Inflammation and White Matter Injury in Animal Models of Ischemic Stroke

  • Lyanne C. SchlichterEmail author
  • Sarah Hutchings
  • Starlee Lively
Part of the Springer Series in Translational Stroke Research book series (SSTSR, volume 4)


Ischemic stroke is rarely confined to gray matter, and primary white matter injury occurs in a significant proportion of human strokes. In preclinical investigations searching for stroke therapies, the emphasis is shifting away from primary neurotoxicity to the secondary injury phase, which occurs in a time window that is more amenable to treatment in hospital. This phase is characterized by a prominent inflammatory response in the brain that can last for hours to days. This chapter focuses on the intersection of inflammation and white matter injury in experimental models of ischemic stroke. We first describe the main rodent models and methods used to monitor white matter damage, and discuss we prefer some approaches. Next, we describe the main immune cells involved in animal models of ischemia, how to monitor them, and present key findings. We then summarize the limited literature addressing the intersection of ischemic stroke, white matter injury, and inflammation in adult and neonatal rodent ischemia models, and finally comment on specific needs for further research.


White Matter Middle Cerebral Artery Occlusion Myelin Basic Protein White Matter Tract Transient Ischemia 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.



Anterior choroidal artery occlusion


2-Amino-3-(3-hydroxy-5-methyl-isoxazol-4-yl)propanoic acid


Adenomatous polyposis coli


Amyloid precursor protein


Adenosine triphosphate


Blood–brain barrier


Bilateral common carotid artery occlusion


Cerebral blood flow


Central nervous system




Complement component receptor 3 alpha


Degraded myelin basic protein


Endothelial nitric oxide synthase




Fluorescence-activated cell sorting


Gamma-aminobutyric acid


Green fluorescent protein


Hematoxylin and eosin




Isolectin B4


Ionized calcium binding adapter molecule 1


Internal carotid artery


Intracerebral hemorrhage




Integrin alpha M


Leukocyte common antigen


Luxol fast blue


Macrophage-1 alpha antigen


Myelin basic protein


Middle cerebral artery occlusion


Major histocompatibility complex


Matrix metallopeptidase




Magnetic resonance imaging


Natural killer T cells


Nitric oxide


Nitric oxide synthase


Oxygen-glucose deprivation


Recombination activating gene 1


Transforming growth factor beta


Tissue inhibitor of metallopeptidase


Tumor necrosis factor alpha


Tissue plasminogen activator


  1. Stroke therapy Academic Industry Roundtable, Fisher MC (1999) Recommendations for standards regarding preclinical neuroprotective and restorative drug development. Stroke 30:2752–2758Google Scholar
  2. Acarin L, Vela JM, Gonzalez B et al (1994) Demonstration of poly-N-acetyl lactosamine residues in ameboid and ramified microglial cells in rat brain by tomato lectin binding. J Histochem Cytochem 42:1033–1041PubMedGoogle Scholar
  3. Adams HP Jr, Bendixen BH, Kappelle LJ et al (1993) Classification of subtype of acute ischemic stroke. Definitions for use in a multicenter clinical trial. TOAST. Trial of Org 10172 in Acute Stroke Treatment. Stroke 24:35–41PubMedGoogle Scholar
  4. Akiyama H, McGeer PL (1990) Brain microglia constitutively express beta-2 integrins. J Neuro-immunol 30:81–93PubMedGoogle Scholar
  5. Anderson CS, Chakera TM, Stewart-Wynne EG et al (1994) Spectrum of primary intracerebral haemorrhage in Perth, Western Australia, 1989–90: incidence and outcome. J Neurol Neurosurg Psychiatry 57:936–940PubMedGoogle Scholar
  6. Arai K, Lo EH (2009) Experimental models for analysis of oligodendrocyte pathophysiology in stroke. Exp Transl Stroke Med 1:6PubMedGoogle Scholar
  7. Barone FC, Hillegass LM, Price WJ et al (1991) Polymorphonuclear leukocyte infiltration into cerebral focal ischemic tissue: myeloperoxidase activity assay and histologic verification. J Neurosci Res 29:336–345PubMedGoogle Scholar
  8. Batteur-Parmentier S, Margaill I, Plotkine M (2000) Modulation by nitric oxide of cerebral neutrophil accumulation after transient focal ischemia in rats. J Cereb Blood Flow Metab 20:812–819PubMedGoogle Scholar
  9. Bauer MK, Lieb K, Schulze-Osthoff K et al (1997) Expression and regulation of cyclooxygenase-2 in rat microglia. Eur J Biochem 243:726–731PubMedGoogle Scholar
  10. Baumann N, Pham-Dinh D (2001) Biology of oligodendrocyte and myelin in the mammalian central nervous system. Physiol Rev 81:871–927PubMedGoogle Scholar
  11. Becker K, Kindrick D, Relton J et al (2001) Antibody to the alpha4 integrin decreases infarct size in transient focal cerebral ischemia in rats. Stroke 32:206–211PubMedGoogle Scholar
  12. Beray-Berthat V, Croci N, Plotkine M et al (2003) Polymorphonuclear neutrophils contribute to infarction and oxidative stress in the cortex but not in the striatum after ischemia-reperfusion in rats. Brain Res 987:32–38PubMedGoogle Scholar
  13. Bhat RV, Axt KJ, Fosnaugh JS et al (1996) Expression of the APC tumor suppressor protein in oligodendroglia. Glia 17:169–174PubMedGoogle Scholar
  14. Biran V, Joly LM, Heron A et al (2006) Glial activation in white matter following ischemia in the neonatal P7 rat brain. Exp Neurol 199:103–112PubMedGoogle Scholar
  15. Boche D, Perry VH, Nicoll JA (2013) Review: activation patterns of microglia and their identification in the human brain. Neuropathol Appl Neurobiol 39:3–18PubMedGoogle Scholar
  16. Bradley PP, Priebat DA, Christensen RD et al (1982) Measurement of cutaneous inflammation: estimation of neutrophil content with an enzyme marker. J Invest Dermatol 78:206–209PubMedGoogle Scholar
  17. Braeuninger S, Kleinschnitz C (2009) Rodent models of focal cerebral ischemia: procedural pitfalls and translational problems. Exp Transl Stroke Med 1:8PubMedGoogle Scholar
  18. Brait VH, Jackman KA, Walduck AK et al (2010) Mechanisms contributing to cerebral infarct size after stroke: gender, reperfusion, T lymphocytes, and Nox2-derived superoxide. J Cereb Blood Flow Metab 30:1306–1317PubMedGoogle Scholar
  19. Brait VH, Arumugam TV, Drummond GR et al (2012) Importance of T lymphocytes in brain injury, immunodeficiency, and recovery after cerebral ischemia. J Cereb Blood Flow Metab 32:598–611PubMedGoogle Scholar
  20. Brochu ME, Girard S, Lavoie K et al (2011) Developmental regulation of the neuroinflammatory responses to LPS and/or hypoxia-ischemia between preterm and term neonates: an experimental study. J Neuroinflammation 8:55PubMedGoogle Scholar
  21. Brott T, Bogousslavsky J (2000) Treatment of acute ischemic stroke. N Engl J Med 343:710–722PubMedGoogle Scholar
  22. Bruni EJ, Montemurro DG (2009) Human neuroanatomy: a text, brain atlas, and laboratory dissection guide, 3rd edn. Oxford University Press, New YorkGoogle Scholar
  23. Calvert JW, Zhang JH (2005) Pathophysiology of an hypoxic-ischemic insult during the perinatal period. Neurol Res 27:246–260PubMedGoogle Scholar
  24. Candelario-Jalil E, Fiebich BL (2008) Cyclooxygenase inhibition in ischemic brain injury. Curr Pharm Des 14:1401–1418PubMedGoogle Scholar
  25. Carmichael ST (2005) Rodent models of focal stroke: size, mechanism, and purpose. NeuroRx 2:396–409PubMedGoogle Scholar
  26. Carty ML, Wixey JA, Colditz PB et al (2008) Post-insult minocycline treatment attenuates hypoxia-ischemia-induced neuroinflammation and white matter injury in the neonatal rat: a comparison of two different dose regimens. Int J Dev Neurosci 26:477–485PubMedGoogle Scholar
  27. Carty ML, Wixey JA, Reinebrant HE et al (2011) Ibuprofen inhibits neuroinflammation and attenuates white matter damage following hypoxia-ischemia in the immature rodent brain. Brain Res 1402:9–19PubMedGoogle Scholar
  28. Castellani RJ, Alexiev BA, Phillips D et al (2007) Microscopic investigations in neurodegenerative diseases. In: Mendez-Vilas A, Diaz J (eds) Modern research and educational topics in microscopy, vol 1. Formatex, Badajoz, Spain, pp 171–182Google Scholar
  29. Ceulemans AG, Zgavc T, Kooijman R et al (2010) The dual role of the neuroinflammatory response after ischemic stroke: modulatory effects of hypothermia. J Neuroinflammation 7:74PubMedGoogle Scholar
  30. Chapman KZ, Dale VQ, Denes A et al (2009) A rapid and transient peripheral inflammatory response precedes brain inflammation after experimental stroke. J Cereb Blood Flow Metab 29:1764–1768PubMedGoogle Scholar
  31. Chen H, Chopp M, Zhang RL et al (1994) Anti-CD11b monoclonal antibody reduces ischemic cell damage after transient focal cerebral ischemia in rat. Ann Neurol 35:458–463PubMedGoogle Scholar
  32. Cho KO, La HO, Cho YJ et al (2006) Minocycline attenuates white matter damage in a rat model of chronic cerebral hypoperfusion. J Neurosci Res 83:285–291PubMedGoogle Scholar
  33. Choi BR, Kwon KJ, Park SH et al (2011) Alternations of septal-hippocampal system in the adult wistar rat with spatial memory impairments induced by chronic cerebral hypoperfusion. Exp Neurobiol 20:92–99PubMedGoogle Scholar
  34. Cioffi GA (2005) Ischemic model of optic nerve injury. Trans Am Ophthalmol Soc 103:592–613PubMedGoogle Scholar
  35. Cioffi GA, Orgul S, Onda E et al (1995) An in vivo model of chronic optic nerve ischemia: the dose-dependent effects of endothelin-1 on the optic nerve microvasculature. Curr Eye Res 14:1147–1153PubMedGoogle Scholar
  36. Clark RK, Lee EV, White RF et al (1994) Reperfusion following focal stroke hastens inflammation and resolution of ischemic injured tissue. Brain Res Bull 35:387–392PubMedGoogle Scholar
  37. Clozel M, Gray GA, Breu V et al (1992) The endothelin ETB receptor mediates both vasodilation and vasoconstriction in vivo. Biochem Biophys Res Commun 186:867–873PubMedGoogle Scholar
  38. Coleman MP, Perry VH (2002) Axon pathology in neurological disease: a neglected therapeutic target. Trends Neurosci 25:532–537PubMedGoogle Scholar
  39. Colton CA (2009) Heterogeneity of microglial activation in the innate immune response in the brain. J Neuroimmune Pharmacol 4:399–418PubMedGoogle Scholar
  40. Colton CA (2013) Immune heterogeneity in neuroinflammation: dendritic cells in the brain. J Neuroimmune Pharmacol 8:145–162PubMedGoogle Scholar
  41. Colton CA, Gilbert DL (1987) Production of superoxide anions by a CNS macrophage, the microglia. FEBS Lett 223:284–288PubMedGoogle Scholar
  42. Connolly ES Jr, Winfree CJ, Stern DM et al (1996a) Procedural and strain-related variables significantly affect outcome in a murine model of focal cerebral ischemia. Neurosurgery 38:523–531, discussion 32PubMedGoogle Scholar
  43. Connolly ES Jr, Winfree CJ, Springer TA et al (1996b) Cerebral protection in homozygous null ICAM-1 mice after middle cerebral artery occlusion. Role of neutrophil adhesion in the pathogenesis of stroke. J Clin Invest 97:209–216PubMedGoogle Scholar
  44. Damoiseaux JG, Dopp EA, Calame W et al (1994) Rat macrophage lysosomal membrane antigen recognized by monoclonal antibody ED1. Immunology 83:140–147PubMedGoogle Scholar
  45. del Zoppo GJ (1998) Clinical trials in acute stroke: why have they not been successful? Neurology 51:S59–S61PubMedGoogle Scholar
  46. del Zoppo GJ, Schmid-Schonbein GW, Mori E et al (1991) Polymorphonuclear leukocytes occlude capillaries following middle cerebral artery occlusion and reperfusion in baboons. Stroke 22:1276–1283PubMedGoogle Scholar
  47. del Zoppo GJ, Poeck K, Pessin MS et al (1992) Recombinant tissue plasminogen activator in acute thrombotic and embolic stroke. Ann Neurol 32:78–86PubMedGoogle Scholar
  48. Denes A, Vidyasagar R, Feng J et al (2007) Proliferating resident microglia after focal cerebral ischaemia in mice. J Cereb Blood Flow Metab 27:1941–1953PubMedGoogle Scholar
  49. Denes A, Thornton P, Rothwell NJ et al (2010) Inflammation and brain injury: acute cerebral ischaemia, peripheral and central inflammation. Brain Behav Immun 24:708–723PubMedGoogle Scholar
  50. Deng Y, Lu J, Sivakumar V et al (2008) Amoeboid microglia in the periventricular white matter induce oligodendrocyte damage through expression of proinflammatory cytokines via MAP kinase signaling pathway in hypoxic neonatal rats. Brain Pathol 18:387–400PubMedGoogle Scholar
  51. Dijkstra CD, Dopp EA, Joling P et al (1985) The heterogeneity of mononuclear phagocytes in lymphoid organs: distinct macrophage subpopulations in the rat recognized by monoclonal antibodies ED1, ED2 and ED3. Immunology 54:589–599PubMedGoogle Scholar
  52. Diringer MN, Skolnick BE, Mayer SA et al (2008) Risk of thromboembolic events in controlled trials of rFVIIa in spontaneous intracerebral hemorrhage. Stroke 39:850–856PubMedGoogle Scholar
  53. Dirnagl U (2006) Bench to bedside: the quest for quality in experimental stroke research. J Cereb Blood Flow Metab 26:1465–1478PubMedGoogle Scholar
  54. Drake C, Boutin H, Jones MS et al (2011) Brain inflammation is induced by co-morbidities and risk factors for stroke. Brain Behav Immun 25:1113–1122PubMedGoogle Scholar
  55. Durukan A, Tatlisumak T (2007) Acute ischemic stroke: overview of major experimental rodent models, pathophysiology, and therapy of focal cerebral ischemia. Pharmacol Biochem Behav 87:179–197PubMedGoogle Scholar
  56. Emsley HC, Tyrrell PJ (2002) Inflammation and infection in clinical stroke. J Cereb Blood Flow Metab 22:1399–1419PubMedGoogle Scholar
  57. Endres M, Engelhardt B, Koistinaho J et al (2008) Improving outcome after stroke: overcoming the translational roadblock. Cerebrovasc Dis 25:268–278PubMedGoogle Scholar
  58. Engelhardt B, Sorokin L (2009) The blood–brain and the blood-cerebrospinal fluid barriers: function and dysfunction. Semin Immunopathol 31:497–511PubMedGoogle Scholar
  59. Enzmann G, Mysiorek C, Gorina R et al (2013) The neurovascular unit as a selective barrier to polymorphonuclear granulocyte (PMN) infiltration into the brain after ischemic injury. Acta Neuropathol 125:395–412PubMedGoogle Scholar
  60. Farkas E, Donka G, de Vos RA et al (2004) Experimental cerebral hypoperfusion induces white matter injury and microglial activation in the rat brain. Acta Neuropathol 108:57–64PubMedGoogle Scholar
  61. Farkas E, Luiten PG, Bari F (2007) Permanent, bilateral common carotid artery occlusion in the rat: a model for chronic cerebral hypoperfusion-related neurodegenerative diseases. Brain Res Rev 54:162–180PubMedGoogle Scholar
  62. Ferguson B, Matyszak MK, Esiri MM et al (1997) Axonal damage in acute multiple sclerosis lesions. Brain 120(pt 3):393–399PubMedGoogle Scholar
  63. Fischer U, Arnold M, Nedeltchev K et al (2006) Impact of comorbidity on ischemic stroke outcome. Acta Neurol Scand 113:108–113PubMedGoogle Scholar
  64. Fontainhas AM, Wang M, Liang KJ et al (2011) Microglial morphology and dynamic behavior is regulated by ionotropic glutamatergic and GABAergic neurotransmission. PLoS One 6:e15973PubMedGoogle Scholar
  65. Ford AL, Goodsall AL, Hickey WF et al (1995) Normal adult ramified microglia separated from other central nervous system macrophages by flow cytometric sorting. Phenotypic differences defined and direct ex vivo antigen presentation to myelin basic protein-reactive CD4+ T cells compared. J Immunol 154:4309–4321PubMedGoogle Scholar
  66. Fordyce CB, Jagasia R, Zhu X et al (2005) Microglia Kv1.3 channels contribute to their ability to kill neurons. J Neurosci 25:7139–7149PubMedGoogle Scholar
  67. Garcia JH, Liu KF, Ho KL (1995) Neuronal necrosis after middle cerebral artery occlusion in Wistar rats progresses at different time intervals in the caudoputamen and the cortex. Stroke 26:636–642, discussion 43PubMedGoogle Scholar
  68. Gautier S, Ouk T, Petrault O et al (2009) Neutrophils contribute to intracerebral haemorrhages after treatment with recombinant tissue plasminogen activator following cerebral ischaemia. Br J Pharmacol 156:673–679PubMedGoogle Scholar
  69. Gelderblom M, Leypoldt F, Steinbach K et al (2009) Temporal and spatial dynamics of cerebral immune cell accumulation in stroke. Stroke 40:1849–1857PubMedGoogle Scholar
  70. Gentleman SM, Roberts GW, Gennarelli TA et al (1995) Axonal injury: a universal consequence of fatal closed head injury? Acta Neuropathol 89:537–543PubMedGoogle Scholar
  71. Gibbings D, Befus AD (2009) CD4 and CD8: an inside-out coreceptor model for innate immune cells. J Leukoc Biol 86:251–259PubMedGoogle Scholar
  72. Ginhoux F, Greter M, Leboeuf M et al (2010) Fate mapping analysis reveals that adult microglia derive from primitive macrophages. Science 330:841–845PubMedGoogle Scholar
  73. Ginsberg MD (2009) Current status of neuroprotection for cerebral ischemia: synoptic overview. Stroke 40:S111–S114PubMedGoogle Scholar
  74. Girard S, Sebire H, Brochu ME et al (2012) Postnatal administration of IL-1Ra exerts neuroprotective effects following perinatal inflammation and/or hypoxic-ischemic injuries. Brain Behav Immun 26:1331–1339PubMedGoogle Scholar
  75. Goldberg MP, Ransom BR (2003) New light on white matter. Stroke 34:330–332PubMedGoogle Scholar
  76. Gordon S (2003) Alternative activation of macrophages. Nat Rev Immunol 3:23–35PubMedGoogle Scholar
  77. Gresle MM, Jarrott B, Jones NM et al (2006) Injury to axons and oligodendrocytes following endothelin-1-induced middle cerebral artery occlusion in conscious rats. Brain Res 1110:13–22PubMedGoogle Scholar
  78. Guillemin GJ, Brew BJ (2004) Microglia, macrophages, perivascular macrophages, and pericytes: a review of function and identification. J Leukoc Biol 75:388–397PubMedGoogle Scholar
  79. Hanisch UK, Kettenmann H (2007) Microglia: active sensor and versatile effector cells in the normal and pathologic brain. Nat Neurosci 10:1387–1394PubMedGoogle Scholar
  80. Hansen R, Sauder C, Czub S et al (2001) Activation of microglia cells is dispensable for the induction of rat retroviral spongiform encephalopathy. J Neurovirol 7:501–510PubMedGoogle Scholar
  81. Harris AK, Ergul A, Kozak A et al (2005) Effect of neutrophil depletion on gelatinase expression, edema formation and hemorrhagic transformation after focal ischemic stroke. BMC Neurosci 6:49PubMedGoogle Scholar
  82. Hartl R, Schurer L, Schmid-Schonbein GW et al (1996) Experimental antileukocyte interventions in cerebral ischemia. J Cereb Blood Flow Metab 16:1108–1119PubMedGoogle Scholar
  83. Haynes WG, Strachan FE, Webb DJ (1995) Endothelin ETA and ETB receptors cause vasoconstriction of human resistance and capacitance vessels in vivo. Circulation 92:357–363PubMedGoogle Scholar
  84. He Z, Yamawaki T, Yang S et al (1999) Experimental model of small deep infarcts involving the hypothalamus in rats: changes in body temperature and postural reflex. Stroke 30:2743–2751, discussion 51PubMedGoogle Scholar
  85. He Z, Yang SH, Naritomi H et al (2000) Definition of the anterior choroidal artery territory in rats using intraluminal occluding technique. J Neurol Sci 182:16–28PubMedGoogle Scholar
  86. Hedtjarn M, Leverin AL, Eriksson K et al (2002) Interleukin-18 involvement in hypoxic-ischemic brain injury. J Neurosci 22:5910–5919PubMedGoogle Scholar
  87. Hedtjarn M, Mallard C, Arvidsson P et al (2005) White matter injury in the immature brain: role of interleukin-18. Neurosci Lett 373:16–20PubMedGoogle Scholar
  88. Horie N, Maag AL, Hamilton SA et al (2008) Mouse model of focal cerebral ischemia using endothelin-1. J Neurosci Methods 173:286–290PubMedGoogle Scholar
  89. Howells DW, Porritt MJ, Rewell SS et al (2010) Different strokes for different folks: the rich diversity of animal models of focal cerebral ischemia. J Cereb Blood Flow Metab 30:1412–1431PubMedGoogle Scholar
  90. Huang Z, Huang PL, Ma J et al (1996) Enlarged infarcts in endothelial nitric oxide synthase knockout mice are attenuated by nitro-L-arginine. J Cereb Blood Flow Metab 16:981–987PubMedGoogle Scholar
  91. Hughes PM, Anthony DC, Ruddin M et al (2003) Focal lesions in the rat central nervous system induced by endothelin-1. J Neuropathol Exp Neurol 62:1276–1286PubMedGoogle Scholar
  92. Imai Y, Ibata I, Ito D et al (1996) A novel gene iba1 in the major histocompatibility complex class III region encoding an EF hand protein expressed in a monocytic lineage. Biochem Biophys Res Commun 224:855–862PubMedGoogle Scholar
  93. Irving EA, Yatsushiro K, McCulloch J et al (1997) Rapid alteration of tau in oligodendrocytes after focal ischemic injury in the rat: involvement of free radicals. J Cereb Blood Flow Metab 17:612–622PubMedGoogle Scholar
  94. Irving EA, Bentley DL, Parsons AA (2001) Assessment of white matter injury following prolonged focal cerebral ischaemia in the rat. Acta Neuropathol 102:627–635PubMedGoogle Scholar
  95. Isaksson J, Farooque M, Holtz A et al (1999) Expression of ICAM-1 and CD11b after experimental spinal cord injury in rats. J Neurotrauma 16:165–173PubMedGoogle Scholar
  96. Ito D, Imai Y, Ohsawa K et al (1998) Microglia-specific localisation of a novel calcium binding protein, Iba1. Brain Res Mol Brain Res 57:1–9PubMedGoogle Scholar
  97. Ito D, Tanaka K, Suzuki S et al (2001) Enhanced expression of Iba1, ionized calcium-binding adapter molecule 1, after transient focal cerebral ischemia in rat brain. Stroke 32:1208–1215PubMedGoogle Scholar
  98. Jander S, Kraemer M, Schroeter M et al (1995) Lymphocytic infiltration and expression of intercellular adhesion molecule-1 in photochemically induced ischemia of the rat cortex. J Cereb Blood Flow Metab 15:42–51PubMedGoogle Scholar
  99. Jin R, Yang G, Li G (2010) Inflammatory mechanisms in ischemic stroke: role of inflammatory cells. J Leukoc Biol 87:779–789PubMedGoogle Scholar
  100. Johnson GA, Calabrese E, Badea A et al (2012) A multidimensional magnetic resonance histology atlas of the Wistar rat brain. Neuroimage 62:1848–1856PubMedGoogle Scholar
  101. Johnston MV, Ferriero DM, Vannucci SJ et al (2005) Models of cerebral palsy: which ones are best? J Child Neurol 20:984–987PubMedGoogle Scholar
  102. Jordan J, Segura T, Brea D et al (2008) Inflammation as therapeutic objective in stroke. Curr Pharm Des 14:3549–3564PubMedGoogle Scholar
  103. Justicia C, Panes J, Sole S et al (2003) Neutrophil infiltration increases matrix metalloproteinase-9 in the ischemic brain after occlusion/reperfusion of the middle cerebral artery in rats. J Cereb Blood Flow Metab 23:1430–1440PubMedGoogle Scholar
  104. Kalimo H, del Zoppo GJ, Paetau A et al (2013) Polymorphonuclear neutrophil infiltration into ischemic infarctions: myth or truth? Acta Neuropathol 125:313–316PubMedGoogle Scholar
  105. Kanematsu Y, Kanematsu M, Kurihara C et al (2011) Critical roles of macrophages in the formation of intracranial aneurysm. Stroke 42:173–178PubMedGoogle Scholar
  106. Kaushal V, Schlichter LC (2008) Mechanisms of microglia-mediated neurotoxicity in a new model of the stroke penumbra. J Neurosci 28:2221–2230PubMedGoogle Scholar
  107. Kaushal V, Koeberle PD, Wang Y et al (2007) The Ca2+-activated K+ channel KCNN4/KCa3.1 contributes to microglia activation and nitric oxide-dependent neurodegeneration. J Neurosci 27:234–244PubMedGoogle Scholar
  108. Kelly-Hayes M, Robertson JT, Broderick JP et al (1998) The American Heart Association stroke outcome classification. Stroke 29:1274–1280PubMedGoogle Scholar
  109. Kettenmann H, Hanisch UK, Noda M et al (2011) Physiology of microglia. Physiol Rev 91:461–553PubMedGoogle Scholar
  110. Khanna R, Roy L, Zhu X et al (2001) K+ channels and the microglial respiratory burst. Am J Physiol Cell Physiol 280:C796–C806PubMedGoogle Scholar
  111. Kirby RS, Wingate MS, Van Naarden BK et al (2011) Prevalence and functioning of children with cerebral palsy in four areas of the United States in 2006: a report from the Autism and Developmental Disabilities Monitoring Network. Res Dev Disabil 32:462–469PubMedGoogle Scholar
  112. Kleinig TJ, Vink R (2009) Suppression of inflammation in ischemic and hemorrhagic stroke: therapeutic options. Curr Opin Neurol 22:294–301PubMedGoogle Scholar
  113. Kleinschnitz C, Bendszus M, Frank M et al (2003) In vivo monitoring of macrophage infiltration in experimental ischemic brain lesions by magnetic resonance imaging. J Cereb Blood Flow Metab 23:1356–1361PubMedGoogle Scholar
  114. Kleinschnitz C, Schwab N, Kraft P et al (2010) Early detrimental T-cell effects in experimental cerebral ischemia are neither related to adaptive immunity nor thrombus formation. Blood 115:3835–3842PubMedGoogle Scholar
  115. Kleinschnitz C, Kraft P, Dreykluft A et al (2012) Regulatory T cells are strong promoters of acute ischemic stroke in mice by inducing dysfunction of the cerebral microvasculature. Blood 121:679–691PubMedGoogle Scholar
  116. Kluver H, Barrera E (1953) A method for the combined staining of cells and fibers in the nervous system. J Neuropathol Exp Neurol 12:400–403PubMedGoogle Scholar
  117. Koch M, Broecker V, Heratizadeh A et al (2008) Induction of chronic renal allograft injury by injection of a monoclonal antibody against a donor MHC Ib molecule in a nude rat model. Transpl Immunol 19:187–191PubMedGoogle Scholar
  118. Koizumi J, Yoshida Y, Nakazawa T et al (1986) Experimental studies of ischemic brain edema, I: a new experimental model of cerebral embolism in rats in which recirculation can be introduced in the ischemic area. Jpn J Stroke 8:1–8Google Scholar
  119. Krafft PR, Bailey EL, Lekic T et al (2012) Etiology of stroke and choice of models. Int J Stroke 7:398–406PubMedGoogle Scholar
  120. Kuge Y, Minematsu K, Yamaguchi T et al (1995) Nylon monofilament for intraluminal middle cerebral artery occlusion in rats. Stroke 26:1655–1657, discussion 8PubMedGoogle Scholar
  121. Lai AY, Todd KG (2008) Differential regulation of trophic and proinflammatory microglial effectors is dependent on severity of neuronal injury. Glia 56:259–270PubMedGoogle Scholar
  122. Laing RJ, Jakubowski J, Laing RW (1993) Middle cerebral artery occlusion without craniectomy in rats. Which method works best? Stroke 24:294–297PubMedGoogle Scholar
  123. Lakhan SE, Kirchgessner A, Hofer M (2009) Inflammatory mechanisms in ischemic stroke: therapeutic approaches. J Transl Med 7:97PubMedGoogle Scholar
  124. Lee EJ, Lee MY, Chen HY et al (2005) Melatonin attenuates gray and white matter damage in a mouse model of transient focal cerebral ischemia. J Pineal Res 38:42–52PubMedGoogle Scholar
  125. Leifer D, Kowall NW (1993) Immunohistochemical patterns of selective cellular vulnerability in human cerebral ischemia. J Neurol Sci 119:217–228PubMedGoogle Scholar
  126. Lerouet D, Beray-Berthat V, Palmier B et al (2002) Changes in oxidative stress, iNOS activity and neutrophil infiltration in severe transient focal cerebral ischemia in rats. Brain Res 958:166–175PubMedGoogle Scholar
  127. Liesz A, Suri-Payer E, Veltkamp C et al (2009) Regulatory T cells are key cerebroprotective immunomodulators in acute experimental stroke. Nat Med 15:192–199PubMedGoogle Scholar
  128. Liesz A, Zhou W, Mracsko E et al (2011) Inhibition of lymphocyte trafficking shields the brain against deleterious neuroinflammation after stroke. Brain 134:704–720PubMedGoogle Scholar
  129. Lin Y, Stanworth S, Birchall J et al (2012) Recombinant factor VIIa for the prevention and treatment of bleeding in patients without haemophilia. Cochrane Database Syst Rev (3):CD005011Google Scholar
  130. Liu F, McCullough LD (2011) Middle cerebral artery occlusion model in rodents: methods and potential pitfalls. J Biomed Biotechnol 2011:464701PubMedGoogle Scholar
  131. Lively S, Schlichter LC (2012) SC1/hevin identifies early white matter injury after ischemia and intracerebral hemorrhage in young and aged rats. J Neuropathol Exp Neurol 71:480–493PubMedGoogle Scholar
  132. Lively S, Moxon-Emre I, Schlichter LC (2011) SC1/hevin and reactive gliosis after transient ischemic stroke in young and aged rats. J Neuropathol Exp Neurol 70:913–929PubMedGoogle Scholar
  133. Lopez AD, Mathers CD (2006) Measuring the global burden of disease and epidemiological transitions: 2002–2030. Ann Trop Med Parasitol 100:481–499PubMedGoogle Scholar
  134. Luo XG, Chen SD (2010) The changing phenotype of microglia from homeostasis to disease. Transl Neurodegener 1:9Google Scholar
  135. Macrae IM (1992) New models of focal cerebral ischaemia. Br J clin Pharmacol 34:302–308Google Scholar
  136. Mao H, Fang X, Floyd KM et al (2007) Induction of microglial reactive oxygen species production by the organochlorinated pesticide dieldrin. Brain Res 1186:267–274PubMedGoogle Scholar
  137. Marcoux FW, Morawetz RB, Crowell RM et al (1982) Differential regional vulnerability in transient focal cerebral ischemia. Stroke 13:339–346PubMedGoogle Scholar
  138. Matsumoto H, Kumon Y, Watanabe H et al (2007) Antibodies to CD11b, CD68, and lectin label neutrophils rather than microglia in traumatic and ischemic brain lesions. J Neurosci Res 85:994–1009PubMedGoogle Scholar
  139. Matsuo Y, Onodera H, Shiga Y et al (1994) Correlation between myeloperoxidase-quantified neutrophil accumulation and ischemic brain injury in the rat. Effects of neutrophil depletion. Stroke 25:1469–1475PubMedGoogle Scholar
  140. Matsuo A, Lee GC, Terai K et al (1997) Unmasking of an unusual myelin basic protein epitope during the process of myelin degeneration in humans: a potential mechanism for the generation of autoantigens. Am J Pathol 150:1253–1266PubMedGoogle Scholar
  141. Matute C, Domercq M, Perez-Samartin A et al (2013) Protecting white matter from stroke injury. Stroke 44:1204–1211PubMedGoogle Scholar
  142. Mawhinney LA, Thawer SG, Lu WY et al (2012) Differential detection and distribution of microglial and hematogenous macrophage populations in the injured spinal cord of lys-EGFP-ki transgenic mice. J Neuropathol Exp Neurol 71:180–197PubMedGoogle Scholar
  143. Mayer SA, Brun NC, Broderick J et al (2005) Safety and feasibility of recombinant factor VIIa for acute intracerebral hemorrhage. Stroke 36:74–79PubMedGoogle Scholar
  144. Mayer SA, Brun NC, Begtrup K et al (2008) Efficacy and safety of recombinant activated factor VII for acute intracerebral hemorrhage. N Engl J Med 358:2127–2137PubMedGoogle Scholar
  145. McColl BW, Allan SM, Rothwell NJ (2009) Systemic infection, inflammation and acute ischemic stroke. Neuroscience 158:1049–1061PubMedGoogle Scholar
  146. McCracken E, Fowler JH, Dewar D et al (2002) Grey matter and white matter ischemic damage is reduced by the competitive AMPA receptor antagonist, SPD 502. J Cereb Blood Flow Metab 22:1090–1097PubMedGoogle Scholar
  147. Meairs S, Wahlgren N, Dirnagl U et al (2006) Stroke research priorities for the next decade–a representative view of the European scientific community. Cerebrovasc Dis 22:75–82PubMedGoogle Scholar
  148. Medana IM, Esiri MM (2003) Axonal damage: a key predictor of outcome in human CNS diseases. Brain 126:515–530PubMedGoogle Scholar
  149. Mizutani M, Pino PA, Saederup N et al (2012) The fractalkine receptor but not CCR2 is present on microglia from embryonic development throughout adulthood. J Immunol 188:29–36PubMedGoogle Scholar
  150. Monsma PC, Brown A (2012) FluoroMyelin Red is a bright, photostable and non-toxic fluorescent stain for live imaging of myelin. J Neurosci Methods 209:344–350PubMedGoogle Scholar
  151. Morrison HW, Filosa JA (2013) A quantitative spatiotemporal analysis of microglia morphology during ischemic stroke and reperfusion. J Neuroinflammation 10:4PubMedGoogle Scholar
  152. Moxon-Emre I, Schlichter LC (2010) Evolution of inflammation and white matter injury in a model of transient focal ischemia. J Neuropathol Exp Neurol 69:1–15PubMedGoogle Scholar
  153. Moxon-Emre I, Schlichter LC (2011) Neutrophil depletion reduces blood–brain barrier breakdown, axon injury, and inflammation after intracerebral hemorrhage. J Neuropathol Exp Neurol 70:218–235PubMedGoogle Scholar
  154. Nauta WJ (1952) Selective silver impregnation of degenerating axons in the central nervous system. Stain Technol 27:175–179PubMedGoogle Scholar
  155. Neumann J, Sauerzweig S, Ronicke R et al (2008) Microglia cells protect neurons by direct engulfment of invading neutrophil granulocytes: a new mechanism of CNS immune privilege. J Neurosci 28:5965–5975PubMedGoogle Scholar
  156. Nguyen HX, O’Barr TJ, Anderson AJ (2007) Polymorphonuclear leukocytes promote neurotoxicity through release of matrix metalloproteinases, reactive oxygen species, and TNF-alpha. J Neurochem 102:900–912PubMedGoogle Scholar
  157. Nimmerjahn A, Kirchhoff F, Helmchen F (2005) Resting microglial cells are highly dynamic surveillants of brain parenchyma in vivo. Science 308:1314–1318PubMedGoogle Scholar
  158. Noda M, Suzumura A (2012) Sweepers in the CNS: microglial migration and phagocytosis in the Alzheimer disease pathogenesis. Int J Alzheimers Dis 2012:891087PubMedGoogle Scholar
  159. O’Collins VE, Macleod MR, Donnan GA et al (2006) 1,026 experimental treatments in acute stroke. Ann Neurol 59:467–477PubMedGoogle Scholar
  160. Ohta H, Nishikawa H, Kimura H et al (1997) Chronic cerebral hypoperfusion by permanent internal carotid ligation produces learning impairment without brain damage in rats. Neuroscience 79:1039–1050PubMedGoogle Scholar
  161. Olah M, Amor S, Brouwer N et al (2012) Identification of a microglia phenotype supportive of remyelination. Glia 60:306–321PubMedGoogle Scholar
  162. Pantoni L, Garcia JH, Gutierrez JA (1996) Cerebral white matter is highly vulnerable to ischemia. Stroke 27:1641–1646, discussion 7PubMedGoogle Scholar
  163. Perry VH, Cowey A (1984) Retinal ganglion cells that project to the superior colliculus and pretectum in the macaque monkey. Neuroscience 12:1125–1137PubMedGoogle Scholar
  164. Perry VH, Oehler R, Cowey A (1984) Retinal ganglion cells that project to the dorsal lateral geniculate nucleus in the macaque monkey. Neuroscience 12:1101–1123PubMedGoogle Scholar
  165. Perry VH, Hume DA, Gordon S (1985) Immunohistochemical localization of macrophages and microglia in the adult and developing mouse brain. Neuroscience 15:313–326PubMedGoogle Scholar
  166. Petrault O, Ouk T, Gautier S et al (2005) Pharmacological neutropenia prevents endothelial dysfunction but not smooth muscle functions impairment induced by middle cerebral artery occlusion. Br J Pharmacol 144:1051–1058PubMedGoogle Scholar
  167. Petty MA, Wettstein JG (1999) White matter ischaemia. Brain Res Brain Res Rev 31:58–64PubMedGoogle Scholar
  168. Petzold A (2005) Neurofilament phosphoforms: surrogate markers for axonal injury, degeneration and loss. J Neurol Sci 233:183–198PubMedGoogle Scholar
  169. Phillips JB, Williams AJ, Adams J et al (2000) Proteasome inhibitor PS519 reduces infarction and attenuates leukocyte infiltration in a rat model of focal cerebral ischemia. Stroke 31:1686–1693PubMedGoogle Scholar
  170. Piani D, Frei K, Do KQ et al (1991) Murine brain macrophages induced NMDA receptor mediated neurotoxicity in vitro by secreting glutamate. Neurosci Lett 133:159–162PubMedGoogle Scholar
  171. Planas AM, Chamorro A (2009) Regulatory T cells protect the brain after stroke. Nat Med 15:138–139PubMedGoogle Scholar
  172. Prestigiacomo CJ, Kim SC, Connolly ES Jr et al (1999) CD18-mediated neutrophil recruitment contributes to the pathogenesis of reperfused but not nonreperfused stroke. Stroke 30:1110–1117PubMedGoogle Scholar
  173. Qureshi AI, Mendelow AD, Hanley DF (2009) Intracerebral haemorrhage. Lancet 373:1632–1644PubMedGoogle Scholar
  174. Relton JK, Sloan KE, Frew EM et al (2001) Inhibition of alpha4 integrin protects against transient focal cerebral ischemia in normotensive and hypertensive rats. Stroke 32:199–205PubMedGoogle Scholar
  175. Robinson RG, Shoemaker WJ, Schlumpf M et al (1975) Effect of experimental cerebral infarction in rat brain on catecholamines and behaviour. Nature 255:332–334PubMedGoogle Scholar
  176. Robinson AP, White TM, Mason DW (1986) Macrophage heterogeneity in the rat as delineated by two monoclonal antibodies MRC OX-41 and MRC OX-42, the latter recognizing complement receptor type 3. Immunology 57:239–247PubMedGoogle Scholar
  177. Robinson MJ, Macrae IM, Todd M et al (1990) Reduction of local cerebral blood flow to pathological levels by endothelin-1 applied to the middle cerebral artery in the rat. Neurosci Lett 118:269–272PubMedGoogle Scholar
  178. Rock RB, Gekker G, Hu S et al (2004) Role of microglia in central nervous system infections. Clin Microbiol Rev 17:942–964, table of contentsGoogle Scholar
  179. Roman GC, Erkinjuntti T, Wallin A et al (2002) Subcortical ischaemic vascular dementia. Lancet Neurol 1:426–436Google Scholar
  180. Saijo K, Glass CK (2011) Microglial cell origin and phenotypes in health and disease. Nat Rev Immunol 11:775–787PubMedGoogle Scholar
  181. Salthouse TN (1962) Luxol fast blue ARN: a new solvent azo dye with improved staining qualities for myelin and phospholipids. Stain Technol 37:313–316PubMedGoogle Scholar
  182. Scheikl T, Pignolet B, Mars LT et al (2010) Transgenic mouse models of multiple sclerosis. Cell Mol Life Sci 67:4011–4034PubMedGoogle Scholar
  183. Schilling M, Besselmann M, Muller M et al (2005) Predominant phagocytic activity of resident microglia over hematogenous macrophages following transient focal cerebral ischemia: an investigation using green fluorescent protein transgenic bone marrow chimeric mice. Exp Neurol 196:290–297PubMedGoogle Scholar
  184. Schlichter LC, Kaushal V, Moxon-Emre I et al (2010) The Ca2+ activated SK3 channel is expressed in microglia in the rat striatum and contributes to microglia-mediated neurotoxicity in vitro. J Neuroinflammation 7:4PubMedGoogle Scholar
  185. Schmued L, Bowyer J, Cozart M et al (2008) Introducing Black-Gold II, a highly soluble gold phosphate complex with several unique advantages for the histochemical localization of myelin. Brain Res 1229:210–217PubMedGoogle Scholar
  186. Schonbeck U, Mach F, Libby P (1998) Generation of biologically active IL-1 beta by matrix metalloproteinases: a novel caspase-1-independent pathway of IL-1 beta processing. J Immunol 161:3340–3346PubMedGoogle Scholar
  187. Schroeter M, Jander S, Huitinga I et al (1997) Phagocytic response in photochemically induced infarction of rat cerebral cortex. The role of resident microglia. Stroke 28:382–386PubMedGoogle Scholar
  188. Sedgwick JD, Schwender S, Imrich H et al (1991) Isolation and direct characterization of resident microglial cells from the normal and inflamed central nervous system. Proc Natl Acad Sci U S A 88:7438–7442PubMedGoogle Scholar
  189. Seo B, Oemar BS, Siebenmann R et al (1994) Both ETA and ETB receptors mediate contraction to endothelin-1 in human blood vessels. Circulation 89:1203–1208PubMedGoogle Scholar
  190. Sivagnanam V, Zhu X, Schlichter LC (2010) Dominance of E. coli phagocytosis over LPS in the inflammatory response of microglia. J Neuroimmunol 227:111–119PubMedGoogle Scholar
  191. Smith ME (1993) Phagocytosis of myelin by microglia in vitro. J Neurosci Res 35:480–487PubMedGoogle Scholar
  192. Smith ME, van der Maesen K, Somera FP (1998) Macrophage and microglial responses to cytokines in vitro: phagocytic activity, proteolytic enzyme release, and free radical production. J Neurosci Res 54:68–78PubMedGoogle Scholar
  193. Smith DH, Meaney DF, Shull WH (2003) Diffuse axonal injury in head trauma. J Head Trauma Rehabil 18:307–316PubMedGoogle Scholar
  194. Souza-Rodrigues RD, Costa AM, Lima RR et al (2008) Inflammatory response and white matter damage after microinjections of endothelin-1 into the rat striatum. Brain Res 1200:78–88PubMedGoogle Scholar
  195. Sozmen EG, Kolekar A, Havton LA et al (2009) A white matter stroke model in the mouse: axonal damage, progenitor responses and MRI correlates. J Neurosci Methods 180:261–272PubMedGoogle Scholar
  196. Sozmen EG, Hinman JD, Carmichael ST (2012) Models that matter: white matter stroke models. Neurotherapeutics 9:349–358PubMedGoogle Scholar
  197. Sprinkle TJ, Sheedlo HJ, Buxton TB et al (1983) Immunochemical identification of 2′, 3′-cyclic nucleotide 3′-phosphodiesterase in central and peripheral nervous system myelin, the Wolfgram protein fraction, and bovine oligodendrocytes. J Neurochem 41:1664–1671PubMedGoogle Scholar
  198. Sternberger LA, Sternberger NH (1983) Monoclonal antibodies distinguish phosphorylated and nonphosphorylated forms of neurofilaments in situ. Proc Natl Acad Sci U S A 80:6126–6130PubMedGoogle Scholar
  199. Sternberger NH, Itoyama Y, Kies MW et al (1978) Myelin basic protein demonstrated immunocytochemically in oligodendroglia prior to myelin sheath formation. Proc Natl Acad Sci U S A 75:2521–2524PubMedGoogle Scholar
  200. Stevens SL, Bao J, Hollis J et al (2002) The use of flow cytometry to evaluate temporal changes in inflammatory cells following focal cerebral ischemia in mice. Brain Res 932:110–119PubMedGoogle Scholar
  201. Stilwell DL (1957) A sudan black B myelin stain for peripheral nerves. Stain Technol 32:19–23PubMedGoogle Scholar
  202. Streilein JW (1993) Immune privilege as the result of local tissue barriers and immunosuppressive microenvironments. Curr Opin Immunol 5:428–432PubMedGoogle Scholar
  203. Streit WJ, Kreutzberg GW (1987) Lectin binding by resting and reactive microglia. J Neurocytol 16:249–260PubMedGoogle Scholar
  204. Svedin P, Hagberg H, Savman K et al (2007) Matrix metalloproteinase-9 gene knock-out protects the immature brain after cerebral hypoxia-ischemia. J Neurosci 27:1511–1518PubMedGoogle Scholar
  205. Tayag EC, Jeng AY, Savage P et al (1996) Rat striatum contains pure population of ETB receptors. Eur J Pharmacol 300:261–265PubMedGoogle Scholar
  206. Tonnesen MG (1989) Neutrophil-endothelial cell interactions: mechanisms of neutrophil adherence to vascular endothelium. J Invest Dermatol 93:53S–58SPubMedGoogle Scholar
  207. Towfighi J, Zec N, Yager J et al (1995) Temporal evolution of neuropathologic changes in an immature rat model of cerebral hypoxia: a light microscopic study. Acta Neuropathol 90:375–386PubMedGoogle Scholar
  208. Traystman RJ (2003) Animal models of focal and global cerebral ischemia. ILAR J 44:85–95PubMedGoogle Scholar
  209. Trotter J, DeJong LJ, Smith ME (1986) Opsonization with antimyelin antibody increases the uptake and intracellular metabolism of myelin in inflammatory macrophages. J Neurochem 47:779–789PubMedGoogle Scholar
  210. Turrin NP, Rivest S (2006) Molecular and cellular immune mediators of neuroprotection. Mol Neurobiol 34:221–242PubMedGoogle Scholar
  211. Uehara H, Yoshioka H, Kawase S et al (1999) A new model of white matter injury in neonatal rats with bilateral carotid artery occlusion. Brain Res 837:213–220PubMedGoogle Scholar
  212. Valeriani V, Dewar D, McCulloch J (2000) Quantitative assessment of ischemic pathology in axons, oligodendrocytes, and neurons: attenuation of damage after transient ischemia. J Cereb Blood Flow Metab 20:765–771PubMedGoogle Scholar
  213. Van Dyken SJ, Locksley RM (2013) Interleukin-4- and interleukin-13-mediated alternatively activated macrophages: roles in homeostasis and disease. Annu Rev Immunol 31:317–343PubMedGoogle Scholar
  214. Vannucci SJ, Hagberg H (2004) Hypoxia-ischemia in the immature brain. J Exp Biol 207:3149–3154PubMedGoogle Scholar
  215. Vannucci RC, Vannucci SJ (1997) A model of perinatal hypoxic-ischemic brain damage. Ann N Y Acad Sci 835:234–249PubMedGoogle Scholar
  216. Vannucci RC, Lyons DT, Vasta F (1988) Regional cerebral blood flow during hypoxia-ischemia in immature rats. Stroke 19:245–250PubMedGoogle Scholar
  217. Varin A, Gordon S (2009) Alternative activation of macrophages: immune function and cellular biology. Immunobiology 214:630–641PubMedGoogle Scholar
  218. Varvel NH, Grathwohl SA, Baumann F et al (2012) Microglial repopulation model reveals a robust homeostatic process for replacing CNS myeloid cells. Proc Natl Acad Sci U S A 109:18150–18155PubMedGoogle Scholar
  219. Verhaar MC, Strachan FE, Newby DE et al (1998) Endothelin-A receptor antagonist-mediated vasodilatation is attenuated by inhibition of nitric oxide synthesis and by endothelin-B receptor blockade. Circulation 97:752–756PubMedGoogle Scholar
  220. Villapol S, Fau S, Renolleau S et al (2011) Melatonin promotes myelination by decreasing white matter inflammation after neonatal stroke. Pediatr Res 69:51–55PubMedGoogle Scholar
  221. Wake H, Moorhouse AJ, Jinno S et al (2009) Resting microglia directly monitor the functional state of synapses in vivo and determine the fate of ischemic terminals. J Neurosci 29:3974–3980PubMedGoogle Scholar
  222. Wakita H, Tomimoto H, Akiguchi I et al (1994) Glial activation and white matter changes in the rat brain induced by chronic cerebral hypoperfusion: an immunohistochemical study. Acta Neuropathol 87:484–492PubMedGoogle Scholar
  223. Wakita H, Tomimoto H, Akiguchi I et al (1995) Protective effect of cyclosporin A on white matter changes in the rat brain after chronic cerebral hypoperfusion. Stroke 26:1415–1422PubMedGoogle Scholar
  224. Wakita H, Tomimoto H, Akiguchi I et al (1998) Dose-dependent, protective effect of FK506 against white matter changes in the rat brain after chronic cerebral ischemia. Brain Res 792:105–113PubMedGoogle Scholar
  225. Walker CA, Huttner AJ, O’Connor KC (2011) Cortical injury in multiple sclerosis; the role of the immune system. BMC Neurol 11:152PubMedGoogle Scholar
  226. Wang J, Dore S (2007) Inflammation after intracerebral hemorrhage. J Cereb Blood Flow Metab 27:894–908PubMedGoogle Scholar
  227. Wang X, Lo EH (2003) Triggers and mediators of hemorrhagic transformation in cerebral ischemia. Mol Neurobiol 28:229–244PubMedGoogle Scholar
  228. Wang X, Tsuji K, Lee SR et al (2004) Mechanisms of hemorrhagic transformation after tissue plasminogen activator reperfusion therapy for ischemic stroke. Stroke 35:2726–2730PubMedGoogle Scholar
  229. Wang Q, Tang XN, Yenari MA (2007) The inflammatory response in stroke. J Neuroimmunol 184:53–68PubMedGoogle Scholar
  230. Wang Y, Li B, Li Z et al (2013) Improvement of hypoxia-ischemia-induced white matter injury in immature rat brain by ethyl pyruvate. Neurochem Res 38:742–752PubMedGoogle Scholar
  231. Ward JM, Erexson CR, Faucette LJ et al (2006) Immunohistochemical markers for the rodent immune system. Toxicol Pathol 34:616–630PubMedGoogle Scholar
  232. Wasserman JK, Schlichter LC (2007) Neuron death and inflammation in a rat model of intracerebral hemorrhage: effects of delayed minocycline treatment. Brain Res 1136:208–218PubMedGoogle Scholar
  233. Wasserman JK, Schlichter LC (2008) White matter injury in young and aged rats after intracerebral hemorrhage. Exp Neurol 214:266–275PubMedGoogle Scholar
  234. Wasserman JK, Yang H, Schlichter LC (2008) Glial responses, neuron death and lesion resolution after intracerebral hemorrhage in young vs. aged rats. Eur J Neurosci 28:1316–1328PubMedGoogle Scholar
  235. Weinstein JR, Koerner IP, Moller T (2010) Microglia in ischemic brain injury. Future Neurol 5:227–246PubMedGoogle Scholar
  236. Weston RM, Jones NM, Jarrott B et al (2007) Inflammatory cell infiltration after endothelin-1-induced cerebral ischemia: histochemical and myeloperoxidase correlation with temporal changes in brain injury. J Cereb Blood Flow Metab 27:100–114PubMedGoogle Scholar
  237. Whiteland JL, Nicholls SM, Shimeld C et al (1995) Immunohistochemical detection of T-cell subsets and other leukocytes in paraffin-embedded rat and mouse tissues with monoclonal antibodies. J Histochem Cytochem 43:313–320PubMedGoogle Scholar
  238. Whiteley W, Jackson C, Lewis S et al (2009) Inflammatory markers and poor outcome after stroke: a prospective cohort study and systematic review of interleukin-6. PLoS Med 6:e1000145PubMedGoogle Scholar
  239. Wiley KE, Davenport AP (2004) Endothelin receptor pharmacology and function in the mouse: comparison with rat and man. J Cardiovasc Pharmacol 44(suppl 1):S4–S6PubMedGoogle Scholar
  240. Williams AJ, Hale SL, Moffett JR et al (2003) Delayed treatment with MLN519 reduces infarction and associated neurologic deficit caused by focal ischemic brain injury in rats via antiinflammatory mechanisms involving nuclear factor-kappaB activation, gliosis, and leukocyte infiltration. J Cereb Blood Flow Metab 23:75–87PubMedGoogle Scholar
  241. Won SM, Lee JH, Park UJ et al (2011) Iron mediates endothelial cell damage and blood–brain barrier opening in the hippocampus after transient forebrain ischemia in rats. Exp Mol Med 43:121–128PubMedGoogle Scholar
  242. Wynn TA, Chawla A, Pollard JW (2013) Macrophage biology in development, homeostasis and disease. Nature 496:445–455PubMedGoogle Scholar
  243. Xu J, He L, Ahmed SH et al (2000) Oxygen-glucose deprivation induces inducible nitric oxide synthase and nitrotyrosine expression in cerebral endothelial cells. Stroke 31:1744–1751PubMedGoogle Scholar
  244. Yang Y, Jalal FY, Thompson JF et al (2011) Tissue inhibitor of metalloproteinases-3 mediates the death of immature oligodendrocytes via TNF-alpha/TACE in focal cerebral ischemia in mice. J Neuroinflammation 8:108PubMedGoogle Scholar
  245. Yilmaz G, Arumugam TV, Stokes KY et al (2006) Role of T lymphocytes and interferon-gamma in ischemic stroke. Circulation 113:2105–2112PubMedGoogle Scholar
  246. Yokota N, Daniels F, Crosson J et al (2002) Protective effect of T cell depletion in murine renal ischemia-reperfusion injury. Transplantation 74:759–763PubMedGoogle Scholar
  247. Zhang ZG, Chopp M (1997) Measurement of myeloperoxidase immunoreactive cells in ischemic brain after transient middle cerebral artery occlusion in the rat. Neurosci Res Commun 20:85–91Google Scholar
  248. Zhang K, Sejnowski TJ (2000) A universal scaling law between gray matter and white matter of cerebral cortex. Proc Natl Acad Sci U S A 97:5621–5626PubMedGoogle Scholar
  249. Zhang W, Stanimirovic D (2002) Current and future therapeutic strategies to target inflammation in stroke. Curr Drug Targets Inflamm Allergy 1:151–166PubMedGoogle Scholar
  250. Zhao BQ, Chauhan AK, Canault M et al (2009) von Willebrand factor-cleaving protease ADAMTS13 reduces ischemic brain injury in experimental stroke. Blood 114:3329–3334PubMedGoogle Scholar
  251. Zwacka RM, Zhang Y, Halldorson J et al (1997) CD4(+) T-lymphocytes mediate ischemia/reperfusion-induced inflammatory responses in mouse liver. J Clin Invest 100:279–289PubMedGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2014

Authors and Affiliations

  • Lyanne C. Schlichter
    • 1
    • 2
    Email author
  • Sarah Hutchings
    • 1
    • 2
  • Starlee Lively
    • 1
  1. 1.Genes & Development, Toronto Western Research InstituteUniversity Health NetworkTorontoCanada
  2. 2.Department of PhysiologyUniversity of TorontoTorontoCanada

Personalised recommendations