Neuroinflammation und Schlaganfall

Zusammenfassung

Der ischämische Schlaganfall ist die häufigste Ursache bleibender neurologischer Behinderung und mit hoher sekundärer Mortalität behaftet. Mit der Thrombolyse steht nur in einem engen Zeitfenster von 3 bis 6 Stunden ein partiell wirksames Theerapieverfahren zur Verfügung. Demgegenüber ist die Infarktentwicklung ein dynamischer Prozess, der über mehrere Tage noch zu einer Zunahme der Läsionsgröße führt und in einer Defektheilung mit variablem neurologischen Defizit resultiert. Lokale Entzündungsprozesse sind ein integraler Bestandteil der Läsionspathogenese. Innerhalb weniger Stunden werden residente Hirnmakrophagen (Mikroglia) aktiviert, während die Rekrutierung hämatogener Makrophagen verzögert erfolgt. Entzündungsmediatoren können zur Ausdehnung des Infarktschadens beitragen und die zelluläre Regeneration inhibieren, vermitteln aber auch Neuroprotektion und sind an der Läsionsreparatur beteiligt. Neue zellspezifische Kontrastmittel für die Kernspintomographie ermöglichen die nichtinvasive Detektion von Neuroinflammation beim Hirninfarkt. Hiervon erhoffen wir uns Ansatzpunkte für die gezielte immunologische Therapie des ischämischen Schlaganfalls.

Summary

Stroke due to focal brain ischemia is the leading cause of persistent neurological disability in modern western societies. Current thrombolysis therapy is only effective within a narrow time window of 3 to 6 hours. Substantial evidence however indicates that the evolution of ischemic brain damage is a dynamic process extending well into subacute stages of days to weeks after the insult. Lesion-associated inflammation is an integral part of the cellular pathobiology of brain infarction. Within hours after ischemia resident brain macrophages/microglia are activated and produce a wide range of potentially harmful mediators. During later stages, activated monocytes and macrophages migrate from the blood stream into infarcted brain tissue. Brain inflammation may cause secondary infarct growth and inhibit the regenerative capacity of injured brain tissue, but can also mediate neuroprotection and lesion repair. Inflammatory cell recruitment can now be monitored using iron oxide nanoparticles as cell-specific contrast agents for magnetic resonance imaging. These new imaging techniques will contribute to the development of therapies targeting neuroinflammation in ischemic stroke.

Schlüsselwörter

Schlaganfall - zerebrale Ischämie - Entzündung - Kernspintomographie

Keywords

Stroke - cerebral ischemia - inflammation - magnetic resonance imaging

• Literatur

• 1 Allan SM, Rothwell N. Cytokines and acute neurodegeneration. Nat Rev Neurosci 2001; 2: 734-44.
• 2 Arvidsson A, Collin T, Kirik D, Kokaia Z, Lindvall O. Neuronal replacement from endogenous precursors in the adult brain after stroke. Nat Med 2002; 8: 963-70.
• 3 Arvin B, Neville LF, Barone FC, Feuerstein GZ. The role of inflammation and cytokines in brain injury. Neurosci Biobehav Rev 1996; 20: 445-52.
• 4 Banati RB, Newcombe J, Gunn RN, Cagnin A, Turkheimer F, Heppner F, Price G, Wegner F, Giovannoni G, Miller DH, Perkin GD, Smith T, Hewson AK, Bydder G, Kreutzberg GW, Jones T, Cuzner ML, Myers R. The peripheral benzodiazepine binding site in the brain in multiple sclerosis: quantitative in vivo imaging of microglia as a measure of disease activity. Brain 2000; 123: 2321-37.
• 5 Barone FC, Arvin B, White RF, Miller A, Webb CL, Willette RN, Lysko PG, Feuerstein GZ. Tumor necrosis factor-α: a mediator of focal ischemic brain injury. Stroke 1997; 28: 1233-44.
• 6 Becker KJ, McCarron RM, Ruetzler C, Laban O, Sternberg E, Flanders KC, Hallenbeck JM. Immunologic tolerance to myelin basic protein decreases stroke size after transient focal cerebral ischemia. Proc Natl Acad Sci U S A 1997; 94: 10873-8.
• 7 Bruce AJ, Boling W, Kindy MS, Peschon J, Kraemer PJ, Carpenter MK, Holtsberg FW, Mattson MP. Altered neuronal and microglial responses to excitotoxic and ischemic brain injury in mice lacking TNF receptors. Nat Med 1996; 2: 788-94.
• 8 Cheng B, Christakos S, Mattson MP. Tumor necrosis factors protect neurons against metabolic-excitotoxic insults and promote maintenance of calcium homeostasis. Neuron 1994; 12: 139-53.
• 9 del Zoppo G, Ginis I, Hallenbeck JM, Iadecola C, Wang X, Feuerstein GZ. Inflammation and stroke: putative role for cytokines, adhesion molecules and iNOS in brain response to ischemia. Brain Pathol 2000; 10: 95-112.
• 10 Dirnagl U. Inflammation in stroke: the good, the bad, and the unknown. Ernst Schering Res Found Workshop 2004; 47: 87-99.
• 11 Doerfler A, Engelhorn T, Heiland S, Knauth M, Wanke I, Forsting M. MR contrast agents in acute experimental cerebral ischemia: potential adverse impacts on neurologic outcome and infarction size. J Magn Reson Imaging 2000; 11: 418-24.
• 12 Ekdahl CT, Claasen JH, Bonde S, Kokaia Z, Lindvall O. Inflammation is detrimental for neurogenesis in adult brain. Proc Natl Acad Sci U S A 2003; 100: 13632-7.
• 13 Frenkel D, Huang Z, Maron R, Koldzic DN, Hancock WW, Moskowitz MA, Weiner HL. Nasal vaccination with myelin oligodendrocyte glycoprotein reduces stroke size by inducing IL-10-producing CD4+ T cells. J Immunol 2003; 171: 6549-55.
• 14 Garcia JH, Liu KF, Yoshida Y, Lian J, Chen S, Del Zoppo GJ. Influx of leucocytes and platelets in an evolving brain infarct (Wistar rat). Am J Pathol 1994; 144: 188-99.
• 15 Hallenbeck JM. The many faces of tumor necrosis factor in stroke. Nat Med 2002; 8: 1363-8.
• 16 Hewett SJ, Csernansky CA, Choi DW. Selective potentiation of NMDA-induced neuronal injury following induction of astrocytic iNOS. Neuron 1994; 13: 487-94.
• 17 Iadecola C, Zhang F, Casey R, Nagayama M, Ross ME. Delayed reduction of ischemic brain injury and neurological deficits in mice lacking the inducible nitric oxide synthase gene. J Neurosci 1997; 17: 9157-64.
• 18 Jander S, Kraemer M, Schroeter M, Witte OW, Stoll G. Lymphocytic infiltration and expression of intercellular adhesion molecule-1 in photochemically induced ischemia of the rat cortex. J Cereb Blood Flow Metab 1995; 15: 42-51.
• 19 Jander S, Schroeter M, Peters O, Witte OW, Stoll G. Cortical spreading depression induces proinflammatory cytokine gene expression in the rat brain. J Cereb Blood Flow Metab 2001; 21: 218-25.
• 20 Jander S, Schroeter M, Stoll G. Role of NMDA receptor signaling in the regulation of inflammatory gene expression after focal brain ischemia. J Neuroimmunol 2000; 109: 181-7.
• 21 Jander S, Schroeter M, Stoll G. Interleukin-18 expression after focal ischemia of the rat brain: association with the late-stage inflammatory response. J Cereb Blood Flow Metab 2002; 22: 62-70.
• 22 Kempermann G, Neumann H. Microglia: the enemy within. Science 2003; 302: 1689-90.
• 23 Kleinschnitz C, Bendszus M, Frank M, Solymosi L, Toyka KV, Stoll G. In vivo monitoring of macrophage infiltration in experimental ischemic brain lesions by magnetic resonance imaging. J Cereb Blood Flow Metab 2003; 23: 1356-61.
• 24 Kury P, Schroeter M, Jander S. Transcriptional response to circumscribed cortical brain ischemia: spatiotemporal patterns in ischemic vs. remote non-ischemic cortex. Eur J Neurosci 2004; 19: 1708-20.
• 25 Lambertsen KL, Gregersen R, Finsen B. Microglial-macrophage synthesis of tumor necrosis factor after focal cerebral ischemia in mice is strain dependent. J Cereb Blood Flow Metab 2002; 22: 785-97.
• 26 Lindsberg PJ, Carpén O, Paetau A, Karjalainen-Lindsberg M-L, Kaste M. Endothelial ICAM-1 expression associated with inflammatory cell reponse in human ischemic stroke. Circulation 1996; 94: 939-45.
• 27 Liu J, Ginis I, Spatz M, Hallenbeck JM. Hypoxic preconditioning protects cultured neurons against hypoxic stress via TNF-alpha and ceramide. Am J Physiol Cell Physiol 2000; 278: C144-C153.
• 28 Monje ML, Toda H, Palmer TD. Inflammatory Blockade Restores Adult Hippocampal Neurogenesis. Science 2003; 302: 1760-5.
• 29 Nakatomi H, Kuriu T, Okabe S, Yamamoto S, Hatano O, Kawahara N, Tamura A, Kirino T, Nakafuku M. Regeneration of hippocampal pyramidal neurons after ischemic brain injury by recruitment of endogenous neural progenitors. Cell 2002; 110: 429-41.
• 30 Neumann H, Wekerle H. Neuronal control of the immune response in the central nervous system: linking brain immunity to neurodegeneration. J Neuropathol Exp Neurol 1998; 57: 1-9.
• 31 Pappata S, Levasseur M, Gunn RN, Myers R, Crouzel C, Syrota A, Jones T, Kreutzberg GW, Banati RB. Thalamic microglial activation in ischemic stroke detected in vivo by PET and [11C]PK11195. Neurology 2000; 55: 1052-4.
• 32 Priller J, Flugel A, Wehner T, Boentert M, Haas CA, Prinz M, Fernandez-Klett F, Prass K, Bechmann I, de Boer BA, Frotscher M, Kreutzberg GW, Persons DA, Dirnagl U. Targeting genemodified hematopoietic cells to the central nervous system: use of green fluorescent protein uncovers microglial engraftment. Nat Med 2001; 7: 1356-61.
• 33 Rausch M, Sauter A, Frohlich J, Neubacher U, Radu EW, Rudin M. Dynamic patterns of USPIO enhancement can be observed in macrophages after ischemic brain damage. Magn Reson Med 2001; 46: 1018-22.
• 34 Reichmann G, Schroeter M, Jander S, Fischer HG. Dendritic cells and dendritic-like microglia in focal cortical ischemia of the mouse brain. J Neuroimmunol 2002; 129: 125-32.
• 35 Relton JK, Rothwell NJ. Interleukin-1 receptor antagonist inhibits ischaemic and excitotoxic neuronal damage in the rat. Brain Res Bull 1992; 29: 243-6.
• 36 Saleh A, Schroeter M, Jonkmanns C, Hartung HP, Mödder U, Jander S. In vivo MRI of brain inflammation in human ischaemic stroke. Brain 2004; 127: 1670-7.
• 37 Saleh A, Wiedermann D, Schroeter M, Jonkmanns C, Jander S, Hoehn M. Central nervous system inflammatory response after cerebral infarction as detected by magnetic resonance imaging. NMR Biomed 2004; 17: 163-9.
• 38 Schilling M, Besselmann M, Leonhard C, Mueller M, Ringelstein EB, Kiefer R. Microglial activation precedes and predominates over macrophage infiltration in transient focal cerebral ischemia: a study in green fluorescent protein transgenic bone marrow chimeric mice. Exp Neurol 2003; 183: 25-33.
• 39 Schroeter M, Franke C, Stoll G, Hoehn M. Dynamic changes of magnetic resonance imaging abnormalities in relation to inflammation and glial responses after photothrombotic cerebral infarction in the rat brain. Acta Neuropathol (Berl) 2001; 101: 114-22.
• 40 Schroeter M, Jander S, Huitinga I, Witte OW, Stoll G. Phagocytic response in photochemically induced infarction of the rat cerebral cortex: the role of resident microglia. Stroke 1997; 28: 382-6.
• 41 Schroeter M, Saleh A, Wiedermann D, Hoehn M, Jander S. Histochemical detection of ultrasmall superparamagnetic iron oxide (USPIO) contrast medium uptake in experimental brain ischemia. Magn Reson Med 2004; 52: 403-6.
• 42 Stoll G, Jander S, Schroeter M. Inflammation and glial responses in ischemic brain lesions. Prog Neurobiol 1998; 56: 149-71.
• 43 Strijbos PJ, Rothwell NJ. Interleukin-1 beta attenuates excitatory amino acid-induced neurodegeneration in vitro: involvement of nerve growth factor. J Neurosci 1995; 15: 3468-74.
• 44 Tanaka R, Komine-Kobayashi M, Mochizuki H, Yamada M, Furuya T, Migita M, Shimada T, Mizuno Y, Urabe T. Migration of enhanced green fluorescent protein expressing bone marrow-derived microglia/macrophage into the mouse brain following permanent focal ischemia. Neuroscience 2003; 117: 531-9.
• 45 Wang X, Li X, Erhardt JA, Barone FC, Feuerstein GZ. Detection of tumor necrosis factoralpha mRNA induction in ischemic brain tolerance by means of real-time polymerase chain reaction. J Cereb Blood Flow Metab 2000; 20: 15-20.
• 46 Wang X, Yue TL, Barone FC, White RF, Gagnon RC, Feuerstein GZ. Concomitant expression of TNF-α and IL-1β mRNAs follows early response gene expression in transient focal ischemia. Mol Chem Neuropathol 1994; 23: 103-14.
• 47 Wang X, Yue TL, White RF, Barone FC, Feuerstein GZ. Transforming growth factor-beta 1 exhibits delayed gene expression following focal cerebral ischemia. Brain Res Bull 1995; 36: 607-9.
• 48 Wang YX, Hussain SM, Krestin GP. Superparamagnetic iron oxide contrast agents: physicochemical characteristics and applications in MR imaging. Eur Radiol 2001; 11: 2319-31.
• 49 Weissleder R, Elizondo G, Wittenberg J, Rabito CA, Bengele HH, Josephson L. Ultrasmall superparamagnetic iron oxide: characterization of a new class of contrast agents for MR imaging. Radiology 1990; 175: 489-93.
• 50 Yrjanheikki J, Tikka T, Keinanen R, Goldsteins G, Chan PH, Koistinaho J. A tetracycline derivative, minocycline, reduces inflammation and protects against focal cerebral ischemia with a wide therapeutic window. Proc Natl Acad Sci U S A 1999; 96: 13496-500.
• 51 Zhang RL, Chopp M, Jiang N, Tang WX, Prostak J, Manning AM, Anderson DC. Antiintercellular adhesion molecule-1 reduces ischemic cell damage after transient but not permanent middle cerebral artery occlusion in the Wistar rat. Stroke 1995; 26: 1438-43.