Selective platelet deposition during focal cerebral ischemia in cats.

Jafar, J J; Menoni, R; Feinberg, Harold; LeBreton, Guy C.; Crowell, Robert M.

doi:10.1161/01.str.20.5.664

Cited by 20 publications

(6 citation statements)

References 38 publications

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“…The effects of platelets on microvascular endothelial cells are poorly understood, although interactions between these cellular entities are documented in the brain in response to cerebral ischemia in several species [5][6][7][8][9] and in cerebral malaria in humans. 10 Platelet activation occurs in response to stroke in humans 11,12 and in patients with multiple sclerosis.…”

Section: Introductionmentioning

confidence: 99%

Platelet interleukin-1α drives cerebrovascular inflammation

Thornton

McColl

Greenhalgh

et al. 2010

Blood

156

133

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IntroductionCerebrovascular inflammation is a major contributor to diverse forms of brain injury, including cerebral ischemia, multiple sclerosis, cerebral infection, and epilepsy. 1-3 Peripheral circulating cells play critical roles in cerebral inflammation. Platelets are one of the first cell types to arrive at the site of vascular dysfunction 4 and can induce vascular inflammation, thus contributing to disease progression, particularly in larger vessels.The effects of platelets on microvascular endothelial cells are poorly understood, although interactions between these cellular entities are documented in the brain in response to cerebral ischemia in several species 5-9 and in cerebral malaria in humans. 10 Platelet activation occurs in response to stroke in humans 11,12 and in patients with multiple sclerosis. 13 Platelet consumption or brain accumulation 14 in the infarct area may account for the drop in platelet numbers after clinical stroke. 15 Inhibition of platelet adhesion to brain endothelium may protect against diverse brain insults. Neutralizing platelet glycoprotein (GP) VI or GPIb surface adhesion receptors reduces damage in mouse focal cerebral ischemia. 16 Inhibition of platelet-brain endothelial interactions, through blockade of platelet GPIIb receptor, protects mice against cerebral malaria pathogenesis. 17 Mice lacking platelet GPIIb 18 or mice receiving a small molecule inhibitor of GPIIb/IIIa (CD41/CD61) are also protected against cerebral ischemia. 5 However, the mechanisms by which platelets contribute to brain injury are unknown.Current therapies for the treatment of acute cerebral ischemia target platelet function, with protective effects dependent on anticoagulant or fibrinolytic actions. However, inhibition of coagulatory pathways reduces inflammation. 19 Thus, the antiinflammatory effects of platelet inhibition may mediate some of the protection afforded by these therapies in cerebral ischemia. Platelet interleukin-1␣ (IL-1␣), IL-1␤, or CD40L can activate peripheral endothelial cells, [20][21][22][23][24] and platelets contribute to leukocyte infiltration in peripheral tissues. 25,26 Similar mechanisms may contribute to brain endothelial activation.Here, we tested the hypothesis that platelets induce inflammatory activation of brain endothelial cells. We show, for the first time, that platelet-secreted IL-1␣ drives mouse brain endothelial activation, leading to the induction of endothelial ICAM-1 and VCAM-1, CXCL1 release, and neutrophil transendothelial migration (TEM). This study is the first to show that actions of platelet IL-1␣ on brain endothelium may be critical to inflammationmediated injury in the brain. MethodsMore details regarding the procedures outlined herein are given in supplemental Methods (available on the Blood Web site; see the Supplemental Materials link at the top of the online article). Focal cerebral ischemia and immunohistochemistryFocal cerebral ischemia in C57/BL6 or IL-1␣/␤ Ϫ/Ϫ mice (on a C57/BL6 background 27 ) induced by transient (60 minutes) middle cer...

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Section: Introductionmentioning

confidence: 99%

Platelet interleukin-1α drives cerebrovascular inflammation

Thornton

McColl

Greenhalgh

et al. 2010

Blood

156

133

View full text Add to dashboard Cite

show abstract

“…Studies on experimental and human stroke suggest that platelets play a role in the development and progression of cell damage after focal cerebral ischemia (del Zoppo, 1998). Platelets aggregate in regions of low blood flow during the postischemic period in animal models of focal cerebral ischemia (Dietrich et al, 1993; Jafar et al , 1989; Kochanek et al , 1988; Obrenovitch and Hallenbeck, 1985), and acute stroke patients show evidence of platelet activation (Dougherty et al , 1977; Fisher et al , 1982). Platelets aggregate dynamically at the site of an embolus occluding the MCA, and may contribute to resistance to thrombolysis with duration of ischemia, since platelets retract clots and release plasminogen activator inhibitor 1 (PAI-1), α 2 -antiplasmin, and factor XIII, all of which reduce thrombolysis (Zhang ZG et al , 2001).…”

Section: Introductionmentioning

confidence: 99%

Analysis of Combined Treatment of Embolic Stroke in Rat with r-tPA and a GPIIb/IIIa Inhibitor

Ding¹,

Jiang²,

Zhang³

et al. 2005

J Cereb Blood Flow Metab

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Suppression of platelet activation improves the efficacy of thrombolytic therapy for stroke. Thus, combination treatment with recombinant tissue plasminogen activator (r-tPA) and 7E3 F(ab 0 ) 2 , a GPIIb/IIIa inhibitor that binds the platelet to fibrin, may improve the efficacy of thrombolytic therapy in embolic stroke. Magnetic resonance imaging (MRI) was used to monitor treatment response in rats subjected to embolic middle cerebral artery (MCA) occlusion (MCAo). Animals were randomized into treated (n ¼ 12) and control (n ¼ 10) groups and received intravenous combination therapy or saline, respectively, 4 hours after MCAo. Magnetic resonance imaging (MRI) measurements performed 1 hour after MCAo showed no difference between groups. However, an increased incidence (50%) of MCA recanalization was found in the treated group at 24 hours compared with 20% in the control group. The area of low cerebral blood flow at 24 and 48 hours was significantly smaller in the combination treatment group, and the lesion size, as indicated from the T 2 and T 1 maps, differed significantly between groups. Fluorescence microscopy measurements of cerebral microvessels perfused with fluorescein isothiocyanate-dextran and measurements of infarct volume revealed that the combination treatment significantly increased microvascular patency and reduced infarct volume, respectively, compared with the control rats. The efficacy of combination treatment 4 hours after ischemia is reflected by MRI indices of tissue perfusion, MCA recanalization, and reduction of lesion volume. The treatment also reduced secondary microvascular perfusion deficits.

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“…In humans, patients with essential thrombocythemia have a propensity towards ischemic stroke (12). In animal models of ischemic stroke, scintigraphic studies in rats (13), cats (14), and dogs (15,16) show that 111 Indium (In)-labeled platelets accumulate in the ipsilateral ischemic cerebral cortex. Although the platelet inhibitor aspirin is effective in terms of primary prevention of stroke (17), it is not clear that aspirin is efficacious when used to treat acute stroke in evolution.…”

Section: Introductionmentioning

confidence: 99%

Reduced microvascular thrombosis and improved outcome in acute murine stroke by inhibiting GP IIb/IIIa receptor-mediated platelet aggregation.

Choudhri¹,

Hoh²,

Zerwes³

et al. 1998

J. Clin. Invest.

229

189

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Treatment options in acute stroke are limited by a dearth of safe and effective regimens for recanalization of an occluded cerebrovascular tributary, as well as by the fact that patients present only after the occlusive event is established. We hypothesized that even if the site of major arterial occlusion is recanalized after stroke, microvascular thrombosis continues to occur at distal sites, reducing postischemic flow and contributing to ongoing neuronal death. To test this hypothesis, and to show that microvascular thrombosis occurs as an ongoing, dynamic process after the onset of stroke, we tested the effects of a potent antiplatelet agent given both before and after the onset of middle cerebral arterial (MCA) occlusion in a murine model of stroke. After 45 min of MCA occlusion and 23 h of reperfusion, fibrin accumulates in the ipsilateral cerebral hemisphere, based upon immunoblotting, and localizes to microvascular lumena, based upon immunostaining. In concordance with these data, there is a nearly threefold increase in the ipsilateral accumulation of 111 In-labeled platelets in mice subjected to stroke compared with mice not subjected to stroke. When a novel inhibitor of the glycoprotein IIb/IIIa receptor (SDZ GPI 562) was administered immediately before MCA occlusion, platelet accumulation was reduced 48%, and fibrin accumulation was reduced by 47% by immunoblot densitometry. GPI 562 exhibited a dose-dependent reduction of cerebral infarct volumes measured by triphenyltetrazolium chloride staining, as well as improvement in postischemic cerebral blood flow, measured by laser doppler. GPI 562 caused a dose-dependent increase in tail vein bleeding time, but intracerebral hemorrhage (ICH) was not significantly increased at therapeutic doses; however, there was an increase in ICH at the highest doses tested. When given immediately after withdrawal of the MCA occluding suture, GPI 562 was shown to reduce cerebral infarct volumes by 70%. These data support the hypothesis that in ischemic regions of brain, microvascular thrombi continue to accumulate even after recanalization of the MCA, contributing to postischemic hypoperfusion and ongoing neuronal damage. ( J. Clin. Invest. 1998. 102:1301-1310.)

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Selective platelet deposition during focal cerebral ischemia in cats.

Cited by 20 publications

References 38 publications

Platelet interleukin-1α drives cerebrovascular inflammation

Platelet interleukin-1α drives cerebrovascular inflammation

Analysis of Combined Treatment of Embolic Stroke in Rat with r-tPA and a GPIIb/IIIa Inhibitor

Reduced microvascular thrombosis and improved outcome in acute murine stroke by inhibiting GP IIb/IIIa receptor-mediated platelet aggregation.

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