CP-0597, a Selective Bradykinin B
            <sub>2</sub>
            Receptor Antagonist, Inhibits Brain Injury in a Rat Model of Reversible Middle Cerebral Artery Occlusion

Relton, Jane K.; Beckey, Virginia E.; Hanson, W. L.; Whalley, Eric T.

doi:10.1161/01.str.28.7.1430

Cited by 86 publications

(47 citation statements)

References 30 publications

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“…These mice, lacking the B 2 receptor, have smaller infarct volumes, less postischemic brain edema, and a reduced mortality as compared with wild-type animals after MCAO. Because the phenotype and the expression of the B 1 receptor of B 2 À/À mice is not different from that of control animals, the observed neuroprotection has to be related to the expression of the bradykinin B 2 receptor, as also suggested by us and others based on studies using B 2 receptor antagonists (Relton et al, 1997;Zausinger et al, 2002;Ding-Zhou et al, 2003).…”

Section: Role Of Bradykinin B 2 Receptors For Neuronal Cell Death Aftmentioning

confidence: 55%

“…In experimental stroke, several studies using bradykinin B 2 receptor antagonists showed reduced brain edema and infarct formation after transient and permanent occlusion of the middle cerebral artery (MCA) in mouse and rat (Relton et al, 1996(Relton et al, , 1997Zausinger et al, 2002;Ding-Zhou et al, 2003). Despite these encouraging results, the kallikrein-kinin system has not been studied further in focal cerebral ischemia.…”

Section: Introductionmentioning

confidence: 99%

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Release of Bradykinin and Expression of Kinin B₂Receptors in the Brain: Role for Cell Death and Brain Edema Formation After Focal Cerebral Ischemia in Mice

Gröger¹,

Lebesgue

Pruneau

et al. 2005

J Cereb Blood Flow Metab

127

112

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Pharmacological studies using bradykinin B 2 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 B 2 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 B 2 receptor mRNA and protein expression. Brain edema, infarct volume, functional outcome, and long-term survival were assessed in WT and B 2 À/À mice 24 h or 7 days after MCAO. Tissue bradykinin was maximally increased 12 h after ischemia (three-fold), while kinin B 2 receptor mRNA upregulation peaked 24 to 48 h after MCAO (10-to 12-fold versus naïve brain tissue). Immunohistochemistry revealed that kinin B 2 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. B 2 À/À mice had improved motor function (Po0.05), smaller infarct volumes (À38%; Po0.01), developed less brain edema (À87%; Po0.05), and survived longer (Po0.01) as compared with wild-type controls. The current results show that bradykinin is produced in the brain, kinin B 2 receptors are upregulated on dying cells, and B 2 receptors are involved in cell death and brain edema formation after experimental stroke.

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Section: Role Of Bradykinin B 2 Receptors For Neuronal Cell Death Aftmentioning

confidence: 55%

Section: Introductionmentioning

confidence: 99%

Release of Bradykinin and Expression of Kinin B₂Receptors in the Brain: Role for Cell Death and Brain Edema Formation After Focal Cerebral Ischemia in Mice

Gröger¹,

Lebesgue

Pruneau

et al. 2005

J Cereb Blood Flow Metab

127

112

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“…There is evidence that loss of the blood-brain barrier and the microvascular ECM results from the actions of bradykinin (Kamiya et al, 1993;Aschner et al, 1997), VEGF Zhang et al, 2000), thrombin (Okada et al, 1994a;Aschner et al, 1997), active matrix metalloproteinases (MMPs) , proteases released by activated leukocytes (Hasty et al, 1990;Garcia et al, 1994;Armao et al, 1997;Opdenakker et al, 2001), and other protease activities (Hosomi et al, 2001). Blockade of bradykinin receptors has been associated with reduced injury and edema formation (Relton et al, 1997). Thrombin can increase edema formation by direct action on the cerebral microvascular endothelium (Aschner et al, 1997;Lee et al, 1997;Kubo et al, 2000).…”

Section: Effects Of Middle Cerebral Artery Occlusion On the Microvascmentioning

confidence: 99%

Cerebral Microvessel Responses to Focal Ischemia

Zoppo

Mabuchi

2003

J Cereb Blood Flow Metab

539

449

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Summary:Cerebral microvessels have a unique ultrastructure form, which allows for the close relationship of the endothelium and blood elements to the neurons they serve, via intervening astrocytes. To focal ischemia, the cerebral microvasculature rapidly displays multiple dynamic responses. Immediate events include breakdown of the primary endothelial cell permeability barrier, with transudation of plasma, expression of endothelial cell-leukocyte adhesion receptors, loss of endothelial cell and astrocyte integrin receptors, loss of their matrix ligands, expression of members of several matrix-degrading protease families, and the appearance of receptors associated with angiogenesis and neovascularization. These events occur pari passu with neuron injury. Alterations in the microvessel matrix after the onset of ischemia also suggest links to changes in nonvascular cell viability. Microvascular obstruction within the ischemic territory occurs after occlusion and reperfusion of the feeding arteries ("focal no-reflow" phenomenon). This can result from extrinsic compression and intravascular events, including leukocyte(-platelet) adhesion, platelet-fibrin interactions, and activation of coagulation. All of these events occur in microvessels heterogeneously distributed within the ischemic core. The panorama of acute microvessel responses to focal cerebral ischemia provide opportunities to understand interrelationships between neurons and their microvascular supply and changes that underlie a number of central nervous system neurodegenerative disorders.

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“…Rats were scored on a ranking scale of 0 to 10, which reflects the cumulative score of the individual tests with a score of 10 reflecting normal behavior. 15 Representative TTC staining is shown in Figure 2 to illustrate neuroprotective effects of 1, 2 and (±)-3. Area stained red with TTC was considered normal, while area not stained red with TTC was considered infarcted.…”

Section: -9mentioning

confidence: 99%

Neuroprotective Effects of Quercetin 3-O-Methyl Ether, Quercetin and (±)-Dihydroquercetin in a Rat Model of Transient Focal Cerebral Ischemia

Kim¹,

Lee²,

Cho³

et al. 2012

Bulletin of the Korean Chemical Society

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Stroke is the third leading cause of death in most industrialized countries, and the most important source of chronic disability, among which cerebral ischemic stroke represents about 85% of all.1 Ischemic stroke occurs by thrombotic or embolic blockade of an artery to the brain resulting in a deficiency in blood flow and causing a brain infarction. During ischemic stroke, diminished blood flow initiates a series of events such as inducing excessive release of excitatory amino acids and subsequent several receptor activations leading to elevated calcium influx that may result in damage to brain cells. 2Oxidative stress is one of the primary factors that exacerbate damage in cerebral ischemia.3,4 Moreover, the reactive oxygen species can create a secondary source of extensive cell injury and death since re-supply of oxygen to the brain through the reperfusion is relevant during the ischemic phase.5 Therefore, antioxidants that can scavenge oxygen free radicals have the therapeutic potential for the treatment of neuronal injury following ischemia and reperfusion. 6Many natural antioxidants are reported to reduce reactive oxygen species and protect neuronal cells in animal models of cerebral ischemia. 7-9Previously, we reported protective effects of quercetin 3-O-methyl ether (1) and its related compounds (2, 3) isolated from Opuntia ficus-indica var. saboten against oxidative neuronal injuries induced in primary cultured rat cortical cells (Fig. 1).10 Quercetin (2) was found to inhibit H 2 O 2 -or xanthine (X)/xanthine oxidase (XO)-induced oxidative neuronal cell injury with an estimated IC 50 value of 4-5 µg/ mL. (+)-Dihydroquercetin (3) inhibited oxidative neuronal injuries concentration-dependently, but it was 2-3 fold less potent than 2. On the other hand, quercetin 3-O-methyl ether (1) potently inhibited H 2 O 2 -and X/XO-induced neuronal injuries with IC 50 values of 0.6 and 0.7 µg/mL, respectively, indicating that 1 appeared to be the most potent neuroprotectant among three flavonoids isolated from this plant. Recently, antioxidative activities in cell-free systems of 1 have also been reported.11,12 However, neuroprotective effects of 1 in ischemic animal models have not yet been reported. The present study, therefore, examined neuroprotective effects of 1 in a transient focal cerebral ischemic rat model and compared with those of related flavonoids 2 and (±)-3.The middle cerebral artery occlusion (MCAO) model has usually been used for assessing neuroprotective effects since most ischemic strokes occur in the territory of the middle cerebral artery. Transient focal cerebral ischemia was induced by occlusion of the right middle cerebral artery for 2 h with a silicone-coated 4-0 nylon monofilament in male Sprague-Dawley rats.13 The antioxidative flavonoids dissolved in 0.9% saline vehicle were administered intraperitoneally at a dose of 10 mg/kg 30 min after onset of ischemia. Infarct size and % edema were measured 24 h after onset of ischemia using a 2,3,5-triphenyltetrazolium chloride (TTC) staining method....

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CP-0597, a Selective Bradykinin B ₂ Receptor Antagonist, Inhibits Brain Injury in a Rat Model of Reversible Middle Cerebral Artery Occlusion

Abstract: The present data demonstrate the significant overall efficacy profile of CP-0597 in a rat model of reversible MCAO and provide strong rationale for the use of such bradykinin B2 receptor antagonist in the treatment of stroke.

Cited by 86 publications

References 30 publications

Release of Bradykinin and Expression of Kinin B₂Receptors in the Brain: Role for Cell Death and Brain Edema Formation After Focal Cerebral Ischemia in Mice

Release of Bradykinin and Expression of Kinin B₂Receptors in the Brain: Role for Cell Death and Brain Edema Formation After Focal Cerebral Ischemia in Mice

Cerebral Microvessel Responses to Focal Ischemia

Neuroprotective Effects of Quercetin 3-O-Methyl Ether, Quercetin and (±)-Dihydroquercetin in a Rat Model of Transient Focal Cerebral Ischemia

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CP-0597, a Selective Bradykinin B 2 Receptor Antagonist, Inhibits Brain Injury in a Rat Model of Reversible Middle Cerebral Artery Occlusion

Abstract: The present data demonstrate the significant overall efficacy profile of CP-0597 in a rat model of reversible MCAO and provide strong rationale for the use of such bradykinin B2 receptor antagonist in the treatment of stroke.

Cited by 86 publications

References 30 publications

Release of Bradykinin and Expression of Kinin B2Receptors in the Brain: Role for Cell Death and Brain Edema Formation After Focal Cerebral Ischemia in Mice

Release of Bradykinin and Expression of Kinin B2Receptors in the Brain: Role for Cell Death and Brain Edema Formation After Focal Cerebral Ischemia in Mice

Cerebral Microvessel Responses to Focal Ischemia

Neuroprotective Effects of Quercetin 3-O-Methyl Ether, Quercetin and (±)-Dihydroquercetin in a Rat Model of Transient Focal Cerebral Ischemia

Contact Info

Product

Resources

About

CP-0597, a Selective Bradykinin B ₂ Receptor Antagonist, Inhibits Brain Injury in a Rat Model of Reversible Middle Cerebral Artery Occlusion

Release of Bradykinin and Expression of Kinin B₂Receptors in the Brain: Role for Cell Death and Brain Edema Formation After Focal Cerebral Ischemia in Mice

Release of Bradykinin and Expression of Kinin B₂Receptors in the Brain: Role for Cell Death and Brain Edema Formation After Focal Cerebral Ischemia in Mice