Format

Send to

Choose Destination
Arterioscler Thromb Vasc Biol. 2016 Jun;36(6):1247-53. doi: 10.1161/ATVBAHA.115.306883. Epub 2016 Apr 21.

The Novel Oral Syk Inhibitor, Bl1002494, Protects Mice From Arterial Thrombosis and Thromboinflammatory Brain Infarction.

Author information

1
From the Department of Experimental Biomedicine (J.M.M.v.E., D.S., S.B., I.T., B.N.) and Department of Neurology (P.K., G.S.), University Hospital Würzburg and Rudolf Virchow Center for Experimental Biomedicine (J.M.M.v.E., D.S., S.B., I.T., B.N.), University of Würzburg, Würzburg, Germany; Respiratory Diseases Research, Boehringer Ingelheim Pharma GmbH & Co KG, Biberach an der Riß, Germany (D.J.L.); Mammalian Cell Signaling Laboratory, Department of Vascular Cell Biology, Max Planck Institute for Molecular Biomedicine, Münster, Germany (F.K.); and Walter Brendel Centre of Experimental Medicine, Department of Cardiovascular Physiology and Pathophysiology, Ludwig Maximilian University of Munich, Munich, Germany (B.W.).
2
From the Department of Experimental Biomedicine (J.M.M.v.E., D.S., S.B., I.T., B.N.) and Department of Neurology (P.K., G.S.), University Hospital Würzburg and Rudolf Virchow Center for Experimental Biomedicine (J.M.M.v.E., D.S., S.B., I.T., B.N.), University of Würzburg, Würzburg, Germany; Respiratory Diseases Research, Boehringer Ingelheim Pharma GmbH & Co KG, Biberach an der Riß, Germany (D.J.L.); Mammalian Cell Signaling Laboratory, Department of Vascular Cell Biology, Max Planck Institute for Molecular Biomedicine, Münster, Germany (F.K.); and Walter Brendel Centre of Experimental Medicine, Department of Cardiovascular Physiology and Pathophysiology, Ludwig Maximilian University of Munich, Munich, Germany (B.W.). bernhard.nieswandt@virchow.uni-wuerzburg.de.

Abstract

OBJECTIVE:

Ischemic stroke, which is mainly caused by thromboembolic occlusion of brain arteries, is the second leading cause of death and disability worldwide with limited treatment options. The platelet collagen receptor glycoprotein VI (GPVI) is a key player in arterial thrombosis and a critical determinant of stroke outcome, making its signaling pathway an attractive target for pharmacological intervention. The spleen tyrosine kinase (Syk) is an essential signaling mediator downstream of not only GPVI but also other platelet and immune cell receptors. We sought to assess whether Syk might be an effective antithrombotic target.

APPROACH AND RESULTS:

We demonstrate that mice lacking Syk in platelets specifically are protected from arterial thrombus formation and ischemic stroke but display unaltered hemostasis. Furthermore, we show that mice treated with the novel, selective, and orally bioavailable Syk inhibitor BI1002494 were protected in a model of arterial thrombosis and had smaller infarct sizes and a significantly better neurological outcome 24 hours after transient middle cerebral artery occlusion, also when BI1002494 was administered therapeutically, that is, after ischemia.

CONCLUSIONS:

These results provide direct evidence that pharmacological Syk inhibition might provide a safe therapeutic strategy to prevent arterial thrombosis and to limit infarct progression in acute stroke.

KEYWORDS:

Syk kinase; mice; platelets; stroke; thrombosis

Comment in

PMID:
27102960
DOI:
10.1161/ATVBAHA.115.306883
[Indexed for MEDLINE]

Supplemental Content

Full text links

Icon for Atypon
Loading ...
Support Center