Published Online
on January 16, 2003

A more recent version of this article appeared on February 1, 2003

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Submitted on August 13, 2002
Accepted on August 23, 2002

Inhibition of Factor Xa Reduces Ischemic Brain Damage After Thromboembolic Stroke in Rats

Xinkang Wang PhD^*; Lin Xu MD; Hugh Wang PhD; Reinhard Grzanna PhD; Yutian Zhan MS; Robert M. Knabb PhD; Joseph M. Luettgen MS; Tracy A. Bozarth MS; Robert A. Galemmo PhD; Pancras C. Wong PhD; Roberta Bernard MS; Hugo Vargas PhD; Michael Chopp PhD; Steven M. Friedman MD; and Giora Z. Feuerstein MD

From the Departments of Cardiovascular Sciences (X.W., L.X., H.W., R.M.K., J.M.L., T.A.B., P.C.W., R.B., S.M.F., G.Z.F.), Neurosciences (R.G., Y.Z.), General Pharmacology (H.V., S.M.F.), and Medicinal Chemistry (R.A.G.), Bristol-Myers Squibb Company, Wilmington, Del, and Department of Neurology, Henry Ford Health Sciences Center, Detroit, Mich (M.C.).

^* To whom correspondence should be addressed. E-mail: xinkang.wang{at}BMS.com.

Background and Purpose--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.

Key words: anticoagulants • cerebral blood flow • cerebral ischemia • coagulation • thromboembolism

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