Document Detail


The KCa3.1 blocker TRAM-34 reduces infarction and neurological deficit in a rat model of ischemia/reperfusion stroke.
MedLine Citation:
PMID:  21750563     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
Microglia and brain infiltrating macrophages significantly contribute to the secondary inflammatory damage in the wake of ischemic stroke. Here, we investigated whether inhibition of KCa3.1 (IKCa1/KCNN4), a calcium-activated K(+) channel that is involved in microglia and macrophage activation and expression of which increases on microglia in the infarcted area, has beneficial effects in a rat model of ischemic stroke. Using an HPLC/MS assay, we first confirmed that our small molecule KCa3.1 blocker TRAM-34 effectively penetrates into the brain and achieves micromolar plasma and brain concentrations after intraperitoneal injection. Then, we subjected male Wistar rats to 90 minutes of middle cerebral artery occlusion (MCAO) and administered either vehicle or TRAM-34 (10 or 40 mg/kg intraperitoneally twice daily) for 7 days starting 12 hours after reperfusion. Both compound doses reduced infarct area by ≈ 50% as determined by hematoxylin & eosin staining on day 7 and the higher dose also significantly improved neurological deficit. We further observed a significant reduction in ED1(+)-activated microglia and TUNEL-positive neurons as well as increases in NeuN(+) neurons in the infarcted hemisphere. Our findings suggest that KCa3.1 blockade constitutes an attractive approach for the treatment of ischemic stroke because it is still effective when initiated 12 hours after the insult.
Authors:
Yi-Je Chen; Girija Raman; Silke Bodendiek; Martha E O'Donnell; Heike Wulff
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Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't     Date:  2011-07-13
Journal Detail:
Title:  Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism     Volume:  31     ISSN:  1559-7016     ISO Abbreviation:  J. Cereb. Blood Flow Metab.     Publication Date:  2011 Dec 
Date Detail:
Created Date:  2011-12-01     Completed Date:  2012-01-13     Revised Date:  2013-06-28    
Medline Journal Info:
Nlm Unique ID:  8112566     Medline TA:  J Cereb Blood Flow Metab     Country:  United States    
Other Details:
Languages:  eng     Pagination:  2363-74     Citation Subset:  IM    
Affiliation:
Department of Pharmacology, Genome and Biomedical Sciences Facility, University of California, Davis, California 95616, USA.
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MeSH Terms
Descriptor/Qualifier:
Animals
Blood Proteins / metabolism
Brain / metabolism
Chromatography, High Pressure Liquid
Immunohistochemistry
In Situ Nick-End Labeling
Infarction, Middle Cerebral Artery / pathology,  prevention & control*
Intermediate-Conductance Calcium-Activated Potassium Channels / antagonists & inhibitors*
Macrophage Activation / physiology
Macrophages / metabolism
Male
Mass Spectrometry
Microglia / metabolism
Nervous System Diseases / pathology,  prevention & control*
Neuroprotective Agents / pharmacokinetics,  therapeutic use*
Permeability
Protein Binding
Pyrazoles / pharmacokinetics,  therapeutic use*
Rats
Rats, Sprague-Dawley
Rats, Wistar
Reperfusion Injury / pathology,  prevention & control*
Grant Support
ID/Acronym/Agency:
R01 GM076063/GM/NIGMS NIH HHS; R01 GM076063/GM/NIGMS NIH HHS
Chemical
Reg. No./Substance:
0/Blood Proteins; 0/Intermediate-Conductance Calcium-Activated Potassium Channels; 0/Kcnn4 protein, rat; 0/Neuroprotective Agents; 0/Pyrazoles; 0/TRAM 34
Comments/Corrections

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