Protective role of reactive astrocytes in brain ischemia.

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.

• 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
• Journal: Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism (J Cereb Blood Flow Metab) Vol. 28 Issue 3 Pg. 468-81 (Mar 2008) ISSN: 0271-678X [Print] United States
• PMID: 17726492 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Glial Fibrillary Acidic Protein
• Plasminogen Activator Inhibitor 1
• Receptor, Endothelin B
• Vimentin
• Glutamic Acid

Topics

• 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)