Relative importance of proteinase-activated receptor-1 versus matrix metalloproteinases in intracerebral hemorrhage-mediated neurotoxicity in mice.
OBJECTIVE
To reduce bleeding and damage to central nervous system tissue in intracerebral hemorrhage, the coagulant effect of thrombin is essential. However, thrombin itself can kill neurons in intracerebral hemorrhage as can the matrix metalloproteinases (MMPs), which are also elevated in this condition, in part due to thrombin-mediated activation of MMPs. It is thus important to understand and block the neurotoxic effects of thrombin without inhibiting its therapeutic outcomes. In this study, we have investigated the relative roles of proteinase activated receptor-1, a thrombin receptor, and MMPs in brain injury induced by thrombin or blood.


METHODS
Mice were subjected to stereotactic intracerebral injections of saline, thrombin, and autologous blood, with or without hirudin, a thrombin inhibitor, or GM6001, an MMP inhibitor. Twenty-four hours later, tissue sections were obtained to evaluate the area of brain damage and extent of dying neurons. Data from wild-type mice were compared with results obtained with proteinase activated receptor-1 null mice.


RESULTS
In blood-induced damage to the brain parenchyma, both hirudin and GM6001 significantly reduced injury to a comparable extent (>40%) implicating both thrombin and MMPs in neurotoxicity. In proteinase activated receptor-1 null mice, blood-induced brain damage was reduced by 22.6% relative to wild-type animals; by comparison, the blood-induced brain damage was reduced by 48.3% using GM6001.


CONCLUSIONS
The neurotoxicity of blood in intracerebral hemorrhage involves both proteinase activated receptor-1 and MMP activation, with the latter appearing more prominent in causing death.
Xue
Mengzhou
M
Hotchkiss Brain Institute and Department of Clinical Neurosciences, University of Calgary, 3330 Hospital Drive, Calgary, Alberta T2N 4N1, Canada.
Hollenberg
Morley D
MD
Demchuk
Andrew
A
Yong
V Wee
VW
D000818:Animals; D000991:Antithrombins / Q000627:therapeutic use; D001804:Blood Transfusion, Autologous; D001921:Brain / Q000473:pathology; D016923:Cell Death / Q000187:drug effects; D002543:Cerebral Hemorrhage / Q000378:metabolism* / Q000473:pathology; D004151:Dipeptides / Q000494:pharmacology; D005260:Female; D005780:Gelatin / Q000737:chemistry; D006629:Hirudins; D008297:Male; D061965:Matrix Metalloproteinase Inhibitors; D020782:Matrix Metalloproteinases / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D020258:Neurotoxicity Syndromes / Q000473:pathology / Q000517:prevention & control*; D011480:Protease Inhibitors / Q000494:pharmacology / Q000627:therapeutic use; D044463:Receptor, PAR-1 / Q000235:genetics / Q000378:metabolism*; D013917:Thrombin / Q000037:antagonists & inhibitors* / Q000633:toxicity*
D000991:Antithrombins; D004151:Dipeptides; D006629:Hirudins; D061965:Matrix Metalloproteinase Inhibitors; C078131:N-(2(R)-2-(hydroxamidocarbonylmethyl)-4-methylpentanoyl)-L-tryptophan methylamide; D011480:Protease Inhibitors; D044463:Receptor, PAR-1; D005780:Gelatin; D013917:Thrombin; D020782:Matrix Metalloproteinases