Inducing Hemorrhagic Transformation Following Middle Cerebral Artery Occlusion via Acute Hyperglycemia in Rats

2019 ◽  
pp. 173-187
Author(s):  
Devin W. McBride ◽  
Derek Nowrangi ◽  
Wing Mann Ho ◽  
Jiping Tang ◽  
John H. Zhang
Keyword(s):  
Middle Cerebral Artery ◽  
Middle Cerebral Artery Occlusion ◽  
Cerebral Artery ◽  
Hemorrhagic Transformation ◽  
Artery Occlusion ◽  
Acute Hyperglycemia ◽  
Cerebral Artery Occlusion

Abstract T MP111: Gpr124 Regulates Post-Stroke Cerebrovascular Integrity

Stroke ◽  
2014 ◽  
Vol 45 (suppl_1) ◽  
Author(s):  
Michael Mancuso ◽  
Junlei Chang ◽  
Carolina Maier-Albers ◽  
Cynthia Kosinski ◽  
Xibin Liang ◽  
...  
Keyword(s):  
Middle Cerebral Artery ◽  
Middle Cerebral Artery Occlusion ◽  
Blood Brain Barrier ◽  
Cerebral Artery ◽  
Hemorrhagic Transformation ◽  
Artery Occlusion ◽  
Stroke Model ◽  
Post Stroke ◽  
Adult Mice ◽  
Cerebral Artery Occlusion

Introduction: GPR124/TEM5 is an orphan G-protein coupled receptor (GPCR) with a large extracellular domain. We and others have previously demonstrated that GPR124 exerts CNS-specific angiogenesis regulation with knockout mice exhibiting embryonic lethality from hemorrhagic glomeruloid vascular malformations in forebrain and neural tube (c.f. Kuhnert et al., Science , Nov 12;330(6006):985-9 . (2010)). Hypothesis: GPR124 regulates adult angiogenesis and blood-brain barrier (BBB) integrity during homeostasis or after stroke. Methods: To bypass GPR124 embryonic lethality, we generated GPR124 conditional knockout (cko) mice allowing temporally-regulated deletion. Tamoxifen treatment of GPR124 flox/- ; ROSA-CreER mice versus GPR124 flox/+; ROSA-CreER littermate controls allowed GPR124 cko versus heterozygosity, respectively, in adult mice. GPR124 deletion was followed by analyses of microvascular structure and patterning and blood-brain barrier (BBB) integrity). GPR124 cko mice versus controls were also subjected to 60 minute middle cerebral artery occlusion (MCAO) and effects on stroke volume, survival and microvascular structure assessed. Results: GPR124 deletion in neonatal or adult mice was well-tolerated without impairment of postnatal vascular patterning, BBB maturation or BBB integrity. However, GPR124 cko mice subjected to the middle cerebral artery occlusion (MCAO) stroke model exhibited impaired survival and a profound microvascular hemorrhagic transformation that was confined to the infarct region relative to wild-type controls. GPR124 cko stroke vasculature also exhibited numerous cellular and architectural defects relative to controls that will be discussed. Conclusions: GPR124 deletion is well tolerated in adult mice but results in marked hemorrhagic transformation in the MCAO stroke model. GPR124 represents a novel receptor whose function is essential for cerebrovascular integrity in the post-stroke setting, with attendant therapeutic implications.

scholarly journals Protective Effect of ApoA1 (Apolipoprotein A1)-Milano in a Rat Model of Large Vessel Occlusion Stroke

Stroke ◽  
2020 ◽  
Vol 51 (6) ◽  
pp. 1886-1890 ◽  
Author(s):  
Célina Ducroux ◽  
Jean-Philippe Desilles ◽  
Marie-Anne Mawhin ◽  
Sandrine Delbosc ◽  
Benoit Ho-Tin-Noé ◽  
...  
Keyword(s):  
Platelet Aggregation ◽  
Middle Cerebral Artery ◽  
Middle Cerebral Artery Occlusion ◽  
Cerebral Artery ◽  
Infarct Volume ◽  
Hemorrhagic Transformation ◽  
Artery Occlusion ◽  
Apolipoprotein A1 ◽  
Transformation Rate ◽  
Cerebral Artery Occlusion

Background and Purpose— Previous experimental studies found that the infusion of human purified nascent HDL (high-density lipoprotein) significantly reduced infarct volume and hemorrhagic transformation rate by decreasing neutrophil recruitment. ApoA1-M (apolipoprotein A1-Milano) is a natural variant of human ApoA1 that confers protection against atherosclerosis. Recombinant ApoA1-M has been formulated as a complex with phospholipids to mimic the properties of nascent HDL. The aim of this study was to assess the impact of intravenous ApoA1-M in a transient middle cerebral artery occlusion stroke model in rats. Methods— In a first experiment, rats were subjected to 120-minute transient middle cerebral artery occlusion and intravenous ApoA1-M was infused immediately or 4 hours after occlusion. In a second experiment, rats were subjected to 240-minute transient middle cerebral artery occlusion and intravenous ApoA1-M was infused with or without recombinant tPA (tissue-type plasminogen activator) immediately after recanalization. Primary outcome criteria were the infarct volume and hemorrhagic transformation rate measured at 24 hours. Platelets, coagulation, and neutrophil activation biomarkers were measured in brain homogenates and plasma. Additional in vitro experiments studied the effects of ApoA1-M on platelet aggregation and platelet-neutrophil interactions. Results— The infusion of ApoA1-M immediately or 4 hours after 120-minute transient middle cerebral artery occlusion significantly reduced the infarct volume compared with saline ( P =0.034 and P =0.036, respectively). Compared with tPA alone, co-administration of ApoA1-M and tPA showed similar rates of hemorrhagic transformation. ApoA1-M had no significant inhibition effect on neutrophil activation biomarkers. Platelet activation was slightly decreased in rats treated with ApoA1-M compared with saline. In vitro, the incubation of human and rat platelet-rich plasma with ApoA1-M significantly reduced ADP-induced platelet aggregation ( P =0.001 and P =0.02, respectively). Conclusions— ApoA1-Milano significantly decreased the infarct volume through an inhibition of platelet aggregation but did not reduce hemorrhagic transformation and neutrophils activation as expected after previous experimental studies with nascent HDL. Visual Overview— An online visual overview is available for this article.

scholarly journals Cilostazol Ameliorates Warfarin-Induced Hemorrhagic Transformation After Cerebral Ischemia in Mice

Stroke ◽  
2013 ◽  
Vol 44 (10) ◽  
pp. 2862-2868 ◽  
Author(s):  
Akira Kitashoji ◽  
Yusuke Egashira ◽  
Keisuke Mishiro ◽  
Yukiya Suzuki ◽  
Hideki Ito ◽  
...  
Keyword(s):  
Ischemic Stroke ◽  
Survival Rate ◽  
Cerebral Ischemia ◽  
Middle Cerebral Artery ◽  
Middle Cerebral Artery Occlusion ◽  
Cerebral Artery ◽  
Hemorrhagic Transformation ◽  
Artery Occlusion ◽  
Vascular Endothelial ◽  
Cerebral Artery Occlusion

Background and Purpose— Although long-term treatment with the oral anticoagulant warfarin is widely used to prevent cardioembolic ischemic stroke, it has been reported that warfarin can exacerbate hemorrhagic transformation (HT) after cerebral ischemia. We investigated whether cilostazol, a phosphodiesterase-III inhibitor, suppressed the warfarin-induced HT after cerebral ischemia in mice. Methods— Male ddY mice were treated with oral warfarin before 3-hour middle cerebral artery occlusion followed by 21-hour reperfusion to induce HT. The duration of warfarin pretreatment was determined by measurement of prothrombin time-international normalized ratio value. Cilostazol or vehicle was administered by intraperitoneal injection immediately after reperfusion. The infarct volume, brain swelling, and brain hemoglobin content were evaluated at 24 hours after middle cerebral artery occlusion. We also evaluated the survival rate of each treated group for 7 days after surgery. To investigate the mechanism underlying cilostazol’s effects, the proteins involved in vascular endothelial integrity were investigated using Western blotting. Results— HT volume was exacerbated by warfarin treatment, and cilostazol (3 mg/kg, IP) suppressed this exacerbation (sham, mean±SD, 29.2±13.4 mg/dL; vehicle, 33.3±11.9 mg/dL; warfarin, 379.4±428.9 mg/dL; warfarin+cilostazol 1 mg/kg, 167.5±114.2 mg/dL; warfarin+cilostazol 3 mg/kg, 116.9±152.3 mg/dL). Furthermore, cilostazol improved survival rate and upregulated the expression of tight junction proteins and vascular endothelial cadherin. Conclusions— Cilostazol reduced the warfarin-related risk of HT after ischemia by protecting the vascular endothelial cells. This result suggested that cilostazol administration in patients with acute ischemic stroke might reduce HT.

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