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Protective role of reactive astrocytes in brain ischemia.

Journal article
Authors Lizhen Li
Andrea Lundkvist
Daniel Andersson
Ulrika Wilhelmsson
Nobuo Nagai
Andrea C Pardo
Christina Nodin
Anders Ståhlberg
Karina Aprico
Kerstin Larsson
Takeshi Yabe
Lieve Moons
Andrew Fotheringham
Ioan Davies
Peter Carmeliet
Joan P Schwartz
Marcela Pekna
Mikael Kubista
Fredrik Blomstrand
Nicholas Maragakis
Michael Nilsson
Milos Pekny
Published in Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism
Volume 28
Issue 3
Pages 468-81
ISSN 0271-678X
Publication year 2008
Published at Institute of Neuroscience and Physiology, Department of Clinical Neuroscience and Rehabilitation
Institute of Biomedicine, Department of Medical Biochemistry and Cell Biology
Pages 468-81
Language en
Links dx.doi.org/10.1038/sj.jcbfm.9600546
Keywords Animals, Astrocytes, pathology, physiology, Brain Ischemia, metabolism, pathology, Gap Junctions, Glial Fibrillary Acidic Protein, deficiency, Glutamic Acid, metabolism, Mice, Mice, Knockout, Middle Cerebral Artery, Plasminogen Activator Inhibitor 1, genetics, Receptor, Endothelin B, analysis, Vimentin, deficiency
Subject categories Medical and Health Sciences

Abstract

Reactive astrocytes are thought to protect the penumbra during brain ischemia, but direct evidence has been lacking due to the absence of suitable experimental models. Previously, we generated mice deficient in two intermediate filament (IF) proteins, glial fibrillary acidic protein (GFAP) and vimentin, whose upregulation is the hallmark of reactive astrocytes. GFAP(-/-)Vim(-/-) mice exhibit attenuated posttraumatic reactive gliosis, improved integration of neural grafts, and posttraumatic regeneration. Seven days after middle cerebral artery (MCA) transection, infarct volume was 210 to 350% higher in GFAP(-/-)Vim(-/-) than in wild-type (WT) mice; GFAP(-/-), Vim(-/-) and WT mice had the same infarct volume. Endothelin B receptor (ET(B)R) immunoreactivity was strong on cultured astrocytes and reactive astrocytes around infarct in WT mice but undetectable in GFAP(-/-)Vim(-/-) astrocytes. In WT astrocytes, ET(B)R colocalized extensively with bundles of IFs. GFAP(-/-)Vim(-/-) astrocytes showed attenuated endothelin-3-induced blockage of gap junctions. Total and glutamate transporter-1 (GLT-1)-mediated glutamate transport was lower in GFAP(-/-)Vim(-/-) than in WT mice. DNA array analysis and quantitative real-time PCR showed downregulation of plasminogen activator inhibitor-1 (PAI-1), an inhibitor of tissue plasminogen activator. Thus, reactive astrocytes have a protective role in brain ischemia, and the absence of astrocyte IFs is linked to changes in glutamate transport, ET(B)R-mediated control of gap junctions, and PAI-1 expression.

Page Manager: Webmaster|Last update: 9/11/2012
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