Document Detail


Attenuation of edema and infarct volume following focal cerebral ischemia by early but not delayed administration of a novel small molecule KDR kinase inhibitor.
MedLine Citation:
PMID:  18951929     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
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.
Authors:
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:
Type:  Journal Article     Date:  2008-10-04
Journal Detail:
Title:  Neuroscience research     Volume:  63     ISSN:  0168-0102     ISO Abbreviation:  Neurosci. Res.     Publication Date:  2009 Jan 
Date Detail:
Created Date:  2008-12-22     Completed Date:  2009-04-20     Revised Date:  2009-11-19    
Medline Journal Info:
Nlm Unique ID:  8500749     Medline TA:  Neurosci Res     Country:  Ireland    
Other Details:
Languages:  eng     Pagination:  10-6     Citation Subset:  IM    
Affiliation:
Department of Schizophrenia Research, Merck Research Laboratories, West Point, PA 19486, USA.
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MeSH Terms
Descriptor/Qualifier:
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:
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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