A, Putt ME, Smith DH. Chronic ibuprofen administration worsens cognitive outcome following traumatic brain injury in rats. Exp Neurol 2006;201: 301–307.PubMedCrossRefGoogle Scholar
  93. 93.
    Alano CC, Kauppinen TM, Valls AV, Swanson RA. Minocycline inhibits poly(ADP-ribose) polymerase-1 at nanomolar concentrations. Proc Natl Acad Sci U S A 2006; 103: 9685–9690.PubMedCrossRefGoogle Scholar
  94. 94.
    Maier B, Laurer HL, Rose S, Buurman WA, Marzi I. Physiological levels of pro- and anti-inflammatory mediators in cerebrospinal fluid and plasma: a normative study. J Neurotrauma 2005;22: 822–835.PubMedCrossRefGoogle Scholar
  95. 95.
    Stirling DP, Khodarahmi K, Liu J, et al. Minocycline treatment reduces delayed oligodendrocyte death, attenuates axonal die-back, and improves functional outcome after spinal cord injury. J Neurosci 2004;24: 2182–2190.PubMedCrossRefGoogle Scholar
  96. 96.
    Xu L, Fagan SC, Waller JL, et al. Low dose intravenous minocycline is neuroprotective after middle cerebral artery occlusion-reperfusion in rats. BMC Neurol 2004;4: 7.PubMedCrossRefGoogle Scholar
  97. 97.
    Lawrence CB, Allan SM, Rothwell NJ. Interleukin-1β and the interleukin-1 receptor antagonist act in the striatum to modify excitotoxic brain damage in the rat. Eur J Neurosci 1998; 10: 1188–1195.PubMedCrossRefGoogle Scholar
  98. 98.
    Fattori E, Lazzaro D, Musiani P, Modesti A, Alonzi T, Ciliberto G. IL-6 expression in neurons of transgenic mice causes reactive astrocytosis and increase in ramified microglial cells but no neuronal damage. Eur J Neurosci 1995;7: 2441–2449.PubMedCrossRefGoogle Scholar
  99. 99.
    Schneider A, Krüger C, Steigleder T, et al. The hematopoietic factor G-CSF is a neuronal ligand that counteracts programmed cell death and drives neurogenesis. J Clin Invest 2005;115: 2083–2098.PubMedCrossRefGoogle Scholar
  100. 100.
    Sehara Y, Hayashi T, Deguchi K, et al. Potentiation of neurogenesis and angiogenesis by G-CSF after focal cerebral ischemia in rats. Brain Res 2007;1151: 142–149.PubMedCrossRefGoogle Scholar

Copyright information

© Springer New York 2010

Authors and Affiliations

  • Jenna M. Ziebell
    • 1
  • Maria Cristina Morganti-Kossmann
    • 1
  1. 1.National Trauma Research Institute (NTRI), The Alfred Hospital, and Department of MedicineMonash UniversityMelbourneAustralia

Personalised recommendations