Therapeutic window of bradykinin B2 receptor inhibition after focal cerebral ischemia in rats

Kläsner, Benjamin; Lumenta, David B.; Pruneau, Didier; Zausinger, Stefan; Plesnila, Nikolaus

doi:10.1016/j.neuint.2006.02.010

Cited by 25 publications

(12 citation statements)

References 51 publications

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“…Some reports conflict with this study, reporting that BK/kinin-B2 receptors mediate inflammatory responses resulting in edema formation and secondary brain damage after cerebral ischemia and that BK B2-receptor antagonists show reduced brain edema and infarct formation after MCAO in rats (Klasner et al, 2006). However, increasing evidence indicates that the kallikrein-kinin system mediates neuroprotection in ischemic brain injury Chao, 2005, 2006;Zausinger et al, 2002).…”

Section: Discussionmentioning

confidence: 72%

Human Urinary Kallidinogenase Suppresses Cerebral Inflammation in Experimental Stroke and Downregulates Nuclear Factor-κB

Chen

Huang

Niu

et al. 2010

J Cereb Blood Flow Metab

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The purpose of this study is to investigate the possible mechanism and the neuroprotective effect of human urinary kallidinogenase (HUK) in cerebral ischemia. The mouse middle cerebral artery occlusion (MCAO) model was used. Mice were treated with HUK (20 PNAU/g per day, intravenous) or saline as control, from the beginning of reperfusion to 72 h. Neurological deficits, infarct size, and BWC were measured at 6, 24, 48, and 72 h after MCAO, respectively. Pathological changes of brain were observed by TUNEL assay. Inflammatory factors were measured by real-time PCR and western blotting. Activation of MAPKs, Akt, and nuclear factor-jB (NF-jB) was detected by western blotting. Our results indicated that HUK significantly improved neurofunction, decreased infarct size, and suppressed edema, as well as inflammatory mediators as compared with the vehicle group. Furthermore, HUK inhibited the NF-jB pathway and activated the MAPK/ERK pathway in this neuroprotection.

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Section: Discussionmentioning

confidence: 72%

Human Urinary Kallidinogenase Suppresses Cerebral Inflammation in Experimental Stroke and Downregulates Nuclear Factor-κB

Chen

Huang

Niu

et al. 2010

J Cereb Blood Flow Metab

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“…(iii) LDF has been frequently used to monitor cerebral blood flow drop at occlusion induction in several stroke models, including the intraluminal MCA occlusion. [12][13][14][15]29 This simple and flexible option is probably a method of choice for multicentre neuroprotection studies, provided that its application can be standardized. Different perfusion drop values are considered to confirm intraluminal MCAO induction, varying in the range of 60-80%, [12][13][14][15]30 or being not specified.…”

Section: Discussionmentioning

confidence: 99%

Multi-site laser Doppler flowmetry for assessing collateral flow in experimental ischemic stroke: Validation of outcome prediction with acute MRI

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Cho

et al. 2016

J Cereb Blood Flow Metab

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High variability in infarct size is common in experimental stroke models and affects statistical power and validity of neuroprotection trials. The aim of this study was to explore cerebral collateral flow as a stratification factor for the prediction of ischemic outcome. Transient intraluminal occlusion of the middle cerebral artery was induced for 90 min in 18 Wistar rats. Cerebral collateral flow was assessed intra-procedurally using multi-site laser Doppler flowmetry monitoring in both the lateral middle cerebral artery territory and the borderzone territory between middle cerebral artery and anterior cerebral artery. Multi-modal magnetic resonance imaging was used to assess acute ischemic lesion (diffusion-weighted imaging, DWI), acute perfusion deficit (time-to-peak, TTP), and final ischemic lesion at 24 h. Infarct volumes and typology at 24 h (large hemispheric versus basal ganglia infarcts) were predicted by both intra-ischemic collateral perfusion and acute DWI lesion volume. Collateral flow assessed by multi-site laser Doppler flowmetry correlated with the corresponding acute perfusion deficit using TTP maps. Multi-site laser Doppler flowmetry monitoring was able to predict ischemic outcome and perfusion deficit in good agreement with acute MRI. Our results support the additional value of cerebral collateral flow monitoring for outcome prediction in experimental ischemic stroke, especially when acute MRI facilities are not available.

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“…However, these studies have produced conflicting results 3 . Some studies have shown that B2R blockade reduced infarct size and neuronal damage after transient middle cerebral artery occlusion (MCAO) 19 , 22 – 24 but other suggested that inactivation of this receptor has no effect or even aggravates ischemic brain damage 20 , 25 – 27 . It has also been reported that pharmacological blockade or genetic inactivation of B1R confer neuroprotection in mice 20 .…”

Section: Introductionmentioning

confidence: 99%

Neuroprotective effect of kinin B1 receptor activation in acute cerebral ischemia in diabetic mice

Desposito

Zadigue

Taveau

et al. 2017

Sci Rep

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Activation of the kallikrein-kinin system enhances cardiac and renal tolerance to ischemia. Here we investigated the effects of selective agonists of kinin B1 or B2 receptor (R) in brain ischemiareperfusion in diabetic and non-diabetic mice. The role of endogenous kinins was assessed in tissue kallikrein deficient mice (TK −/− ). Mice underwent 60min-middle cerebral artery occlusion (MCAO), eight weeks after type 1-diabetes induction. Treatment with B1R-, B2R-agonist or saline was started at reperfusion. Neurological deficit (ND), infarct size (IS), brain water content (BWC) were measured at day 0, 1 and 2 after injury. MCAO induced exaggerated ND, mortality and IS in diabetic mice. B2R-agonist increased ND and mortality to 60% and 80% in non-diabetic and diabetic mice respectively, by mechanisms involving hemodynamic failure and renal insufficiency. TK −/− mice displayed reduced ND and IS compared to wild-type littermate, consistent with suppression of B2R activity. B1R mRNA level increased in ischemic brain but B1R-agonist had no effect on ND, mortality or IS in non-diabetic mice. In contrast, in diabetic mice, B1R-agonist tested at two doses significantly reduced ND by 42-52% and IS by 66-71%, without effect on BWC or renal function. This suggests potential therapeutic interest of B1R agonism for cerebral protection in diabetes. Acute brain ischemia secondary to cerebral artery occlusion is a major cause of mortality or permanent disability. Risk of ischemic stroke is increased in diabetic patients and prognosis is poorer 1, 2 . Cerebral artery occlusion causes acute (minutes to hours) and delayed (hours to days or weeks) injury cascades, both implicating multiple pathogenic factors like thrombosis, neuron stunning or necrosis, brain oedema and inflammation 3, 4 . The complexity of mechanisms involved in brain damage explains in part that there is still no clinically effective neuroprotective treatment besides revascularization. The kallikrein-kinin system (KKS) is implicated in physiological vasodilatation, exerts antithrombotic and profibrinolytic actions and reduces oxidative stress in different organs [5][6][7][8] . KKS protects against cardiac and renal damage in the setting of acute ischemia secondary to arterial occlusion. Inhibition of KKS aggravates cardiac and renal ischemic lesions while activation of kinin receptors enhances cardiac tolerance to ischemia and reperfusion [9][10][11][12] . Kinins are generated by proteolytic cleavage of protein precursors, kininogens, by tissue kallikrein (TK) and are mainly inactivated in the circulation by the angiotensin I-converting enzyme (ACE/kininase II) 5 . Kinins, activate two receptor subtypes: B1 (B1R) and B2 (B2R). All components of KKS have been identified in brain tissue from rodents and humans 3, 13-18 . B1R gene expression is low in the brain under normal condition, but it is upregulated by inflammation and ischemia 19,20 . By contrast, B2R is constitutively present in different brain structures and in cerebral arteries and microvessels 18,21 .Role o...

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Therapeutic window of bradykinin B2 receptor inhibition after focal cerebral ischemia in rats

Cited by 25 publications

References 51 publications

Human Urinary Kallidinogenase Suppresses Cerebral Inflammation in Experimental Stroke and Downregulates Nuclear Factor-κB

Human Urinary Kallidinogenase Suppresses Cerebral Inflammation in Experimental Stroke and Downregulates Nuclear Factor-κB

Multi-site laser Doppler flowmetry for assessing collateral flow in experimental ischemic stroke: Validation of outcome prediction with acute MRI

Neuroprotective effect of kinin B1 receptor activation in acute cerebral ischemia in diabetic mice

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