Blockade of Bradykinin Receptor B1 but Not Bradykinin Receptor B2 Provides Protection From Cerebral Infarction and Brain Edema

Austinat, Madeleine; Braeuninger, Stefan; Pesquero, João Bosco; Brede, Marc; Bäder, Michael; Stoll, Guido; Renné, Thomas; Kleinschnitz, Christoph

doi:10.1161/strokeaha.108.526673

Cited by 137 publications

(140 citation statements)

References 53 publications

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“…The absence of FXII is associated with a 50% reduction in bradykinin (BK) formation (24), and BK itself influences leukocyte function (27,28). To determine whether reduced bradykinin signaling contributed to the findings of decreased leukocyte translocation of α M β 2 integrin, increases intracellular calcium concentration, and leads to extracellular DNA release.…”

Section: F12mentioning

confidence: 99%

Factor XII and uPAR upregulate neutrophil functions to influence wound healing

Stavrou

Fang

Bane

et al. 2018

Journal of Clinical Investigation

115

118

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Section: F12mentioning

confidence: 99%

Factor XII and uPAR upregulate neutrophil functions to influence wound healing

Stavrou

Fang

Bane

et al. 2018

Journal of Clinical Investigation

115

118

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“…This model induced a rapid and strong activation of the contact-kinin system, leading to local inflammation and progressive microvascular thrombosis within the brain. 4,13 Although native KNG was present in the brains of sham-operated mice, it was strongly down-regulated in the ischemic (ipsilateral) and contralateral hemispheres of mice with cerebral ischemia 24 hours after tMCAO ( Figure 1). Down-regulation of KNG also in the contralateral hemispheres was probably because of excessive formation of ipsilateral infarct-related edema and subsequent compression of essentially "healthy" (contralateral) brain regions under the experimental condition of 60-minute tMCAO (see next section).…”

Section: Kininogen Deficiency Provides Sustained Protection From Ischmentioning

confidence: 99%

“…13 One central step in this process is the release of the proinflammatory peptide hormone bradykinin from KNG after plasma kallikrein activation. Consequently, the extent of damage to the blood-brain barrier and formation of edema was assessed after focal cerebral ischemia.…”

Section: Kng Deficiency Reduces Blood-brain Barrier Damage and Inflammentioning

confidence: 99%

“…12 In acute ischemic stroke activation of the contactkinin system fosters vascular permeability and stroke-related inflammation by the formation of short-lived kinins, while at the same time it is linked to thrombus formation via the FXII-driven intrinsic coagulation cascade. 4,5,13 Therefore, the contact-kinin system represents a promising multifunctional target for potential stroke therapies. However, to which extent the different molecular constituents of the contact-kinin system contribute to stroke development has been largely unknown, a situation resulting from the lack of appropriate transgenic mouse models.…”

Section: Introductionmentioning

confidence: 99%

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Kininogen deficiency protects from ischemic neurodegeneration in mice by reducing thrombosis, blood-brain barrier damage, and inflammation

Langhauser¹,

Göb²,

Kraft³

et al. 2012

Blood

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Thrombosis and inflammation are hallmarks of ischemic stroke still unamenable to therapeutic interventions. Highmolecular-weight kininogen (KNG) is a central constituent of the contact-kinin system which represents an interface between thrombotic and inflammatory circuits and is critically involved in stroke development. Kng Ϫ/Ϫ mice are protected from thrombosis after artificial vessel wall injury and lack the proinflammatory mediator bradykinin. We investigated the consequences of KNG deficiency in models of ischemic stroke. Kng Ϫ/Ϫ mice of either sex subjected to transient middle cerebral artery occlusion developed dramatically smaller brain infarctions and less severe neurologic deficits without an increase in infarct-associated hemorrhage. This protective effect was preserved at later stages of infarction as well as in elderly mice. Targeting KNG reduced thrombus formation in ischemic vessels and improved cerebral blood flow, and reconstitution of KNG-deficient mice with human KNG or bradykinin restored clot deposition and infarct susceptibility. Moreover, mice deficient in KNG showed less severe blood-brain barrier damage and edema formation, and the local inflammatory response was reduced compared with controls. Because KNG appears to be instrumental in pathologic thrombus formation and inflammation but dispensable for hemostasis, KNG inhibition may offer a selective and safe strategy for combating stroke and other thromboembolic diseases. (Blood. 2012;120(19): 4082-4092) IntroductionThe pathology of ischemic stroke is complex and involves a myriad of distinct molecular pathways and cellular interactions. Among these, progressive thrombus formation in the cerebral microvasculature is a key process that can cause secondary infarct growth despite successful recanalization of larger proximal brain vessels both under experimental conditions as well as in humans. 1,2 We recently identified the intrinsic coagulation cascade as a novel and safe antithrombotic target for the prevention and treatment of acute ischemic stroke. 3 Genetic depletion or pharmacologic blockade of coagulation factor XII (FXII), the origin of the intrinsic pathway, markedly reduced intracerebral thrombus formation and infarct growth in mice without increasing the risk of bleeding complications. 4,5 Clot formation was also significantly reduced in several in vitro models of thrombosis after FXII inhibition. 5 Current pathophysiologic concepts also emphasize the importance of inflammatory mechanisms in stroke. 6 The cerebral endothelium is activated early during the course of an ischemic event, leading to the up-regulation of cell adhesion molecules and successive trafficking of inflammatory cells (neutrophils, macrophages, T cells) from the blood stream into the brain parenchyma. Those cells attracted from the periphery in concert with resident cell populations (endothelial cells, microglia) secrete an array of soluble immune mediators such as cytokines and chemokines that perpetuate the inflammatory response to cause direct or indirect ti...

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“…In a mouse model for focal cerebral ischemia, B1BKR was not activated after the use of B2BKR antagonist (Gröger et al, 2005), avoiding cell death (Ding-Zhou et al, 2003) and protecting the brain against edema and cerebral infarction after stroke (Ding-Zhou et al, 2003). On the other hand, protection against cerebral ischemia was observed when B1BKR was absent (Austinat et al, 2009). These findings indicate that kinins can act as a double sword depending on the conditions, cell type and subtype of activated receptor.…”

Section: +mentioning

confidence: 99%

Kinins and microglial responses in bipolar disorder: a neuroinflammation hypothesis

Naaldijk¹,

Bittencourt²,

Sack

et al. 2016

Biological Chemistry

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Bipolar disorder (BD) is a severe psychiatric disorder that affects up to 15% of the worldwide population. Characterized by switches in mood between mania and depression, its etiology is still unknown and efforts have been made to elucidate the mechanisms involved in first episode, development and progression of the disorder. Microglia activation, abnormal activity of GSK-3β and reduction in neurotrophic factor expression related to neuroinflammatory processes have been indicated to be part of the disorder's pathophysiology. Lithium, the main mood stabilizer used for the treatment and prevention of relapses, acts as an anti-inflammatory agent. Based on that, here we suggest a neuroinflammatory pathway for would be BD progression, in which microglia activation states modulated via constitutive induction of kinin-B1 receptor and reduction of kinin-B2 receptor expression and activity.

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Blockade of Bradykinin Receptor B1 but Not Bradykinin Receptor B2 Provides Protection From Cerebral Infarction and Brain Edema

Abstract: Background and Purpose-Brain edema is detrimental in ischemic stroke and its treatment options are limited. Kinins are proinflammatory peptides that are released during tissue injury.

Cited by 137 publications

References 53 publications

Factor XII and uPAR upregulate neutrophil functions to influence wound healing

Factor XII and uPAR upregulate neutrophil functions to influence wound healing

Kininogen deficiency protects from ischemic neurodegeneration in mice by reducing thrombosis, blood-brain barrier damage, and inflammation

Kinins and microglial responses in bipolar disorder: a neuroinflammation hypothesis

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