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% (nϭ6; PϽ0.001) at 1 to 6 hours. DPC602 demonstrated concentration-and time-dependent reductions in infarct size, with maximal effect (89% reduction; nϭ14; PϽ0.001) at the highest dose over controls. Neurological function was also significantly improved in DPC602-treated rats at days 1, 3, and 7 (nϭ13; PϽ0.01). 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.

Inhibition of Tumor Necrosis Factor-α-Converting Enzyme by a Selective Antagonist Protects Brain from Focal Ischemic Injury in Rats

“…The gas was passed through an isoflurane vaporizer set to deliver 3 to 4% isoflurane during initial induction and 1.5 to 2% during surgery. Details for animal care and monitoring during operation have been described previously (Wang et al, 2003b).…”

“…To induce thromboembolism in the cerebral circulation, an embolus was prepared using a procedure described previously (Zhang et al, 1997;Wang et al, 2003b). Briefly, a femoral artery was dissected from a donor rat under anesthesia and a small volume of blood (1-2 ml) was withdrawn into PE-50 tubing.…”

Up-Regulation of Secretory Leukocyte Protease Inhibitor (SLPI) in the Brain after Ischemic Stroke: Adenoviral Expression of SLPI Protects Brain from Ischemic Injury

“…Neurological deficits were examined for the same groups of animals before TTC staining using the following criteria (Wang et al, 2003): no neurological deficit ϭ 0; right Horner's syndrome counts 1 point; failure to extend left forelimb and hindlimb, 1 point each; turning to left, 1 point; and circling to left, 1 point.…”

Coagulation factor Xa activates thrombin in ischemic neural tissue

“…A FXa inhibitor has previously been used as an antithrombotic treatment in a rat thromboembolic stroke model (Wang et al 2003). Treatment before ischemia improved the cerebral blood flow and attenuated the infarct volume which suggests that the mode of action of the FXa inhibitor was, at least partly, on the intravascular clot (Wang et al 2003). In our in vitro cerebral ischemia model, FX immunoreactivity was seen around condensed nuclei of dying CA1 neurons 24 h after OGD.…”

“…detected in microglial cells as well as in brainstem neurons (Yamada and Nagai 1996;Shikamoto and Morita 1999). A FXa inhibitor has previously been used as an antithrombotic treatment in a rat thromboembolic stroke model (Wang et al 2003). Treatment before ischemia improved the cerebral blood flow and attenuated the infarct volume which suggests that the mode of action of the FXa inhibitor was, at least partly, on the intravascular clot (Wang et al 2003).…”