| Attenuation of edema and infarct volume following focal cerebral ischemia by early but not delayed administration of a novel small molecule KDR kinase inhibitor. | |
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MedLine Citation:
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PMID: 18951929 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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Vascular endothelial growth factor (VEGF) may mediate increases in vascular permeability and hence plasma extravasation and edema following cerebral ischemia. To better define the role of VEGF in edema, we examined the effectiveness of a novel small molecule KDR kinase inhibitor Compound-1 in reducing edema and infarct volume following focal cerebral ischemia in studies utilizing treatment regimens initiated both pre- and post-ischemia, and with study durations of 24-72 h. Rats were subjected to 90 min of middle cerebral artery occlusion (MCAO) followed by reperfusion. Pretreatment with Compound-1 (40 mg/kg p.o.) starting 0.5h before occlusion significantly reduced infarct volume at 72 h post-MCAO (vehicle, 194.1+/-22.9 mm(3) vs. Compound-1, 127.6+/-22.8mm(3) and positive control MK-801, 104.4+/-22.6mm(3), both p<0.05 compared to vehicle control), whereas Compound-1 treatment initiated at 2h after occlusion did not affect infarct volume. Compound-1 pretreatment also significantly reduced brain water content at 24h (vehicle, 80.3+/-0.2% vs. Compound-1, 79.7+/-0.2%, p<0.05) but not at 72 h after MCAO. These results demonstrate that early pretreatment administration of a KDR kinase inhibitor elicited an early, transient decrease in edema and subsequent reduction in infarct volume, implicating VEGF as a mediator of stroke-related vascular permeability and ischemic injury. |
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Authors:
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Kelley A Foster; Hillary K Regan; Andrew P Danziger; Theodore Detwiler; Nancy Kwon; Keith Rickert; Joseph J Lynch; Christopher P Regan |
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Publication Detail:
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Type: Journal Article Date: 2008-10-04 |
Journal Detail:
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Title: Neuroscience research Volume: 63 ISSN: 0168-0102 ISO Abbreviation: Neurosci. Res. Publication Date: 2009 Jan |
Date Detail:
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Created Date: 2008-12-22 Completed Date: 2009-04-20 Revised Date: 2009-11-19 |
Medline Journal Info:
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Nlm Unique ID: 8500749 Medline TA: Neurosci Res Country: Ireland |
Other Details:
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Languages: eng Pagination: 10-6 Citation Subset: IM |
Affiliation:
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Department of Schizophrenia Research, Merck Research Laboratories, West Point, PA 19486, USA. |
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| MeSH Terms | |
Descriptor/Qualifier:
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Animals Brain / drug effects, enzymology, physiopathology Brain Edema / drug therapy*, enzymology, physiopathology Cerebral Infarction / drug therapy*, enzymology, physiopathology Disease Models, Animal Drug Administration Schedule Enzyme Inhibitors / chemistry, therapeutic use* Hypoxia-Ischemia, Brain / drug therapy*, enzymology, physiopathology Indoles / chemistry, therapeutic use* Infarction, Middle Cerebral Artery / drug therapy, enzymology, physiopathology Male Molecular Weight Piperazines / chemistry, therapeutic use* Rats Time Factors Treatment Outcome Vascular Endothelial Growth Factor A / metabolism Vascular Endothelial Growth Factor Receptor-2 / antagonists & inhibitors*, metabolism |
| Chemical | |
Reg. No./Substance:
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0/3-(5-((4-(methylsulfonyl)-1-piperazinyl)methyl)-1H-indole-2-yl)quinolin-2(1H)-one; 0/Enzyme Inhibitors; 0/Indoles; 0/Piperazines; 0/Vascular Endothelial Growth Factor A; EC 2.7.10.1/Vascular Endothelial Growth Factor Receptor-2 |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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