Abstract
Corticosteroids have been used in the treatment of human traumatic brain injury (TBI), which is a leading cause of death and disability, but their efficiency is still a matter of debate. Dexamethasone was considered to delay post-traumatic inflammation and retard neuronal degeneration, resulting in attenuation of secondary injury following experimental TBI. In a rat TBI model, we have investigated the effects of dexamethasone on expression patterns of markers of inflammatory activation of microglia/macrophages by immunohistochemistry. Endothelial-monocyte activating polypeptide II (EMAP-II), P2X4 receptor (P2X4R) and allograft-inflammatory factor-1 (AIF-1) were reported to be associated with the activation of microglia/macrophages post central nervous system (CNS) injury and may play roles in inflammatory cascades of secondary brain damage. Dexamethasone significantly suppressed the accumulation of EMAP-II+, P2X4R+ or AIF+ cells at Day-1 and 2 post-brain-trauma but not on Days 4 and 6, which is in accordance with the reported short- but not long-term protective effects of dexamethasone in TBI. These findings indicate a rather rapid but transient anti-inflammatory effect of dexamethasone in TBI.
Similar content being viewed by others
References
Adelson PD, Whalen MJ, Kochanek PM, Robichaud P, Carlos TM (1998) Blood brain barrier permeability and acute inflammation in two models of traumatic brain injury in the immature rat: a preliminary report. Acta Neurochir Suppl 71:104–106
Auphan N, DiDonato JA, Rosette C, Helmgren A, Karin M (1995) Immunosuppression by glucosteroids: inhibition by NFkB activity through induction of IkB synthesis. Science 270:286–290
Banati RB, Gehrmann J, Schubert P, Kreutzberg GW (1993) Cytotoxicity of microglia. Glia 7:111–118
Beschorner R, Engel S, Mittelbronn M, Adjodah D, Dietz K, Schluesener HJ, Meyermann R, (2000) Differential regulation of the monocytic calcium-binding peptides macrophage-inhibiting factor related protein-8 (MRP8/S100A8) and allograft inflammatory factor-1 (AIF-1) following human traumatic brain injury. Acta Neuropathol 100:627–634
Bosscher KD, Schmitz ML, Berghe WV, Plaisance S, Fiers W, Haegeman G (1997) Glucocorticoid-mediated repression of nuclear factor-kB-dependent transcription involves direct interference with transactivation. Proc Natl Acad Sci USA 94:13504–13509
Brough D, Le Feuvre RA, Iwakura Y, Rothwell NJ (2002) Purinergic (P2X7) receptor activation of microglia induces cell death via an interleukin-1-independent mechanism. Mol Cell Neurosci 19:272–280
Carlos TM, Harlan JM (1994) Leukocyte-endothelial adhesion molecules. Blood 84:2068–2101
Cavaliere F, Florenzano F, Amadio S, Fusco FR, Viscomi MT, D’Ambrosi N, Vacca F, Sancesario G, Bernardi G, Molinari M, Volonte C (2003) Up-regulation of P2X2, P2X4 receptor and ischemic cell death: prevention by P2 antagonists. Neuroscience 120:85–98
Clark RS, Schiding JK, Kaczorowski SL, Marion DW, Kochanek PM (1994) Neutrophil accumulation after traumatic brain injury in rats: comparison of weight drop and controlled cortical impact models. J Neurotrauma 11:499–506
David S, Bouchard C, Tsatas O, Giftochristos N (1990) Macrophages can modify the nonpermissive nature of the adult mammalian central nervous system. Neuron 5:463–469
Colton CA, Chernyshev ON (1996) Inhibition of microglial superoxide anion production by isoproterenol and dexamethasone. Neurochem Int 29:43–53
Deininger MH, Seid K, Engel S, Meyermann R, Schluesener HJ (2000) Allograft inflammatory factor-1 defines a distinct subset of infiltrating macrophages/microglial cells in rat and human gliomas. Acta Neuropathol 100:673–680
Deininger MH, Meyermann R, Schluesener HJ (2002) The allograft inflammatory factor-1 family of proteins. FEBS Lett 514:115–121
Fan L, Young PR, Barone FC, Feuerstein GZ, Smith DH, McIntosh TK (1996) Experimental brain injury induces differential expression of tumor necrosis factor-alpha mRNA in the CNS. Brain Res Mol Brain Res 36:287–291
Fauser S, Nguyen TD, Bekure K, Schluesener HJ, Meyermann R (2001) Differential activation of microglial cells in local and remote areas of IRBP1169-1191-induced rat uveitis. Acta Neuropathol 101:565–571
Feeney DM, Boyeson MG, Linn RT, Murray HM, Dail WG (1981) Responses to cortical injury: I. Methodology and local effects of contusions in the rat. Brain Res 211:67–77
Ferrari D, Chiozzi P, Falzoni S, Hanau S, DiVirgilio F (1997) Purinergic modulation of interleukin-1 beta release from microglial cells stimulated with bacterial endotoxin. J Exp Med 185:579–582
Gahm C, Holmin S, Rudehill S, Mathiesen T (2005) Neuronal degeneration and iNOS expression in experimental brain contusion following treatment with colchicine, examethasone, tirilazad mesylate and nimodipine. Acta Neurochir 147:1071–1084
Gendron FP, Chalimoniuk M, Strosznajder J, Shen S, Gonzalez FA, Weisman GA, Sun GY (2003) P2X7 nucleotide receptor activation enhances IFN gamma-induced type II nitric oxide synthase activity in BV-2 microglial cells. J Neurochem 87:344–352
Golarai G, Greenwood AC, Feeney DM, Connor JA (2001) Physiological and structural evidence for hippocampal involvement in persistent seizure susceptibility after traumatic brain injury. J Neurosci 21:8523–8537
Gottesfeld Z, Moore AN, Dash PK (2002) Acute ethanol intake attenuates inflammatory cytokines after brain injury in rats: a possible role for corticosterone. J Neurotrauma 19:317–326
Gottschall PE (1996) Beta-amyloid induction of gelatinase B secretion in cultured microglia: inhibition by dexamethasone and indomethacin. Neuroreport 7:3077–3080
Gourin CG, Shackford SR (1997) Production of tumor necrosis factor-alpha and interleukin-1beta by human cerebral microvascular endothelium after percussive trauma. J Trauma 42:1101–1107
Graeber MB, Lopez-Redondo F, Ikoma E, Ishikawa M, Imai Y, Nakajima K, Kreutzberg GW, Kohsaka S (1998) The microglia/macrophage response in the neonatal rat facial nucleus following axotomy. Brain Res 813:241–253
Hall ED, McCall JM, Chase RL, Yonkers PA, Braughler JM (1987) A nonglucocorticoid steroid analog of methylprednisolone duplicates its high-dose pharmacology in models of central nervous system trauma and neuronal membrane damage. J Pharmacol Exp Ther 242:137–142
Haynes LE, Griffiths MR, Hyde RE, Barber DJ, Mitchell IJ (2001) Dexamethasone induces limited apoptosis and extensive sublethal damage to specific subregions of the triatum and hippocampus: implications for mood disorders. Neuroscience 104:57–69
He J, Evans CO, Hoffman SW, Oyesiku NM, Stein DG (2004) Progesterone and allopregnanolone reduce inflammatory cytokines after traumatic brain injury. Exp Neurol 189:404–412
Holmin S, Mathiesen T (1996) Dexamethasone and colchicine reduce inflammation and delayed oedema following experimental brain contusion. Acta Neurochir 138:418–424
Ito D, Imai Y, Ohsawa K, Nakajima K, Fukuuchi Y, Kohsaka S (1998) Microglia-specific localisation of a novel calcium binding protein, Ibal. Brain Res Mol Brain Res 57:1–9
Kao J, Ryan J, Brett G, Chen J, Shen H, Fan YG, Godman G, Familletti PC, Wang F, Pan YC (1992) Endothelial monocyte-activating polypeptide II. A novel tumor-derived polypeptide that activates host-response mechanisms. J Biol Chem 267:20239–20247
Kiefer R, Kreutzberg GW (1991) Effects of dexamethasone on microglial activation in vivo: selective downregulation of major histocompatibility complex class II expression in regenerating facial nucleus. J Neuroimmunol 34:99–108
Knies UE, Behrensdorf HA, Mitchell CA, Deutsch U, Risau W, Drexler HC, Clauss M (1998) Regulation of endothelial monocyte-activating polypeptide II release by apoptosis. Proc Natl Acad Sci USA 95:12322–12327
Knoblach SM, Fan L, Faden AI (1999) Early neuronal expression of tumor necrosis factor-alpha after experimental brain injury contributes to neurological impairment. J Neuroimmunol 95:115–125
Kreutzberg GW (1996) Microglia: a sensor for pathological events in the CNS. Trends Neurosci 19:312–318
Ladeby R, Wirenfeldt M, Garcia-Ovejero D, Fenger C, Dissing-Olesen L, Dalmau I, Finsen B (2005) Microglial cell population dynamics in the injured adult central nervous system. Brain Res Brain Res Rev 48:196–206
Lehrmann E, Christensen T, Zimmer J, Diemer NH, Finsen B (1997) Microglial and macrophage reactions mark progressive changes and define the penumbra in the rat neocortex and striatum after transient middle cerebral artery occlusion. J Comp Neurol 386:461–476
Marshall LF, Maas AI, Marshall SB, Bricolo A, Fearnside M, Iannotti F, Klauber MR, Lagarrigue J, Lobato R, Persson L, Pickard JD, Piek J, Servadei F, Wellis GN, Morris GF, Means ED, Musch B (1998) A multicenter trial on the efficacy of using tirilazad mesylate in cases of head injury. J Neurosurg 89:519–525
Mitchell IJ, Cooper AJ, Griffiths MR, Barber DJ (1998) Phencyclidine and corticosteroids induce apoptosis of a subpopulation of striatal neurons: a neural substrate for psychosis? Neuroscience 84:489–501
Mori N, Fukatsu T (1992) Anticonvulsant effect of DN-1417, a derivative of thyrotropin-releasing hormone, and liposome-entrapped DN-1417, on amygdaloid-kindled rats. Epilepsia 33:994–1000
Mueller CA, Schluesener HJ, Conrad S, Meyermann R, Schwab JM (2003a) Lesional expression of a proinflammatory and antiangiogenic cytokine EMAP II confined to endothelium and microglia/macrophages during secondary damage following experimental traumatic brain injury. J Neuroimmunol 135:1–9
Mueller CA, Schluesener HJ, Conrad S, Meyermann R, Schwab JM (2003b) Spinal cord injury induces lesional expression of the proinflammatory and antiangiogenic cytokine EMAP II. J Neurotrauma 20:1007–1015
Narayan RK, Michel ME (2002) Clinical trials in head injury. J Neurotrauma 19:503–557
North RA (2002) Molecular physiology of P2X receptors. Physiol Rev 82:1013–1067
Orihara Y, Ikematsu K, Tsuda R, Nakasono I (2001) Induction of nitric oxide synthase by traumatic brain injury. Forensic Sci Int 123:142–149
Postler E, Rimner A, Beschorner R, Schluesener HJ, Meyermann R (2000) Allograft-inflammatory-factor-1 is upregulated in microglial cells in human cerebral infarctions. J Neuroimmunol 104:85–91
Pulliam L, Zhou M, Stubblebine M, Bitler CM (1998) Differential modulation of cell death proteins in human brain cells by tumor necrosis factor alpha and platelet activating factor. J Neurosci Res 54:530–538
Rabchevsky AG, Streit WJ (1997) Grafting of cultured microglial cells into the lesioned spinal cord of adult rats enhances neurite outgrowth. J Neurosci Res 47:34–48
Sandhir R, Puri V, Klein RM, Berman NE (2004) Differential expression of cytokines and chemokines during secondary neuron death following brain injury in old and young mice. Neurosci Lett 369:28–32
Scheinman RI, Cogswell PC, Lofquist AK, Baldwin AS (1995) Role of transcriptional activation of IkBa in mediating immunosuppression by glucosteroids. Science 270:283–286
Schluesener HJ, Seid K, Zhao Y, Meyermann R (1997) Localization of endothelial-monocyte-activating polypeptide II (EMAP II), a novel proinflammatory cytokine, to lesions of experimental autoimmune encephalomyelitis, neuritis and uveitis: expression by monocytes and activated microglial cells. Glia 20:365–372
Schluesener HJ, Seid K, Kretzschmar J, Meyermann R (1998) Allograft-inflammatory factor-1 in rat experimental autoimmune encephalomyelitis, neuritis, and uveitis: expression by activated macrophages and microglial cells. Glia 24:244–251
Schluesener HJ, Seid K, Meyermann R (1999) Effects of autoantigen and dexamethasone treatment on expression of endothelial-monocyte activating polypeptide II and allograft-inflammatory factor-1 by activated macrophages and microglial cells in lesions of experimental autoimmune encephalomyelitis, neuritis and uveitis. Acta Neuropathol 97:119–126
Schluesener HJ, Seid K, Deininger M, Schwab J (2001) Transient in vivo activation of rat brain macrophages/microglial cells and astrocytes by immunostimulatory multiple CpG oligonucleotides. J Neuroimmunol 113:89–94
Schwab JM, Frei E, Klusman I, Schnell L, Schwab ME, Schluesener HJ (2001) AIF-1 expression defines a proliferating and alert microglial/macrophage phenotype following spinal cord injury in rats. J Neuroimmunol 119:214–222
Schwab JM, Guo L, Schluesener HJ (2005) Spinal cord injury induces early and persistent lesional P2X4 receptor expression. J Neuroimmunol 163:185–189
Shohami E, Novikov M, Bass R, Yamin A, Gallily R (1994) Closed head injury triggers early production of TNF alpha and IL-6 by brain tissue. J Cereb Blood Flow Metab 14:615–619
Tanaka J, Fujita H, Matsuda S, Toku K, Sakanaka M, Maeda N (1997) Glucocorticoid- and mineralcorticoid receptors in microglial cells: the two receptors mediate differential effects of corticosteroids. Glia 20:23–37
Tanaka S, Suzuki K, Watanabe M, Matsuda A, Tone S (1998) Upregulation of a new microglial gene mrf-1, in reponse to programmed neuronal death and degeneration. J Neurosci 18:6258–6369
Tas MP, Murray JC (1996) Endothelial-monocyte-activating polypeptide II. Int J Biochem Cell Biol 28:837–841
Taupin V, Toulmond S, Serrano A, Benavides J, Zavala F (1993) 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 42:177–185
Utans U, Arceci RJ, Yamashita Y, Russell ME (1995) Cloning and characterization of allograft inflammatory factor-1: a novel macrophage factor identified in rat cardiac allografts with chronic rejection. J Clin Invest 95:2954–2962
Utans U, Quist WC, McManus BM, Wilson JE, Arceci RJ, Wallace AF, Russell ME (1996) Allograft inflammatory factory-1: a cytokine-responsive macrophage molecule expressed in transplanted human hearts. Transplantation 61:1387–1392
Wakasugi K, Schimmel P (1999) Two distinct cytokines released from a human aminoacyl-tRNA synthetase. Science 284:147–151
Wennersten A, Holmin S, Mathiesen T (2003) Characterization of Bax and Bcl-2 in apoptosis after experimental traumatic brain injury in the rat. Acta Neuropathol 105:281–288
Yatsiv I, Morganti-Kossmann MC, Perez D, Dinarello CA, Novick D, Rubinstein M, Otto VI, Rancan M, Kossmann T, Redaelli CA, Trentz O, Shohami E, Stahel PF (2002) Elevated intracranial IL-18 in humans and mice after traumatic brain injury and evidence of neuroprotective effects of IL-18-binding protein after experimental closed head injury. J Cereb Blood Flow Metab 22:971–978
Zhang Z, Artelt M, Burnet M, Trautmann K, Schluesener HJ (2006a) Lesional accumulation of P2X4 receptor+ monocytes following experimental traumatic brain injury. Exp Neurol 197:252–257
Zhang Z, Artelt M, Burnet M, Trautmann K, Schluesener HJ (2006b) Early infiltration of CD8+ macrophages/microglia to lesions of rat traumatic brain injury. Neuroscience 141:637–644
Author information
Authors and Affiliations
Corresponding author
Additional information
Zhiyuan Zhang and Zhiren Zhang have equally contributed to this work.
Rights and permissions
About this article
Cite this article
Zhang, Z., Zhang, Z., Artelt, M. et al. Dexamethasone attenuates early expression of three molecules associated with microglia/macrophages activation following rat traumatic brain injury. Acta Neuropathol 113, 675–682 (2007). https://doi.org/10.1007/s00401-007-0195-8
Received:
Revised:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00401-007-0195-8