C1-Inhibitor Protects From Brain Ischemia-Reperfusion Injury by Combined Antiinflammatory and Antithrombotic Mechanisms

Nadine Heydenreich, Marc W. Nolte, Eva Goeb, Friederike Langhauser, Marion Hofmeister, Peter Kraft, Christiane Albert-Weissenberger, Marc Brede, Csanad Varallyay, Kerstin Goebel, Sven G. Meuth, Bernhard Nieswandt, Gerhard Dickneite, Guido Stoll, Christoph Kleinschnitz*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

59 Citations (Web of Science)

Abstract

Inflammation and thrombosis are pathophysiological hallmarks of ischemic stroke still unamenable to therapeutic interventions. The contact-kinin system represents an interface between inflammatory and thrombotic circuits and is involved in stroke development. C1-inhibitor counteracts activation of the contact-kinin system at multiple levels. We investigated the therapeutic potential of C1-inhibitor in models of ischemic stroke.Male and female C57Bl/6 mice and rats of different ages were subjected to middle cerebral artery occlusion and treated with C1-inhibitor after 1 hour or 6 hours. Infarct volumes and functional outcomes were assessed between day 1 and day 7, and findings were validated by magnetic resonance imaging. Blood-brain barrier damage, thrombus formation, and the local inflammatory response were determined poststroke.Treatment with 15.0 U C1-inhibitor, but not 7.5 U, 1 hour after stroke reduced infarct volumes by ?60% and improved clinical scores in mice of either sex on day 1. This protective effect was preserved at later stages of infarction as well as in elderly mice and in another species, ie, rats. Delayed C1-inhibitor treatment still improved clinical outcome. Blood-brain barrier damage, edema formation, and inflammation were significantly lower compared with controls. Moreover, C1-inhibitor showed strong antithrombotic effects.C1-inhibitor is a multifaceted antiinflammatory and antithrombotic compound that protects from ischemic neurodegeneration in clinically meaningful settings.
Original languageEnglish
Pages (from-to)2457-2467
JournalStroke
Volume43
Issue number9
DOIs
Publication statusPublished - Sep 2012

Keywords

  • blood-brain barrier
  • C1-inhibitor
  • inflammation
  • kallikrein-kinin system
  • middle cerebral artery occlusion
  • thrombosis

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