Thrombin activity associated with neuronal damage during acute focal ischemia.
Mechanisms of ischemic neuronal and vascular injury remain obscure. Here we test the hypothesis that thrombin, a blood-borne coagulation factor, contributes to neurovascular injury during acute focal ischemia. Stroke was induced in adult Sprague Dawley rats by occluding the middle cerebral artery. Intra-arterial thrombin infusion during ischemia significantly increased vascular disruption and cellular injury. Intravenous infusion of argatroban, a direct thrombin inhibitor, alleviated neurovascular injury. Immunostaining showed thrombin on neurons in the ischemic core. Using an activatable cell-penetrating peptide engineered to detect thrombin activity, we discovered that thrombin proteolytic activity was specifically associated with neuronal damage during ischemia. Protease activated receptor-1, the presumptive thrombin receptor, appeared to mediate ischemic neurovascular injury. Furthermore, rats receiving thrombin during ischemia showed cognitive deficit, whereas rats receiving argatroban retained intact learning and memory. These results suggest a potential role for thrombin contributing to neurovascular injury and several potential avenues for neuroprotection.
Department of Neurology, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA.
Bo
B
Chen
Beth
B
Friedman
Michael A
MA
Whitney
Jessica A Van
JA
Winkle
I-Farn
IF
Lei
Emilia S
ES
Olson
Qun
Q
Cheng
Benedict
B
Pereira
Lifu
L
Zhao
Roger Y
RY
Tsien
Patrick D
PD
Lyden
D000596:Amino Acids; D000704:Analysis of Variance; D000818:Animals; D000991:Antithrombins / Q000627:therapeutic use; D001120:Arginine / Q000031:analogs & derivatives; D001362:Avoidance Learning / Q000187:drug effects; D001930:Brain Injuries / Q000188:drug therapy / Q000209:etiology* / Q000378:metabolism*; D016923:Cell Death / Q000187:drug effects / Q000502:physiology; D003072:Cognition Disorders / Q000188:drug therapy / Q000209:etiology; D004195:Disease Models, Animal; D005170:Factor X / Q000378:metabolism; D005341:Fibrinolysin / Q000378:metabolism; D005786:Gene Expression Regulation; D020287:In Situ Nick-End Labeling; D020244:Infarction, Middle Cerebral Artery / Q000150:complications*; D008297:Male; D018782:Maze Learning / Q000187:drug effects; D009043:Motor Activity / Q000187:drug effects; D009419:Nerve Tissue Proteins / Q000378:metabolism; D010875:Pipecolic Acids / Q000627:therapeutic use; D011758:Pyrroles; D051381:Rats; D011930:Reaction Time / Q000187:drug effects; D044463:Receptor, PAR-1 / Q000378:metabolism; D013449:Sulfonamides; D013917:Thrombin / Q000378:metabolism* / Q000633:toxicity; D013997:Time Factors
C109824:1-(5-amino-1-carboxypentyl)pyrrole; D000596:Amino Acids; D000991:Antithrombins; D009419:Nerve Tissue Proteins; D010875:Pipecolic Acids; D011758:Pyrroles; D044463:Receptor, PAR-1; D013449:Sulfonamides; D005170:Factor X; D001120:Arginine; D013917:Thrombin; D005341:Fibrinolysin; C031942:argatroban