Protective role of reactive astrocytes in brain ischemia.
Artikel i vetenskaplig tidskrift, 2008

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.

Glutamic Acid

Knockout

Astrocytes

Glial Fibrillary Acidic Protein

Endothelin B

genetics

physiology

deficiency

Animals

analysis

pathology

Mice

Receptor

Plasminogen Activator Inhibitor 1

deficiency

Vimentin

pathology

Brain Ischemia

Middle Cerebral Artery

metabolism

metabolism

Mice

Gap Junctions

Författare

Lizhen Li

Göteborgs universitet

Andrea Lundkvist

Göteborgs universitet

Daniel Andersson

Göteborgs universitet

Ulrika Wilhelmsson

Göteborgs universitet

Nobuo Nagai

KU Leuven

Andrea C Pardo

The Johns Hopkins School of Medicine

Christina Nodin

Göteborgs universitet

Anders Ståhlberg

Chalmers, Kemi- och bioteknik

Karina Aprico

Göteborgs universitet

Kerstin Larsson

Göteborgs universitet

Takeshi Yabe

National Institute of Neurological Disorders and Stroke

Lieve Moons

KU Leuven

Andrew Fotheringham

University of Manchester School of Medicine

Ioan Davies

University of Manchester School of Medicine

Peter Carmeliet

KU Leuven

Joan P Schwartz

National Institute of Neurological Disorders and Stroke

Marcela Pekna

Göteborgs universitet

Mikael Kubista

Chalmers, Kemi- och bioteknik, Molekylär mikroskopi

Fredrik Blomstrand

Göteborgs universitet

Nicholas Maragakis

The Johns Hopkins School of Medicine

Michael Nilsson

Göteborgs universitet

Milos Pekny

Göteborgs universitet

Journal of Cerebral Blood Flow and Metabolism

0271-678X (ISSN)

Vol. 28 468-81

Ämneskategorier

MEDICIN OCH HÄLSOVETENSKAP

DOI

10.1038/sj.jcbfm.9600546

PubMed

17726492