Abstract
We have studied the involvement of the thrombin receptor [protease-activated receptor-1 (PAR-1)] in astrogliosis, because extravasation of PAR-1 activators, such as thrombin, into brain parenchyma can occur after blood-brain barrier breakdown in a number of CNS disorders. PAR1-/- animals show a reduced astrocytic response to cortical stab wound, suggesting that PAR-1 activation plays a key role in astrogliosis associated with glial scar formation after brain injury. This interpretation is supported by the finding that the selective activation of PAR-1 in vivo induces astrogliosis. The mechanisms by which PAR-1 stimulates glial proliferation appear to be related to the ability of PAR-1 receptor signaling to induce sustained extracellular receptor kinase (ERK) activation. In contrast to the transient activation of ERK by cytokines and growth factors, PAR-1 stimulation induces a sustained ERK activation through its coupling to multiple G-protein-linked signaling pathways, including Rho kinase. This sustained ERK activation appears to regulate astrocytic cyclin D1 levels and astrocyte proliferation in vitro and in vivo. We propose that this PAR-1-mediated mechanism underlying astrocyte proliferation will operate whenever there is sufficient injury-induced blood-brain barrier breakdown to allow extravasation of PAR-1 activators.
Publication types
-
Comparative Study
-
Research Support, Non-U.S. Gov't
-
Research Support, U.S. Gov't, P.H.S.
MeSH terms
-
Amides / pharmacology
-
Analysis of Variance
-
Animals
-
Animals, Newborn
-
Astrocytes / pathology*
-
Blotting, Northern / methods
-
Blotting, Western / methods
-
Brain Injuries / pathology*
-
Brain Injuries / physiopathology
-
Bromodeoxyuridine / metabolism
-
Butadienes / pharmacology
-
Cell Count / methods
-
Cell Movement / physiology
-
Cell Proliferation
-
Cells, Cultured
-
Coculture Techniques / methods
-
Colforsin / pharmacology
-
Cyclin D1 / metabolism
-
Disease Models, Animal
-
Drug Interactions
-
Enzyme Inhibitors / pharmacology
-
Functional Laterality
-
Glial Fibrillary Acidic Protein / metabolism
-
Gliosis / etiology*
-
Immunohistochemistry / methods
-
MAP Kinase Kinase Kinases / metabolism
-
Male
-
Mice
-
Mice, Knockout
-
Microglia / pathology
-
Nitriles / pharmacology
-
Oligopeptides / pharmacology
-
Pyridines / pharmacology
-
RNA, Messenger / biosynthesis
-
Receptor, PAR-1 / deficiency
-
Receptor, PAR-1 / metabolism*
-
Reverse Transcriptase Polymerase Chain Reaction / methods
-
Thrombin / pharmacology
-
Time Factors
Substances
-
Amides
-
Butadienes
-
Enzyme Inhibitors
-
Glial Fibrillary Acidic Protein
-
Nitriles
-
Oligopeptides
-
PAR-1-activating peptide
-
Pyridines
-
RNA, Messenger
-
Receptor, PAR-1
-
U 0126
-
Cyclin D1
-
Y 27632
-
Colforsin
-
MAP Kinase Kinase Kinases
-
Thrombin
-
Bromodeoxyuridine