Activation of protease-activated receptor-1 triggers astrogliosis after brain injury.

TitleActivation of protease-activated receptor-1 triggers astrogliosis after brain injury.
Publication TypeJournal Article
Year of Publication2005
AuthorsNicole O, Goldshmidt A, Hamill CE, Sorensen SD, Sastre A, Lyuboslavsky P, Hepler JR, McKeon RJ, Traynelis SF
JournalJ Neurosci
Date Published2005 Apr 27
KeywordsAmides, Analysis of Variance, Animals, Animals, Newborn, Astrocytes, Blotting, Northern, Blotting, Western, Brain Injuries, Bromodeoxyuridine, Butadienes, Cell Count, Cell Movement, Cell Proliferation, Cells, Cultured, Coculture Techniques, Colforsin, Cyclin D1, Disease Models, Animal, Drug Interactions, Enzyme Inhibitors, Functional Laterality, Glial Fibrillary Acidic Protein, Gliosis, Immunohistochemistry, Male, MAP Kinase Kinase Kinases, Mice, Mice, Knockout, Microglia, Nitriles, Oligopeptides, Pyridines, Receptor, PAR-1, Reverse Transcriptase Polymerase Chain Reaction, RNA, Messenger, Thrombin, Time Factors

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.

Alternate JournalJ. Neurosci.
PubMed ID15858058
Grant ListT32 GM008169 / GM / NIGMS NIH HHS / United States