Inhibition of factor Xa reduces ischemic brain damage after thromboembolic stroke in rats.

Abstract

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.

• Authors: Xinkang Wang, Lin Xu, Hugh Wang, Reinhard Grzanna, Yutian Zhan, Robert M Knabb, Joseph M Luettgen, Tracy A Bozarth, Robert A Galemmo, Pancras C Wong, Roberta Bernard, Hugo Vargas, Michael Chopp, Steven M Friedman, Giora Z Feuerstein
• Journal: Stroke (Stroke) Vol. 34 Issue 2 Pg. 468-74 (Feb 2003) ISSN: 1524-4628 [Electronic] United States
• PMID: 12574562 (Publication Type: Journal Article)

Chemical References

• DPC 602
• Enzyme Inhibitors
• Factor Xa Inhibitors
• P-Selectin
• Pyrazoles
• Thrombin
• Tissue Plasminogen Activator

Topics

• Animals
• Behavior, Animal (drug effects)
• Brain (blood supply, drug effects, pathology)
• Brain Ischemia (complications, pathology, prevention & control)
• Cerebral Hemorrhage (etiology)
• Cerebrovascular Circulation (drug effects)
• Disease Models, Animal
• Dose-Response Relationship, Drug
• Drug Evaluation, Preclinical
• Enzyme Inhibitors (adverse effects, blood, therapeutic use)
• Factor Xa Inhibitors
• Immunohistochemistry
• Male
• Middle Cerebral Artery (pathology)
• P-Selectin (analysis)
• Pyrazoles (adverse effects, blood, toxicity)
• Rats
• Rats, Sprague-Dawley
• Stroke (complications, drug therapy, pathology)
• Thrombin (analysis)
• Thromboembolism (complications, drug therapy, pathology)
• Tissue Plasminogen Activator (analysis)
• Treatment Outcome