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Inflammation: the Common Link in Brain Pathologies pp 231–252Cite as

Neuroinflammation in Ischaemic Stroke: Utilizing the Biphasic Niche of Neuroprotection and Neurotoxicity for Clinic

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Abstract

Ischaemic stroke is a devastating disease that results in neurological disorder with maximum disease burden caused by blockade of blood vessels in the brain leading to neuronal cell death and tissue damage. Inflammatory processes have a fundamental role in the pathophysiology of ischaemic stroke, and recent studies indicate that inflammation has a temporally biphasic behaviour and acts as a double-edged sword, not only exacerbating secondary brain injury in the acute stage of stroke, but also thereafter beneficially contributing to brain recovery after the stroke. An initial event of inflammation in ischaemic stroke is activation of microglia, leading to a cascade of delicately balanced orchestration between both pro- and anti-inflammatory mediators, acting through multiple receptor signalling pathways. Understanding how microglia can actuate to both its phenotypes—such as neurotoxic M1 type (‘bad microglia’) vis-à-vis neuroprotective M2 type (‘good microglia’)—may be essential to implement therapeutic strategies of using differential immunomodulatory interventions in ischaemic stroke. We elucidate the role of the bimodality in inflammation in ischaemic stroke, the related signalling pathways, and the resulting immunomodulation and immunosuppression processes. A pathophysiological integration of the findings from cell culture models, animal studies, human investigations and population-based clinical trials, is undertaken. We delineate how one can utilize the manoeuvre the dynamics of inflammation and immunomodulation for enhancing therapeutic interventions on ischaemic stroke.

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References

  • Alessandrini A, Namura S, Moskowitz MA, Bonventre JV (1999) MEK1 protein kinase inhibition protects against damage resulting from focal cerebral ischemia. Proc Natl Acad Sci USA 96:12866–12869

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Barone FC, Irving EA, Ray AM, Lee JC, Kassis S, Kumar S et al (2001) Inhibition of p38 mitogen-activated protein kinase provides neuroprotection in cerebral focal ischemia. Med Res Rev 21:129–145

    Article  CAS  PubMed  Google Scholar 

  • Benakis C, Bonny C, Hirt L (2010) JNK inhibition and inflammation after cerebral ischemia. Brain Behav Immun 24:800–811

    Article  CAS  PubMed  Google Scholar 

  • Bhasin A, Srivastava MV, Kumaran SS, Mohanty S, Bhatia R, Bose S et al (2011) Autologous mesenchymal stem cells in chronic stroke. Cerebrovasc Dis Extra 1:93–104

    Article  PubMed  PubMed Central  Google Scholar 

  • Bhatia S, Fei M, Yarlagadda M, Qi Z, Akira S, Saijo S et al (2011) Rapid host defense against Aspergillus fumigatus involves alveolar macrophages with a predominance of alternatively activated phenotype. PLoS One 6:e15943

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Brenneman M, Sharma S, Harting M, Strong R, Cox CS, Aronowski J et al (2010) Autologous bone marrow mononuclear cells enhance recovery after acute ischemic stroke in young and middle-aged rats. J Cereb Blood Flow Metab 30:140–149

    Article  PubMed  Google Scholar 

  • Brott T, Bogousslavsky J (2000) Treatment of acute ischemic stroke. N Engl J Med 343:710–722

    Article  CAS  PubMed  Google Scholar 

  • Butovsky O, Ziv Y, Schwartz A, Landa G, Talpalar AE, Pluchino S et al (2006) Microglia activated by IL-4 or IFN-gamma differentially induce neurogenesis and oligodendrogenesis from adult stem/progenitor cells. Mol Cell Neurosci 31:149–160

    Article  CAS  PubMed  Google Scholar 

  • Butovsky O, Bukshpan S, Kunis G, Jung S, Schwartz M (2007) Microglia can be induced by IFN-gamma or IL-4 to express neural or dendritic-like markers. Mol Cell Neurosci 35:490–500

    Article  CAS  PubMed  Google Scholar 

  • Candelario-Jalil E (2008) Nimesulide as a promising neuroprotectant in brain ischemia: new experimental evidences. Pharmacol Res 57:266–273

    Article  CAS  PubMed  Google Scholar 

  • Cao CX, Yang QW, Lv FL, Cui J, Fu HB, Wang JZ (2007) Reduced cerebral ischemia-reperfusion injury in Toll-like receptor 4 deficient mice. Biochem Biophys Res Commun 353:509–514

    Article  CAS  PubMed  Google Scholar 

  • Cardoso MM, Franco EC, de Souza CC, da Silva MC, Gouveia A, Gomes-Leal W (2013) Minocycline treatment and bone marrow mononuclear cell transplantation after endothelin-1 induced striatal ischemia. Inflammation 36:197–205

    Article  CAS  PubMed  Google Scholar 

  • Carloni S, Girelli S, Scopa C, Buonocore G, Longini M, Balduini W (2010) Activation of autophagy and Akt/CREB signaling play an equivalent role in the neuroprotective effect of rapamycin in neonatal hypoxia-ischemia. Autophagy 6:366–377

    Article  CAS  PubMed  Google Scholar 

  • Caso JR, Pradillo JM, Hurtado O, Lorenzo P, Moro MA, Lizasoain I (2007) Toll-like receptor 4 is involved in brain damage and inflammation after experimental stroke. Circulation 115:1599–1608

    Article  CAS  PubMed  Google Scholar 

  • Chauhan A, Sharma U, Jagannathan NR, Reeta KH, Gupta YK (2011) Rapamycin protects against middle cerebral artery occlusion induced focal cerebral ischemia in rats. Behav Brain Res 225:603–609

    Article  CAS  PubMed  Google Scholar 

  • Couzin J (2007) Clinical research. ALS trial raises questions about promising drug. Science 318:1227

    Article  CAS  PubMed  Google Scholar 

  • Cullheim S, Thams S (2007) The microglial networks of the brain and their role in neuronal network plasticity after lesion. Brain Res Rev 55:89–96

    Article  CAS  PubMed  Google Scholar 

  • Danton GH, Dietrich WD (2003) Inflammatory mechanisms after ischemia and stroke. J Neuropathol Exp Neurol 62:127–136

    Article  CAS  PubMed  Google Scholar 

  • Davalos D, Grutzendler J, Yang G, Kim JV, Zuo Y, Jung S et al (2005) ATP mediates rapid microglial response to local brain injury in vivo. Nat Neurosci 8:752–758

    Article  CAS  PubMed  Google Scholar 

  • de Vasconcelos Dos Santos A, da Costa Reis J, Diaz Paredes B, Moraes L, Jasmin, Giraldi-Guimarães A, et al (2010) Therapeutic window for treatment of cortical ischemia with bone marrow-derived cells in rats. Brain Res 1306:149–158

    Google Scholar 

  • Denes A, Vidyasagar R, Feng J, Narvainen J, McColl BW, Kauppinen RA et al (2007) Proliferating resident microglia after focal cerebral ischaemia in mice. J Cereb Blood Flow Metab 27:1941–1953

    Article  CAS  PubMed  Google Scholar 

  • Eglitis MA, Mezey E (1997) Hematopoietic cells differentiate into both microglia and macroglia in the brains of adult mice. Proc Natl Acad Sci USA 94:4080–4085

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Ekdahl CT, Claasen JH, Bonde S, Kokaia Z, Lindvall O (2003) Inflammation is detrimental for neurogenesis in adult brain. Proc Natl Acad Sci USA 100:13632–13637

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Emsley HC, Smith CJ, Gavin CM, Georgiou RF, Vail A, Barberan EM et al (2003) An early and sustained peripheral inflammatory response in acute ischaemic stroke: relationships with infection and atherosclerosis. J Neuroimmunol 139:93–101

    Article  CAS  PubMed  Google Scholar 

  • Emsley HC, Smith CJ, Georgiou RF, Vail A, Hopkins SJ, Rothwell NJ et al (2005) A randomised phase II study of interleukin-1 receptor antagonist in acute stroke patients. J Neurol Neurosurg Psychiatry 76:1366–1372

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Faraco G, Fossati S, Bianchi ME, Patrone M, Pedrazzi M, Sparatore B et al (2007) High mobility group box 1 protein is released by neural cells upon different stresses and worsens ischemic neurodegeneration in vitro and in vivo. J Neurochem 103:590–603

    Article  CAS  PubMed  Google Scholar 

  • Fletcher L, Evans TM, Watts LT, Jimenez DF, Digicaylioglu M (2013) Rapamycin treatment improves neuron viability in an in vitro model of stroke. PLoS One 8:e68281

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Franco EC, Cardoso MM, Gouvêia A, Pereira A, Gomes-Leal W (2012) Modulation of microglial activation enhances neuroprotection and functional recovery derived from bone marrow mononuclear cell transplantation after cortical ischemia. Neurosci Res 73:122–132

    Article  CAS  PubMed  Google Scholar 

  • Guan QH, Pei DS, Liu XM, Wang XT, Xu TL, Zhang GY (2006) Neuroprotection against ischemic brain injury by SP600125 via suppressing the extrinsic and intrinsic pathways of apoptosis. Brain Res 1092:36–46

    Article  CAS  PubMed  Google Scholar 

  • Hamanaka J, Hara H (2011) Involvement of Toll-like receptors in ischemia-induced neuronal damage. Cent Nerv Syst Agents Med Chem 11:107–113

    Article  CAS  PubMed  Google Scholar 

  • Hanisch UK, Kettenmann H (2007) Microglia: active sensor and versatile effector cells in the normal and pathologic brain. Nat Neurosci 10:1387–1394

    Article  CAS  PubMed  Google Scholar 

  • Hayakawa K, Qiu J, Lo EH (2010) Biphasic actions of HMGB1 signaling in inflammation and recovery after stroke. Ann N Y Acad Sci 1207:50–57

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Hill WD, Hess DC, Carroll JE, Wakade CG, Howard EF, Chen Q et al (2001) The NF-kappaB inhibitor diethyldithiocarbamate (DDTC) increases brain cell death in a transient middle cerebral artery occlusion model of ischemia. Brain Res Bull 55:375–386

    Article  CAS  PubMed  Google Scholar 

  • Hu X, Li P, Guo Y, Wang H, Leak RK, Chen S et al (2012) Microglia/macrophage polarization dynamics reveal novel mechanism of injury expansion after focal cerebral ischemia. Stroke 43:3063–3070

    Article  CAS  PubMed  Google Scholar 

  • Hu X, Leak RK, Shi Y, Suenaga J, Gao Y, Zheng P et al (2015) Microglial and macrophage polarization—new prospects for brain repair. Nat Rev Neurol 11:56–64

    Article  PubMed  Google Scholar 

  • Hua F, Ma J, Ha T, Xia Y, Kelley J, Williams DL et al (2007) Activation of Toll-like receptor 4 signaling contributes to hippocampal neuronal death following global cerebral ischemia/reperfusion. J Neuroimmunol 190:101–111

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Huang P, Han J, Hui L (2010) MAPK signaling in inflammation-associated cancer development. Protein Cell 1:218–226

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Ikonomidou C, Turski L (2002) Why did NMDA receptor antagonists fail clinical trials for stroke and traumatic brain injury? Lancet Neurol 1:383–386

    Article  CAS  PubMed  Google Scholar 

  • Jiang ZJ, Richardson JS, Yu PH (2008) The contribution of cerebral vascular semicarbazide-sensitive amine oxidase to cerebral amyloid angiopathy in Alzheimer’s disease. Neuropathol Appl Neurobiol 34:194–204

    Article  CAS  PubMed  Google Scholar 

  • Jin R, Yang G, Li G (2010) Inflammatory mechanisms in ischemic stroke: role of inflammatory cells. J Leukoc Biol 87:779–789

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Kaltschmidt B, Widera D, Kaltschmidt C (2005) Signaling via NF-kappaB in the nervous system. Biochim Biophys Acta 1745:287–299

    Article  CAS  PubMed  Google Scholar 

  • Kaminska B (2005) MAPK signalling pathways as molecular targets for anti-inflammatory therapy–from molecular mechanisms to therapeutic benefits. Biochim Biophys Acta 1754:253–262

    Article  CAS  PubMed  Google Scholar 

  • Kanazawa H, Ohsawa K, Sasaki Y, Kohsaka S, Imai Y (2002) Macrophage/microglia-specific protein Iba1 enhances membrane ruffling and Rac activation via phospholipase C-gamma—dependent pathway. J Biol Chem 277:20026–20032

    Article  CAS  PubMed  Google Scholar 

  • Kawasaki H, Morooka T, Shimohama S, Kimura J, Hirano T, Gotoh Y et al (1997) Activation and involvement of p38 mitogen-activated protein kinase in glutamate-induced apoptosis in rat cerebellar granule cells. J Biol Chem 272:18518–18521

    Article  CAS  PubMed  Google Scholar 

  • Keimpema E, Fokkens MR, Nagy Z, Agoston V, Luiten PG, Nyakas C et al (2009) Early transient presence of implanted bone marrow stem cells reduces lesion size after cerebral ischaemia in adult rats. Neuropathol Appl Neurobiol 35:89–102

    Article  CAS  PubMed  Google Scholar 

  • Kempermann G, Neumann H (2003) Neuroscience. Microglia: the enemy within? Science 302:1689–1690

    Google Scholar 

  • Kettenmann H, Kirchhoff F, Verkhratsky A (2013) Microglia: new roles for the synaptic stripper. Neuron 77:10–18

    Article  CAS  PubMed  Google Scholar 

  • Khan M, Sekhon B, Giri S, Jatana M, Gilg AG, Ayasolla K et al (2005) S-Nitrosoglutathione reduces inflammation and protects brain against focal cerebral ischemia in a rat model of experimental stroke. J Cereb Blood Flow Metab 25:177–192

    Article  CAS  PubMed  Google Scholar 

  • Kigerl KA, Gensel JC, Ankeny DP, Alexander JK, Donnelly DJ, Popovich PG (2009) Identification of two distinct macrophage subsets with divergent effects causing either neurotoxicity or regeneration in the injured mouse spinal cord. J Neurosci 29:13435–13444

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Kinouchi H, Sharp FR, Hill MP, Koistinaho J, Sagar SM, Chan PH (1993) Induction of 70-kDa heat shock protein and hsp70 mRNA following transient focal cerebral ischemia in the rat. J Cereb Blood Flow Metab 13:105–115

    Article  CAS  PubMed  Google Scholar 

  • Kobayashi K, Imagama S, Ohgomori T, Hirano K, Uchimura K, Sakamoto K et al (2013) Minocycline selectively inhibits M1 polarization of microglia. Cell Death Dis 4:e525

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Krams M, Lees KR, Hacke W, Grieve AP, Orgogozo JM, Ford GA et al (2003) Acute Stroke Therapy by Inhibition of Neutrophils (ASTIN): an adaptive dose-response study of UK-279,276 in acute ischemic stroke. Stroke 34:2543–2548

    Article  CAS  PubMed  Google Scholar 

  • Lambertsen KL, Clausen BH, Babcock AA, Gregersen R, Fenger C, Nielsen HH et al (2009) Microglia protect neurons against ischemia by synthesis of tumor necrosis factor. J Neurosci 29:1319–1330

    Article  CAS  PubMed  Google Scholar 

  • Lampl Y, Boaz M, Gilad R, Lorberboym M, Dabby R, Rapoport A et al (2007) Minocycline treatment in acute stroke: an open-label, evaluator-blinded study. Neurology 69:1404–1410

    Article  CAS  PubMed  Google Scholar 

  • Laplante M, Sabatini DM (2009) mTOR signaling at a glance. J Cell Sci 122:3589–3594

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Lehnardt S, Schott E, Trimbuch T, Laubisch D, Krueger C, Wulczyn G et al (2008) A vicious cycle involving release of heat shock protein 60 from injured cells and activation of toll-like receptor 4 mediates neurodegeneration in the CNS. J Neurosci 28:2320–2331

    Article  CAS  PubMed  Google Scholar 

  • Liu H, Xin L, Chan BP, Teoh R, Tang BL, Tan YH (2002) Interferon-beta administration confers a beneficial outcome in a rabbit model of thromboembolic cerebral ischemia. Neurosci Lett 327:146–148

    Article  CAS  PubMed  Google Scholar 

  • Liu Z, Fan Y, Won SJ, Neumann M, Hu D, Zhou L et al (2007) Chronic treatment with minocycline preserves adult new neurons and reduces functional impairment after focal cerebral ischemia. Stroke 38:146–152

    Article  CAS  PubMed  Google Scholar 

  • Maddahi A, Edvinsson L (2008) Enhanced expressions of microvascular smooth muscle receptors after focal cerebral ischemia occur via the MAPK MEK/ERK pathway. BMC Neurosci 9:85

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Magnus T, Chan A, Grauer O, Toyka KV, Gold R (2001) Microglial phagocytosis of apoptotic inflammatory T cells leads to down-regulation of microglial immune activation. J Immunol 167:5004–5010

    Article  CAS  PubMed  Google Scholar 

  • Marín-Teva JL, Dusart I, Colin C, Gervais A, van Rooijen N, Mallat M (2004) Microglia promote the death of developing Purkinje cells. Neuron 41:535–547

    Article  PubMed  Google Scholar 

  • Matsukawa N, Yasuhara T, Hara K, Xu L, Maki M, Yu G et al (2009) Therapeutic targets and limits of minocycline neuroprotection in experimental ischemic stroke. BMC Neurosci 10:126

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Mergenthaler P, Meisel A (2012) Do stroke models model stroke? Dis Model Mech 5:718–725

    Article  PubMed  PubMed Central  Google Scholar 

  • Minnerup J, Sutherland BA, Buchan AM, Kleinschnitz C (2012) Neuroprotection for stroke: current status and future perspectives. Int J Mol Sci 13:11753–11772

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Monje ML, Toda H, Palmer TD (2003) Inflammatory blockade restores adult hippocampal neurogenesis. Science 302:1760–1765

    Article  CAS  PubMed  Google Scholar 

  • Napetschnig J, Wu H (2013) Molecular basis of NF-κB signaling. Annu Rev Biophys 42:443–468

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Nechipurenko NI, Kotova SG, Shal’kevich VB, Vlasiuk PA, Griboedova TV (2001) Experimental basis and clinical evaluation of indomethacin efficacy in patients with ischemic stroke. Zh Nevrol Psikhiatr Im S S Korsakova 56–61

    Google Scholar 

  • Nimmerjahn A, Kirchhoff F, Helmchen F (2005) Resting microglial cells are highly dynamic surveillants of brain parenchyma in vivo. Science 308:1314–1318

    Article  CAS  PubMed  Google Scholar 

  • Olsen J, Christensen K, Murray J, Ekbom A (2010) An introduction to epidemiology for health professionals, edn 1. Springer Science and Business Media, New York

    Google Scholar 

  • Pál G, Vincze C, Renner É, Wappler EA, Nagy Z, Lovas G et al (2012) Time course, distribution and cell types of induction of transforming growth factor betas following middle cerebral artery occlusion in the rat brain. PLoS ONE 7:e46731

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Penninger JM, Irie-Sasaki J, Sasaki T, Oliveira-dos-Santos AJ (2001) CD45: new jobs for an old acquaintance. Nat Immunol 2:389–396

    CAS  PubMed  Google Scholar 

  • Peri F, Nüsslein-Volhard C (2008) Live imaging of neuronal degradation by microglia reveals a role for v0-ATPase a1 in phagosomal fusion in vivo. Cell 133:916–927

    Article  CAS  PubMed  Google Scholar 

  • Ponomarev ED, Veremeyko T, Weiner HL (2013) MicroRNAs are universal regulators of differentiation, activation, and polarization of microglia and macrophages in normal and diseased CNS. Glia 61:91–103

    Article  PubMed  Google Scholar 

  • Prasad K, Sharma A, Garg A, Mohanty S, Bhatnagar S, Johri S et al (2014) Intravenous autologous bone marrow mononuclear stem cell therapy for ischemic stroke: a multicentric, randomized trial. Stroke 45:3618–3624

    Article  CAS  PubMed  Google Scholar 

  • Qiu J, Nishimura M, Wang Y, Sims JR, Qiu S, Savitz SI et al (2008) Early release of HMGB-1 from neurons after the onset of brain ischemia. J Cereb Blood Flow Metab 28:927–938

    Article  CAS  PubMed  Google Scholar 

  • Ribes S, Ebert S, Czesnik D, Regen T, Zeug A, Bukowski S et al (2009) Toll-like receptor prestimulation increases phagocytosis of Escherichia coli DH5alpha and Escherichia coli K1 strains by murine microglial cells. Infect Immun 77:557–564

    Article  CAS  PubMed  Google Scholar 

  • Ribes S, Ebert S, Regen T, Agarwal A, Tauber SC, Czesnik D et al (2010) Toll-like receptor stimulation enhances phagocytosis and intracellular killing of nonencapsulated and encapsulated Streptococcus pneumoniae by murine microglia. Infect Immun 78:865–871

    Article  CAS  PubMed  Google Scholar 

  • Ridder DA, Schwaninger M (2009) NF-kappaB signaling in cerebral ischemia. Neuroscience 158:995–1006

    Article  CAS  PubMed  Google Scholar 

  • Salmi M, Jalkanen S (2001) VAP-1: an adhesin and an enzyme. Trends Immunol 22:211–216

    Article  CAS  PubMed  Google Scholar 

  • Sawe N, Steinberg G, Zhao H (2008) Dual roles of the MAPK/ERK1/2 cell signaling pathway after stroke. J Neurosci Res 86:1659–1669

    Article  CAS  PubMed  Google Scholar 

  • Schneider A, Martin-Villalba A, Weih F, Vogel J, Wirth T, Schwaninger M (1999) NF-kappaB is activated and promotes cell death in focal cerebral ischemia. Nat Med 5:554–559

    Article  CAS  PubMed  Google Scholar 

  • Sharma S, Yang B, Strong R, Xi X, Brenneman M, Grotta JC et al (2010) Bone marrow mononuclear cells protect neurons and modulate microglia in cell culture models of ischemic stroke. J Neurosci Res 88:2869–2876

    CAS  PubMed  PubMed Central  Google Scholar 

  • Shichita T, Ago T, Kamouchi M, Kitazono T, Yoshimura A, Ooboshi H (2012a) Novel therapeutic strategies targeting innate immune responses and early inflammation after stroke. J Neurochem 123(Suppl 2):29–38

    Article  CAS  PubMed  Google Scholar 

  • Shichita T, Hasegawa E, Kimura A, Morita R, Sakaguchi R, Takada I et al (2012b) Peroxiredoxin family proteins are key initiators of post-ischemic inflammation in the brain. Nat Med 18:911–917

    Article  CAS  PubMed  Google Scholar 

  • Shin WH, Lee DY, Park KW, Kim SU, Yang MS, Joe EH et al (2004) Microglia expressing interleukin-13 undergo cell death and contribute to neuronal survival in vivo. Glia 46:142–152

    Article  PubMed  Google Scholar 

  • Sughrue ME, Mehra A, Connolly ES, D’Ambrosio AL (2004) Anti-adhesion molecule strategies as potential neuroprotective agents in cerebral ischemia: a critical review of the literature. Inflamm Res 53:497–508

    Article  CAS  PubMed  Google Scholar 

  • Thomson AW, Turnquist HR, Raimondi G (2009) Immunoregulatory functions of mTOR inhibition. Nat Rev Immunol 9:324–337

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Tobin MK, Bonds JA, Minshall RD, Pelligrino DA, Testai FD, Lazarov O (2014) Neurogenesis and inflammation after ischemic stroke: what is known and where we go from here. J Cereb Blood Flow Metab 34:1573–1584

    Article  PubMed  PubMed Central  Google Scholar 

  • Trapp BD, Wujek JR, Criste GA, Jalabi W, Yin X, Kidd GJ et al (2007) Evidence for synaptic stripping by cortical microglia. Glia 55:360–368

    Article  PubMed  Google Scholar 

  • Unzeta M, Solé M, Boada M, Hernández M (2007) Semicarbazide-sensitive amine oxidase (SSAO) and its possible contribution to vascular damage in Alzheimer’s disease. J Neural Transm 114:857–862

    Article  CAS  PubMed  Google Scholar 

  • Varnum MM, Ikezu T (2012) The classification of microglial activation phenotypes on neurodegeneration and regeneration in Alzheimer’s disease brain. Arch Immunol Ther Exp (Warsz) 60:251–266

    Article  CAS  Google Scholar 

  • Veldhuis WB, Derksen JW, Floris S, Van Der Meide PH, De Vries HE, Schepers J et al (2003) Interferon-beta blocks infiltration of inflammatory cells and reduces infarct volume after ischemic stroke in the rat. J Cereb Blood Flow Metab 23:1029–1039

    Article  CAS  PubMed  Google Scholar 

  • Wake H, Moorhouse AJ, Jinno S, Kohsaka S, Nabekura J (2009) Resting microglia directly monitor the functional state of synapses in vivo and determine the fate of ischemic terminals. J Neurosci 29:3974–3980

    Article  CAS  PubMed  Google Scholar 

  • Wang H, Xu L, Venkatachalam S, Trzaskos JM, Friedman SM, Feuerstein GZ et al (2001) Differential regulation of IL-1beta and TNF-alpha RNA expression by MEK1 inhibitor after focal cerebral ischemia in mice. Biochem Biophys Res Commun 286:869–874

    Article  CAS  PubMed  Google Scholar 

  • Wang X, Wang H, Xu L, Rozanski DJ, Sugawara T, Chan PH et al (2003) Significant neuroprotection against ischemic brain injury by inhibition of the MEK1 protein kinase in mice: exploration of potential mechanism associated with apoptosis. J Pharmacol Exp Ther 304:172–178

    Article  CAS  PubMed  Google Scholar 

  • Wang RM, Zhang QG, Li J, Yang LC, Yang F, Brann DW (2009) The ERK5-MEF2C transcription factor pathway contributes to anti-apoptotic effect of cerebral ischemia preconditioning in the hippocampal CA1 region of rats. Brain Res 1255:32–41

    Article  CAS  PubMed  Google Scholar 

  • Wang Y, Zhang Z, Chow N, Davis TP, Griffin JH, Chopp M et al (2012a) An activated protein C analog with reduced anticoagulant activity extends the therapeutic window of tissue plasminogen activator for ischemic stroke in rodents. Stroke 43:2444–2449

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Wang LW, Tu YF, Huang CC, Ho CJ (2012b) JNK signaling is the shared pathway linking neuroinflammation, blood-brain barrier disruption, and oligodendroglial apoptosis in the white matter injury of the immature brain. J Neuroinflammation 9:175

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Wechsler LR, Jovin TG (2012) Intravenous recombinant tissue-type plasminogen activator in the extended time window and the US food and drug administration: confused about the time. Stroke 43:2517–2519

    Article  PubMed  Google Scholar 

  • Weng YC, Kriz J (2007) Differential neuroprotective effects of a minocycline-based drug cocktail in transient and permanent focal cerebral ischemia. Exp Neurol 204:433–442

    Article  CAS  PubMed  Google Scholar 

  • Wiederrecht GJ, Sabers CJ, Brunn GJ, Martin MM, Dumont FJ, Abraham RT (1995) Mechanism of action of rapamycin: new insights into the regulation of G1-phase progression in eukaryotic cells. Prog Cell Cycle Res 1:53–71

    Article  CAS  PubMed  Google Scholar 

  • Xia Z, Dickens M, Raingeaud J, Davis RJ, Greenberg ME (1995) Opposing effects of ERK and JNK-p38 MAP kinases on apoptosis. Science 270:1326–1331

    Article  CAS  PubMed  Google Scholar 

  • Xie L, Sun F, Wang J, Mao X, Yang SH, Su DM et al (2014) mTOR signaling inhibition modulates macrophage/microglia-mediated neuroinflammation and secondary injury via regulatory T cells after focal ischemia. J Immunol 192:6009–6019

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Yamashita T, Ninomiya M, Hernández Acosta P, García-Verdugo JM, Sunabori T, Sakaguchi M et al (2006) Subventricular zone-derived neuroblasts migrate and differentiate into mature neurons in the post-stroke adult striatum. J Neurosci 26:6627–6636

    Article  CAS  PubMed  Google Scholar 

  • Yang QW, Lu FL, Zhou Y, Wang L, Zhong Q, Lin S et al (2011) HMBG1 mediates ischemia-reperfusion injury by TRIF-adaptor independent Toll-like receptor 4 signaling. J Cereb Blood Flow Metab 31:593–605

    Article  CAS  PubMed  Google Scholar 

  • Yenari MA, Kauppinen TM, Swanson RA (2010) Microglial activation in stroke: therapeutic targets. Neurotherapeutics 7:378–391

    Article  CAS  PubMed  Google Scholar 

  • Yokoyama A, Yang L, Itoh S, Mori K, Tanaka J (2004) Microglia, a potential source of neurons, astrocytes, and oligodendrocytes. Glia 45:96–104

    Article  PubMed  Google Scholar 

  • Yokoyama A, Sakamoto A, Kameda K, Imai Y, Tanaka J (2006) NG2 proteoglycan-expressing microglia as multipotent neural progenitors in normal and pathologic brains. Glia 53:754–768

    Article  PubMed  Google Scholar 

  • Zaremba J, Losy J (2001) Early TNF-alpha levels correlate with ischaemic stroke severity. Acta Neurol Scand 104:288–295

    Article  CAS  PubMed  Google Scholar 

  • Zhang J, Takahashi HK, Liu K, Wake H, Liu R, Maruo T et al (2011) Anti-high mobility group box-1 monoclonal antibody protects the blood-brain barrier from ischemia-induced disruption in rats. Stroke 42:1420–1428

    Article  CAS  PubMed  Google Scholar 

  • Zhou X, Spittau B, Krieglstein K (2012) TGFβ signalling plays an important role in IL4-induced alternative activation of microglia. J Neuroinflammation 9:210

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Ziegler G, Harhausen D, Schepers C, Hoffmann O, Röhr C, Prinz V et al (2007) TLR2 has a detrimental role in mouse transient focal cerebral ischemia. Biochem Biophys Res Commun 359:574–579

    Article  CAS  PubMed  Google Scholar 

Download references

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  1. National Brain Research Centre, Deemed University, Manesar, Gurgaon, 122051, Haryana, India

    Mohammed Aftab Alam, V. P. Subramanyam Rallabandi & Prasun Kumar Roy

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  1. Mohammed Aftab Alam
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  2. V. P. Subramanyam Rallabandi
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  3. Prasun Kumar Roy
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Correspondence to Prasun Kumar Roy .

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  1. Molecular and Cellular Neuroscience, National Brain Research Centre, Gurgaon, Delhi, India

    Nihar Jana

  2. Molecular and Cellular Neuroscience, National Brain Research Centre, Gurgaon, Delhi, India

    Anirban Basu

  3. National Brain Research Centre, National Research Professor, National Brain Research Centre, Gurgaon, Delhi, India

    Prakash Narain Tandon

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© 2016 Springer Science+Business Media Singapore

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Alam, M.A., Subramanyam Rallabandi, V.P., Roy, P.K. (2016). Neuroinflammation in Ischaemic Stroke: Utilizing the Biphasic Niche of Neuroprotection and Neurotoxicity for Clinic. In: Jana, N., Basu, A., Tandon, P. (eds) Inflammation: the Common Link in Brain Pathologies. Springer, Singapore. https://doi.org/10.1007/978-981-10-1711-7_9

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