Enhanced cortical reperfusion protects coagulation factor XII-deficient mice from ischemic stroke as revealed by high-field MRI

Pham, Mirko; Kleinschnitz, Christoph; Helluy, Xavier; Bartsch, Andreas J.; Austinat, Madeleine; Behr, Volker C.; Renné, Thomas; Nieswandt, Bernhard; Stoll, Guido; Bendszus, Martin

doi:10.1016/j.neuroimage.2009.11.061

Cited by 47 publications

(44 citation statements)

References 28 publications

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“…These findings support the concept that activated FXII activates PKal during tPA treatment in WT mice after stroke. In agreement with Pham et al, 38 FXII-deficient mice were not protected against infarction in the permanent MCAO model in the absence of exogenous tPA in our study. We also show that PKal blockade reduced edema and cerebrovascular permeability induced by tPA.…”

Section: Discussionsupporting

confidence: 94%

Plasma kallikrein mediates brain hemorrhage and edema caused by tissue plasminogen activator therapy in mice after stroke

Simão

Üstünkaya

Clermont

et al. 2017

Blood

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Section: Discussionsupporting

confidence: 94%

Plasma kallikrein mediates brain hemorrhage and edema caused by tissue plasminogen activator therapy in mice after stroke

Simão

Üstünkaya

Clermont

et al. 2017

Blood

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Section: Discussionsupporting

confidence: 79%

“…Accordingly, C1-inhibitor treatment had no effect on fibrin(ogen) formation after permanent MCAO (not shown). Moreover, the finding in the permanent MCAO model mirrors our observations in FXIIdeficient mice 39 and indicates that blocking of the contactkinin system after stroke is only promising if tissue reperfusion can be achieved in parallel.It is noteworthy from a translational perspective that C1-inhibitor already is used in humans for many years in the therapy of C1-inhibitor deficiency (hereditary or acquired angioedema), so far without any major safety concerns, 40,41 although it is obvious that compensation of naturally lacking C1-inhibitor in individuals with angioedema and raising of C1-inhibitor levels above the normal range in stroke patients reflect different conditions. Moreover, measuring C1-inhibitor plasma levels in mice and rats revealed that the terminal half-life is between 9.0 and 9.5 hours, 42 whereas in healthy humans the C1-inhibitor half-life is Ϸ28 hours, 36 indicating that C1-inhibitor doses used here cannot be directly compared with the human situation.…”

supporting

confidence: 79%

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

Heydenreich

Nolte

Göb

et al. 2012

Stroke

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Background and Purpose-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. Methods-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. Results-Treatment with 15.0 U C1-inhibitor, but not 7.5 U, 1 hour after stroke reduced infarct volumes by Ϸ60% 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. Conclusions-C1-inhibitor is a multifaceted antiinflammatory and antithrombotic compound that protects from ischemic neurodegeneration in clinically meaningful settings. (Stroke. 2012;43:2457-2467.)Key Words: blood-brain barrier Ⅲ C1-inhibitor Ⅲ inflammation Ⅲ kallikrein-kinin system Ⅲ middle cerebral artery occlusion Ⅲ thrombosis T he pathology of brain ischemia-reperfusion injury is complex and involves a myriad of distinct molecular and cellular pathways. Among these inflammation is one of the most relevant processes. 1,2 Activation of the cerebral endothelium early after the ischemic event triggers upregulation of cellular adhesion molecules and successive trafficking of inflammatory cells (neutrophils, macrophages, T cells) from the circulation into the brain parenchyma. Those cells recruited from the periphery in concert with locally activated cell populations (endothelial cells, microglia, astrocytes) produce an array of highly active mediators such as cytokines and chemokines that perpetuate the inflammatory circuits, thereby causing direct or indirect tissue damage. Another characteristic of persisting ischemia is structural disintegration of the blood-brain barrier, which in consequence leads to the formation of brain edema. 3,4 Excessive edema can harm otherwise healthy brain regions by mechanical compression and is a frequent cause of worsening of neurological symptoms in stroke patients. Until now, convincing pharmacological strategies to combat inflammation or edema formation in acute ischemic stroke are lacking. 5 Current pathophysiological concepts also emphasize the importance of progressive thrombus formation...

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“…20,21,[33][34][35][36] Taken together with our findings, these studies indicate that DMT targeting should be achieved as soon as possible following occlusion, even before recanalization, to be effective. In that regard, a recent EVT meta-analysis showed that the likelihood of a favorable outcome increased with the use of previous intravenous thrombolysis with alteplase.…”

Section: Strokesupporting

confidence: 80%

Alteplase Reduces Downstream Microvascular Thrombosis and Improves the Benefit of Large Artery Recanalization in Stroke

Desilles

Loyau

Syvannarath

et al. 2015

Stroke

158

134

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Background and Purpose-Downstream microvascular thrombosis (DMT) is known to be a contributing factor to incomplete reperfusion in acute ischemic stroke. The aim of this study was to determine the timing of DMT with intravital imaging and to test the hypothesis that intravenous alteplase infusion could reduce DMT in a transient middle cerebral artery occlusion (MCAO) rat stroke model. Methods-Rats were subjected to 60-minute transient MCAO. Alteplase (10 mg/kg) was administered 30 minutes after the beginning of MCAO. Real-time intravital fluorescence microscopy through a dura-sparing craniotomy was used to visualize circulating blood cells and fibrinogen. Cerebral microvessel patency was quantitatively evaluated by fluorescein isothiocyanate-dextran perfusion. Results-Immediately after MCAO, platelet and leukocyte accumulation were observed mostly in the venous compartment.Within 30 minutes after MCAO, microthrombi and parietal fibrin deposits were detected in postcapillary microvessels. Alteplase treatment significantly (P=0.006) reduced infarct volume and increased the percentage of perfused vessels during MCAO (P=0.02) compared with saline. Plasma levels of fibrinogen from alteplase-treated rats showed a rapid and profound hypofibrinogenemia. In vitro platelet aggregation demonstrated that alteplase reduced platelet aggregation (P=0.0001) and facilitated platelet disaggregation (P=0.001). These effects were reversible in the presence of exogenous fibrinogen. Conclusions-Our data demonstrate that DMT is an early phenomenon initiated before recanalization. We further show that alteplase-dependent maintenance of downstream perfusion during MCAO improves acute ischemic stroke outcome through a fibrinogen-dependent platelet aggregation reduction. Our results indicate that early targeting of DMT represents a therapeutic strategy to improve the benefit of large artery recanalization in acute ischemic stroke. (Stroke. 2015;46:3241-3248.

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Enhanced cortical reperfusion protects coagulation factor XII-deficient mice from ischemic stroke as revealed by high-field MRI

Cited by 47 publications

References 28 publications

Plasma kallikrein mediates brain hemorrhage and edema caused by tissue plasminogen activator therapy in mice after stroke

Plasma kallikrein mediates brain hemorrhage and edema caused by tissue plasminogen activator therapy in mice after stroke

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

Alteplase Reduces Downstream Microvascular Thrombosis and Improves the Benefit of Large Artery Recanalization in Stroke

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