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- Title
Activation of Protease-Activated Receptor-1 Triggers Astrogliosis after Brain Injury.
- Authors
Nicole, Olivier; Goldshmidt, Anna; Hamill, Cecily E.; Sorensen, Scott D.; Sastre, Aristide; Lyuboslavsky, Polina; Hepler, John R.; McKeon, Robert J.; Traynelis, Stephen F.
- 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.
- Subjects
PROTEOLYTIC enzymes; BRAIN injuries; THROMBIN; GROWTH factors; ASTROCYTES; CYTOKINES
- Publication
Journal of Neuroscience, 2005, Vol 25, Issue 17, p4319
- ISSN
0270-6474
- Publication type
Article
- DOI
10.1523/JNEUROSCI.5200-04.2005