Inhibition of factor Xa reduces ischemic brain damage after thromboembolic stroke in rats.
OBJECTIVE
Factor Xa (FXa) is a key coagulation protease and target for novel antithrombotic agents for prevention and treatment of diverse thromboembolic disorders. In the present study we describe the effect of a novel, potent, and selective FXa inhibitor, DPC602, on brain damage and neurobehavioral consequence in a rat thromboembolic model of stroke.


METHODS
Thromboembolic stroke was induced in rats by placement of an autologous clot into the middle cerebral artery.


RESULTS
Laser-Doppler monitoring of cerebral blood flow demonstrated that DPC602 (8 mg/kg, single IV/IP bolus pretreatment) markedly improved cerebral blood flow after thromboembolic stroke by 25% to 160% (n=6; P<0.001) at 1 to 6 hours. DPC602 demonstrated concentration- and time-dependent reductions in infarct size, with maximal effect (89% reduction; n=14; P<0.001) at the highest dose over controls. Neurological function was also significantly improved in DPC602-treated rats at days 1, 3, and 7 (n=13; P<0.01). DPC602 treatment did not cause cerebral hemorrhage, assessed by free hemoglobin in the ischemic brain tissues.


CONCLUSIONS
These data suggest that anticoagulation with a selective FXa inhibitor might ameliorate the extent of ischemic brain damage and neurological deficits after a thromboembolic event. Enhanced clot dissolution and early reperfusion may account for the cerebrovascular-protective effect of the drug.
Wang
Xinkang
X
Department of Cardiovascular Sciences, Bristol-Myers Squibb Company, Wilmington, Del, USA. xinkang.wang@BMS.com
Xu
Lin
L
Wang
Hugh
H
Grzanna
Reinhard
R
Zhan
Yutian
Y
Knabb
Robert M
RM
Luettgen
Joseph M
JM
Bozarth
Tracy A
TA
Galemmo
Robert A
RA
Wong
Pancras C
PC
Bernard
Roberta
R
Vargas
Hugo
H
Chopp
Michael
M
Friedman
Steven M
SM
Feuerstein
Giora Z
GZ
D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D001921:Brain / Q000098:blood supply / Q000187:drug effects* / Q000473:pathology; D002545:Brain Ischemia / Q000150:complications / Q000473:pathology / Q000517:prevention & control*; D002543:Cerebral Hemorrhage / Q000209:etiology; D002560:Cerebrovascular Circulation / Q000187:drug effects; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004353:Drug Evaluation, Preclinical; D004791:Enzyme Inhibitors / Q000009:adverse effects / Q000097:blood / Q000627:therapeutic use; D065427:Factor Xa Inhibitors; D007150:Immunohistochemistry; D008297:Male; D020768:Middle Cerebral Artery / Q000473:pathology; D019007:P-Selectin / Q000032:analysis; D011720:Pyrazoles / Q000009:adverse effects / Q000097:blood / Q000633:toxicity*; D051381:Rats; D017207:Rats, Sprague-Dawley; D020521:Stroke / Q000150:complications / Q000188:drug therapy* / Q000473:pathology; D013917:Thrombin / Q000032:analysis; D013923:Thromboembolism / Q000150:complications / Q000188:drug therapy* / Q000473:pathology; D010959:Tissue Plasminogen Activator / Q000032:analysis; D016896:Treatment Outcome
C472001:DPC 602; D004791:Enzyme Inhibitors; D065427:Factor Xa Inhibitors; D019007:P-Selectin; D011720:Pyrazoles; D013917:Thrombin; D010959:Tissue Plasminogen Activator