Release of Bradykinin and Expression of Kinin B2 Receptors in the Brain: Role for Cell Death and Brain Edema Formation After Focal Cerebral Ischemia in Mice

Pharmacological studies using bradykinin B2 receptor antagonists suggest that bradykinin, an early mediator of inflammation and the main metabolite of the kallikrein-kinin system, is involved in secondary brain damage after cerebral ischemia. However, the time-course of bradykinin production and kinin receptor expression as well as the conclusive role of bradykinin B2 receptors for brain damage after experimental stroke have not been elucidated so far. C57/Bl6 mice were subjected to 45 mins of middle cerebral artery occlusion (MCAO) and 2, 4, 8, 24, and 48 h later brains were removed for the analysis of tissue bradykinin concentration and kinin B2 receptor mRNA and protein expression. Brain edema, infarct volume, functional outcome, and long-term survival were assessed in WT and B2−/− mice 24 h or 7 days after MCAO. Tissue bradykinin was maximally increased 12 h after ischemia (three-fold), while kinin B2 receptor mRNA upregulation peaked 24 to 48 h after MCAO (10- to 12-fold versus naïve brain tissue). Immunohistochemistry revealed that kinin B2 receptors were constitutively and widely expressed in mouse brain, were upregulated 2 h after ischemia in cells showing signs of ischemic damage, and remained upregulated in the penumbra up to 24 h after ischemia. B2−/− mice had improved motor function ( P<0.05), smaller infarct volumes (–38%; P<0.01), developed less brain edema (–87%; P<0.05), and survived longer ( P<0.01) as compared with wild-type controls. The current results show that bradykinin is produced in the brain, kinin B2 receptors are upregulated on dying cells, and B2 receptors are involved in cell death and brain edema formation after experimental stroke.

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Role of Arginine Vasopressin V1 and V2 Receptors for Brain Damage After Transient Focal Cerebral Ischemia

Journal of Cerebral Blood Flow & Metabolism ◽

10.1038/sj.jcbfm.9600097 ◽

2005 ◽

Vol 25 (8) ◽

pp. 1012-1019 ◽

Cited By ~ 94

Author(s):

Abedin Vakili ◽

Hiroharu Kataoka ◽

Nikolaus Plesnila

Keyword(s):

Ischemic Stroke ◽

Cerebral Ischemia ◽

Brain Edema ◽

Brain Damage ◽

Arginine Vasopressin ◽

Focal Cerebral Ischemia ◽

Edema Formation ◽

Transient Focal Cerebral Ischemia ◽

Brain Edema Formation

Brain edema formation is one of the most important mechanisms responsible for brain damage after ischemic stroke. Despite considerable efforts, no specific therapy is available yet. Arginine vasopressin (AVP) regulates cerebral water homeostasis and has been involved in brain edema formation. In the current study, we investigated the role of AVP V1 and V2 receptors on brain damage, brain edema formation, and functional outcome after transient focal cerebral ischemia, a condition comparable with that of stroke patients undergoing thrombolysis. C57/BL6 mice were subjected to 60-min middle cerebral artery occlusion (MCAO) followed by 23 h of reperfusion. Five minutes after MCAO, 100 or 500 ng of [deamino-Pen(1), O-Me-Tyr(2), Arg(8)]-vasopressin (AVP V1 receptor antagonist) or [adamantaneacetyl(1), O-Et-d-Tyr(2), Val(4), Abu(6), Arg(8,9)]-vasopressin (AVP V2 receptor antagonist) were injected into the left ventricle. Inhibition of AVP V1 receptors reduced infarct volume in a dose-dependent manner by 54% and 70% (to 29±13 and 19±10 mm3 versus 63±17 mm3 in controls; P<0.001), brain edema formation by 67% (to 80.4%±1.0% versus 82.7%±1.2% in controls; P<0.001), blood-brain barrier disruption by 75% ( P<0.001), and functional deficits 24 h after ischemia, while V2 receptor inhibition had no effect. The current findings indicate that AVP V1 but not V2 receptors are involved in the pathophysiology of secondary brain damage after focal cerebral ischemia. Although further studies are needed to clarify the mechanisms of neuroprotection, AVP V1 receptors seem to be promising targets for the treatment of ischemic stroke.

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Neuroprotective effects of 5-HT3 receptor antagonist ondansetron on morphine withdrawal induced brain edema formation, blood-brain barrier dysfunction, neuronal injuries, glial activation and heat shock protein upregulation in the brain

International Review of Neurobiology - New Therapeutic Strategies for Brain Edema and Cell Injury ◽

10.1016/bs.irn.2019.06.011 ◽

2019 ◽

pp. 209-228

Author(s):

Aruna Sharma ◽

Ranjana Patnaik ◽

Hari Shanker Sharma

Keyword(s):

Heat Shock ◽

Heat Shock Protein ◽

Receptor Antagonist ◽

Brain Edema ◽

Blood Brain Barrier ◽

Barrier Dysfunction ◽

Neuroprotective Effects ◽

Edema Formation ◽

The Brain ◽

Brain Edema Formation

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Complement activation in the brain after experimental intracerebral hemorrhage

Journal of Neurosurgery ◽

10.3171/jns.2000.92.6.1016 ◽

2000 ◽

Vol 92 (6) ◽

pp. 1016-1022 ◽

Cited By ~ 115

Author(s):

Ya Hua ◽

Guohua Xi ◽

Richard F. Keep ◽

Julian T. Hoff

Keyword(s):

Brain Edema ◽

Complement Activation ◽

Autologous Blood ◽

Complement Cascade ◽

Edema Formation ◽

Content Type ◽

Erythrocyte Lysis ◽

The Brain ◽

Brain Edema Formation ◽

Fine Print

Object. Brain edema formation following intracerebral hemorrhage (ICH) appears to be partly related to erythrocyte lysis and hemoglobin release. Erythrocyte lysis may be mediated by the complement cascade, which then triggers parenchymal injury. In this study the authors examine whether the complement cascade is activated after ICH and whether inhibition of complement attenuates brain edema around the hematoma.Methods. This study was divided into three parts. In the first part, 100 µl of autologous blood was infused into the rats' right basal ganglia, and the animals were killed at 24 and 72 hours after intracerebral infusion. Their brains were tested for complement factors C9, C3d, and clusterin (a naturally occurring complement inhibitor) by using immunohistochemical analysis. In the second part of the study, the rats were killed at 24 or 72 hours after injection of 100 µl of blood. The C9 and clusterin proteins were quantitated using Western blot analysis. In the third part, the rats received either 100 µl of blood or 100 µl of blood plus 10 µg of N-acetylheparin (a complement activation inhibitor). Then they were killed 24 or 72 hours later for measurement of brain water and ion contents. It was demonstrated on Western blot analysis that there had been a sixfold increase in C9 around the hematoma 24 hours after the infusion of 100 µl of autologous blood. Marked perihematomal C9 immunoreactivity was detected at 72 hours. Clusterin also increased after ICH and was expressed in neurons 72 hours later. The addition of N-acetylheparin significantly reduced brain edema formation in the ipsilateral basal ganglia at 24 hours (78.5 ± 0.5% compared with 81.6 ± 0.8% in control animals, p < 0.001) and at 72 hours (80.9 ± 2.2% compared with 83.6 ± 0.9% in control animals, p < 0.05) after ICH.Conclusions. It was found that ICH causes complement activation in the brain. Activation of complement and the formation of membrane attack complex contributes to brain edema formation after ICH. Blocking the complement cascade could be an important step in the therapy for ICH.

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Therapeutical efficacy of a novel non-peptide bradykinin B2 receptor antagonist on brain edema formation and ischemic tissue damage in focal cerebral ischemia

Brain Edema XII ◽

10.1007/978-3-7091-0651-8_44 ◽

2003 ◽

pp. 205-207 ◽

Cited By ~ 4

Author(s):

Stefan Zausinger ◽

D. B. Lumenta ◽

D. Pruneau ◽

R. Schmid-Elsaesser ◽

N. Plesnila ◽

...

Keyword(s):

Cerebral Ischemia ◽

Receptor Antagonist ◽

Brain Edema ◽

Tissue Damage ◽

Focal Cerebral Ischemia ◽

Edema Formation ◽

Bradykinin B2 Receptor ◽

Ischemic Tissue ◽

Brain Edema Formation

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Blood—Brain Barrier Permeability and Brain Concentration of Sodium, Potassium, and Chloride during Focal Ischemia

Journal of Cerebral Blood Flow & Metabolism ◽

10.1038/jcbfm.1994.5 ◽

1994 ◽

Vol 14 (1) ◽

pp. 29-37 ◽

Cited By ~ 114

Author(s):

A. Lorris Betz ◽

Richard F. Keep ◽

Mary E. Beer ◽

Xiao-Dan Ren

Keyword(s):

Cerebral Ischemia ◽

Brain Edema ◽

Relative Permeability ◽

Sodium Transport ◽

Focal Ischemia ◽

Edema Formation ◽

Ischemic Brain ◽

Early Stages ◽

Brain Edema Formation ◽

Rate Of Accumulation

Brain edema formation during the early stages of focal cerebral ischemia is associated with an increase in both sodium content and blood–brain barrier (BBB) sodium transport. The goals of this study were to determine whether chloride is the principal anion that accumulates in ischemic brain, how the rate of BBB transport of chloride compares with its rate of accumulation, and whether the stimulation seen in BBB sodium transport is also seen with other cations. Focal ischemia was produced by occlusion of the middle cerebral artery (MCAO) in anesthetized rats. Over the first 6 h after MCAO, the amount of brain water in the center of the ischemic cortex increased progressively at a rate of 0.15 ± 0.02 (SE) g/g dry wt/h. This was accompanied by a net increase in brain sodium (48 ± 12 μmol/g dry wt/h) and a loss of potassium (34 ± 7 μmol/g dry wt/h). The net rate of chloride accumulation (16 ± 1 μmol/g dry wt/h) approximated the net rate of increase of cations. Three hours after MCAO, the BBB permeability to three ions (22Na, 36Cl, and 86Rb) and two passive permeability tracers {[3H]α-aminoisobutyric acid (3H]AIB) and [14C]urea} was determined. Permeability to either passive tracer was not increased, indicating that the BBB was intact. The rate of 36Cl influx was 3 times greater and the rate of 22Na influx 1.8 times greater than their respective net rates of accumulation in ischemic brain. The BBB permeability to 22Na relative to that of [3H]AIB was significantly increased in the ischemic cortex, the relative permeability to 86Rb was significantly decreased, and the relative permeability to 36Cl was unchanged. These results indicate that the stimulation in BBB sodium transport is specific for sodium. Further, chloride accumulates with sodium in brain during the early stages of ischemia; however, its rate of accumulation is low compared with its rate of transport from blood to brain. Therefore, inhibition of BBB sodium transport is more likely to reduce edema formation than is inhibition of BBB chloride transport. This study demonstrates that chloride is the principal anion that accompanies the accumulation of sodium in ischemic brain, but its rate of accumulation in brain is much less than its rate of movement into brain, and therefore inhibition of chloride uptake would have little effect on brain edema formation. There is a specific acceleration of blood-to-brain sodium transport during ischemia that is not seen with another positively charged ion, 86Rb. This is consistent with stimulation of brain capillary Na,K-ATPase activity in response to the elevated extracellular potassium concentration. Inhibition of potassium influx across the BBB would probably be more successful in lessening edema formation than accelerating potassium efflux. However, inhibition of blood-to-brain sodium transport is likely to be a more effective approach to reducing brain edema formation during the early stages of cerebral ischemia.

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The Role of Bradykinin B1 and B2 Receptors for Secondary Brain Damage after Traumatic Brain Injury in Mice

Journal of Cerebral Blood Flow & Metabolism ◽

10.1038/jcbfm.2009.196 ◽

2009 ◽

Vol 30 (1) ◽

pp. 130-139 ◽

Cited By ~ 55

Author(s):

Raimund Trabold ◽

Christian Erös ◽

Klaus Zweckberger ◽

Jane Relton ◽

Heike Beck ◽

...

Keyword(s):

Traumatic Brain Injury ◽

Brain Injury ◽

Functional Outcome ◽

Brain Edema ◽

Brain Damage ◽

Secondary Brain Damage ◽

Edema Formation ◽

Receptor Mrna ◽

B2 Receptors

Inflammatory mechanisms are known to contribute to the pathophysiology of traumatic brain injury (TBI). Since bradykinin is one of the first mediators activated during inflammation, we investigated the role of bradykinin and its receptors in posttraumatic secondary brain damage. We subjected wild-type (WT), B1-, and B2-receptor-knockout mice to controlled cortical impact (CCI) and analyzed tissue bradykinin as well as kinin receptor mRNA and protein expression up to 48 h thereafter. Brain edema, contusion volume, and functional outcome were assessed 24 h and 7 days after CCI. Tissue bradykinin was maximally increased 2 h after trauma ( P<0.01 versus sham). Kinin B1 receptor mRNA was upregulated up to four-fold 24 h after CCI. Immunohistochemistry showed that B1 and B2 receptors were expressed in the brain and were significantly upregulated in the traumatic penumbra 1 to 24 h after CCI. B2R−/− mice had significantly less brain edema (−51% versus WT, 24 h; P<0.001), smaller contusion volumes (∼50% versus WT 24 h and 7 d after CCI; P<0.05), and better functional outcome 7 days after TBI as compared with WT mice ( P<0.05). The present results show that bradykinin and its B2 receptors play a causal role for brain edema formation and cell death after TBI.

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