The contribution of protease-activated receptor 1 to neuronal damage caused by transient focal cerebral ischemia

Candice E. Junge*, Taku Sugawara, Guido Mannaioni, Sudar Alagarsamy, P. Jeffrey Conn, Daniel J. Brat, Pak H. Chan, Stephen F. Traynelis

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

167 Scopus citations

Abstract

The serine proteases tissue plasminogen activator, plasmin, and thrombin and their receptors have previously been suggested to contribute to neuronal damage in certain pathological situations. Here we demonstrate that mice lacking protease-activated receptor 1 (PAR1 ) have a 3.1-fold reduction in infarct volume after transient focal cerebral ischemia. Intracerebroventricular injection of PAR1 antagonist BMS-200261 reduced infarct volume 2.7-fold. There are no detectable differences between PAR1-/- and WT mice in cerebrovascular anatomy, capillary density, or capillary diameter, demonstrating that the neuroprotective phenotype is not likely related to congenital abnormalities in vascular development. We also show that the exogenously applied serine proteases thrombin, plasmin, and tissue plasminogen activator can activate PAR1 signaling in brain tissue. These data together suggest that if blood-derived serine proteases that enter brain tissue in ischemic situations can activate PAR1, this sequence of events may contribute to the harmful effects observed. Furthermore, PAR1 immunoreactivity is present in human brain, suggesting that inhibition of PAR1 may provide a novel potential therapeutic strategy for decreasing neuronal damage associated with ischemia and blood-brain barrier breakdown.

Original languageEnglish (US)
Pages (from-to)13019-13024
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume100
Issue number22
DOIs
StatePublished - Oct 28 2003

ASJC Scopus subject areas

  • General

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