Document Detail


Rapid brain penetration of interleukin-1 receptor antagonist in rat cerebral ischaemia: pharmacokinetics, distribution, protection.
MedLine Citation:
PMID:  20412072     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
BACKGROUND AND PURPOSE: Limited data on the brain penetration of potential stroke treatments have been cited as a major weakness contributing to numerous failed clinical trials. Thus, we tested whether interleukin-1 receptor antagonist (IL-1RA), established as a potent inhibitor of brain injury in animals and currently in clinical development, reaches the brain via a clinically relevant administration route, in experimental stroke.
EXPERIMENTAL APPROACH: Male, Sprague-Dawley rats [either naïve or exposed to middle cerebral artery occlusion (MCAo)] were given a single s.c. dose of IL-1RA (100 mg*kg(-1)). The pharmacokinetic profile of IL-1RA was assessed in plasma and CSF up to 24 h post-administration. Brain tissue distribution of administered IL-1RA was assessed using immunohistochemistry. In a separate experiment, the neuroprotective effect of the single s.c. dose of IL-1RA in MCAo was assessed versus a placebo control group.
KEY RESULTS: A single s.c. dose of IL-1RA reduced damage caused by MCAo by 33%. This dose resulted in sustained, high concentrations in plasma and CSF, penetrated brain tissue exclusively in areas of blood-brain barrier breakdown and co-localized with morphologically viable neurones. CSF concentrations did not reflect massive parenchymal infiltration of IL-1RA in MCAo animals compared to naïve.
CONCLUSIONS AND IMPLICATIONS: These data are the first to show that a potential treatment for stroke, IL-1RA, rapidly reaches salvageable brain tissue via an administration route that is clinically relevant. This allows confidence that IL-1RA, as a candidate for further clinical development, is able to confer its protective actions both peripherally and centrally.
Authors:
A D Greenhalgh; J Galea; A Dénes; P J Tyrrell; Nancy J Rothwell
Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't    
Journal Detail:
Title:  British journal of pharmacology     Volume:  160     ISSN:  1476-5381     ISO Abbreviation:  Br. J. Pharmacol.     Publication Date:  2010 May 
Date Detail:
Created Date:  2010-04-23     Completed Date:  2010-07-26     Revised Date:  2014-02-19    
Medline Journal Info:
Nlm Unique ID:  7502536     Medline TA:  Br J Pharmacol     Country:  England    
Other Details:
Languages:  eng     Pagination:  153-9     Citation Subset:  IM    
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MeSH Terms
Descriptor/Qualifier:
Administration, Cutaneous
Animals
Blood-Brain Barrier / metabolism
Brain / metabolism*,  pathology
Brain Infarction / drug therapy,  metabolism,  pathology
Interleukin 1 Receptor Antagonist Protein / administration & dosage,  pharmacokinetics*,  therapeutic use
Ischemic Attack, Transient / drug therapy,  metabolism*,  pathology
Male
Neuroprotective Agents / pharmacokinetics*,  therapeutic use
Rats
Rats, Sprague-Dawley
Receptors, Interleukin-1 / antagonists & inhibitors*
Tissue Distribution
Grant Support
ID/Acronym/Agency:
G0801296//Medical Research Council; //Biotechnology and Biological Sciences Research Council; //Medical Research Council
Chemical
Reg. No./Substance:
0/Interleukin 1 Receptor Antagonist Protein; 0/Neuroprotective Agents; 0/Receptors, Interleukin-1
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