The contribution of protease-activated receptor 1 to neuronal damage caused by transient focal cerebral ischemia.
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.
Junge
Candice E
CE
Department of Pharmacology, Emory University, Atlanta, GA 30322, USA. cjunge@ucla.edu
Sugawara
Taku
T
Mannaioni
Guido
G
Alagarsamy
Sudar
S
Conn
P Jeffrey
PJ
Brat
Daniel J
DJ
Chan
Pak H
PH
Traynelis
Stephen F
SF
D000818:Animals; D002560:Cerebrovascular Circulation / Q000502:physiology; D004195:Disease Models, Animal; D005341:Fibrinolysin / Q000378:metabolism; D006146:Guanidines / Q000008:administration & dosage / Q000494:pharmacology*; D006624:Hippocampus / Q000378:metabolism / Q000473:pathology; D006801:Humans; D006868:Hydrolysis; D007270:Injections, Intra-Articular; D002546:Ischemic Attack, Transient / Q000473:pathology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009474:Neurons / Q000473:pathology*; D009842:Oligopeptides / Q000008:administration & dosage / Q000494:pharmacology*; D010716:Phosphatidylinositols / Q000378:metabolism; D044463:Receptor, PAR-1 / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D013917:Thrombin / Q000378:metabolism; D010959:Tissue Plasminogen Activator / Q000378:metabolism; D010975:Platelet Aggregation Inhibitors
D006146:Guanidines; C479887:N-cinnamoyl-4-fluorophenylalanyl-4-guanidinophenylalanyl-leucyl-arginyl-argininamide; D009842:Oligopeptides; D010716:Phosphatidylinositols; D044463:Receptor, PAR-1; D013917:Thrombin; D010959:Tissue Plasminogen Activator; D005341:Fibrinolysin; D010975:Platelet Aggregation Inhibitors