Pretreatment with rivaroxaban attenuates stroke severity in rats by a dual antithrombotic and anti-inflammatory mechanism.
Stroke outcome is more favourable in patients receiving oral anticoagulants compared with non-anticoagulated patients. The reasons for this "stroke-attenuating" property of oral anticoagulants are largely unknown. This study examined whether prestroke anticoagulation with rivaroxaban, a novel direct factor Xa inhibitor, influences stroke severity, thrombin-mediated intracerebral thrombus formation and pro-inflammatory processes in a rat model of brain ischaemia/reperfusion injury. Male Wistar rats were anticoagulated with rivaroxaban and subjected to 90 minutes of transient middle cerebral artery occlusion. Infarct size, functional outcome and the occurrence of intracranial haemorrhage (ICH) were assessed until day 7. Thrombin generation was determined by measuring the amount of thrombin/antithrombin complex. Intracerebral thrombus formation was evaluated by histology and Western blot. CD68-immunoreactivity and the expression of cytokines and adhesion molecules were investigated to assess postischaemic inflammation. The integrity of the blood-brain barrier was analysed using fluorescein isothiocyanate-dextran. Rats pretreated with rivaroxaban developed significantly smaller strokes and less severe functional deficits compared with controls. Although rivaroxaban strongly reduced thrombin-mediated thrombus formation, this was not accompanied by an increased risk of ICH. In addition, rivaroxaban dampened the inflammatory response in the ischaemic brain by downregulating ICAM-1 expression and the activation of CD68+-immune cells. In contrast, rivaroxaban had no effect on the integrity of the blood-brain barrier after stroke. Here, we identified reduced thrombo-inflammation as a major determinant of the stroke-protective property of rivaroxaban in rats. Further studies are needed to assess the therapeutic potential of novel oral anticoagulants in the acute phase after a stroke.
Melanie
M
Dittmeier
Peter
P
Kraft
Michael K
MK
Schuhmann
Felix
F
Fluri
Christoph Kleinschnitz, MD, Department of Neurology, University Hospital Würzburg, Josef-Schneider Strasse 11, 97080 Würzburg, Germany, Tel.: +49 931 201 23756, Fax: +49 931 201 23488, E-mail: christoph.kleinschnitz@uni-wuerzburg.de.
Christoph
C
Kleinschnitz
D000818:Animals; D000893:Anti-Inflammatory Agents / Q000627:therapeutic use*; D000925:Anticoagulants / Q000627:therapeutic use*; D001812:Blood-Brain Barrier / Q000187:drug effects; D018450:Disease Progression; D065427:Factor Xa Inhibitors / Q000627:therapeutic use*; D006801:Humans; D018799:Intercellular Adhesion Molecule-1 / Q000235:genetics / Q000378:metabolism; D008213:Lymphocyte Activation; D008297:Male; D051381:Rats; D017208:Rats, Wistar; D000069552:Rivaroxaban / Q000627:therapeutic use*; D020521:Stroke / Q000188:drug therapy*; D013917:Thrombin / Q000378:metabolism
D000893:Anti-Inflammatory Agents; D000925:Anticoagulants; D065427:Factor Xa Inhibitors; D018799:Intercellular Adhesion Molecule-1; D000069552:Rivaroxaban; D013917:Thrombin
cerebral inflammation; experimental stroke; rivaroxaban; tMCAO; thrombin