• Open Access

The thrombomodulin analog Solulin promotes reperfusion and reduces infarct volume in a thrombotic stroke model

Authors


Daniel A. Lawrence, University of Michigan, 7301-MSRBIII, 1150 W. Medical Center Drive, Ann Arbor, MI 48109-5644, USA.
Tel.: +1 734 936 9549; fax: +1 734 936 2641.
E-mail: dlawrenc@umich.edu

Abstract

See also Andreou AP, Crawley JTB. Thrombomodulin analogues for the treatment of ischemic stroke. This issue, pp 1171–3.

Summary.

Background: Currently there is no approved anticoagulant for treating acute stroke. This is largely because of concern for hemorrhagic complications, and suggests a critical need for safer anticoagulants. Solulin is a soluble analog of the endothelial cell receptor thrombomodulin, able to bind free thrombin and convert it to an activator of the anticoagulant, protein C. Objective: Solulin was tested for its ability to inhibit middle cerebral artery occlusion (MCAO) induced by photothrombosis, and to restore MCA patency after establishment of stable occlusion. Methods: Cerebral blood flow (CBF) was monitored by laser Doppler for 1.5 h after occlusion and again 72 h later. Results: Solulin treatment 30 min before thrombosis resulted in an approximately 50% increase in time to form a stable occlusion. When administered 30 or 60 min after MCAO, Solulin significantly improved CBF within 90 min of treatment. In contrast, none of the vehicle-treated mice showed restoration of CBF in the first 90 min and only 17% did so by 72 h. Solulin treatment was associated with a significant reduction in infarct volume, and was well tolerated with no overt hemorrhage observed in any treatment group. Mechanistic studies in mice homozygous for the factor (F)V Leiden mutation, suggest that Solulin’s efficacy derives primarily from the anticoagulant activity of the thrombin–Solulin complex and not from direct anti-inflammatory or neuroprotective effects of Solulin or activated protein C. Conclusions: Our data indicate that Solulin is a safe and effective anticoagulant that is able to antagonize active thrombosis in acute ischemic stroke, and to reduce infarct volume.

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