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Inhibition of factor Xa reduces ischemic brain damage after thromboembolic stroke in rats
Xinkang Wang1, Lin Xu, Hugh Wang
1Department of Cardiovascular Sciences, Bristol-Myers Squibb Company, Wilmington, Del, USA. xinkang.wang@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.
Insights
A novel Factor Xa inhibitor, DPC602, significantly reduced brain damage and improved neurological function in a rat stroke model. This selective anticoagulant shows promise for treating thromboembolic disorders without causing hemorrhage.
Area of Science:
- Neuroscience
- Pharmacology
- Cardiovascular Research
Background:
- Factor Xa (FXa) is a critical enzyme in blood coagulation and a therapeutic target for antithrombotic agents.
- Thromboembolic disorders, including stroke, represent a significant unmet medical need.
Purpose of the Study:
- To evaluate the efficacy of DPC602, a novel, potent, and selective FXa inhibitor, in a rat thromboembolic stroke model.
- To assess the impact of DPC602 on brain damage, neurobehavioral outcomes, and safety.
Main Methods:
- Thromboembolic stroke was induced in rats by middle cerebral artery occlusion using an autologous clot.
- Cerebral blood flow was monitored using Laser-Doppler.
- Infarct size, neurological function, and cerebral hemorrhage were assessed.
Main Results:
- DPC602 pretreatment (8 mg/kg) significantly improved cerebral blood flow (25-160%) post-stroke.
- Concentration- and time-dependent reductions in infarct size were observed, with an 89% maximal reduction.
- Significant improvements in neurological function were noted at days 1, 3, and 7 post-stroke.
- No cerebral hemorrhage was detected in DPC602-treated rats.
Conclusions:
- Selective FXa inhibition with DPC602 may ameliorate ischemic brain damage and neurological deficits.
- Enhanced clot dissolution and early reperfusion are potential mechanisms for the cerebrovascular-protective effects.
- DPC602 demonstrates a favorable safety profile regarding hemorrhage in this stroke model.