| Rapid brain penetration of interleukin-1 receptor antagonist in rat cerebral ischaemia: pharmacokinetics, distribution, protection. | |
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MedLine Citation:
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PMID: 20412072 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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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. |
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Authors:
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A D Greenhalgh; J Galea; A Dénes; P J Tyrrell; Nancy J Rothwell |
Publication Detail:
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Type: Journal Article; Research Support, Non-U.S. Gov't |
Journal Detail:
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Title: British journal of pharmacology Volume: 160 ISSN: 1476-5381 ISO Abbreviation: Br. J. Pharmacol. Publication Date: 2010 May |
Date Detail:
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Created Date: 2010-04-23 Completed Date: 2010-07-26 Revised Date: 2013-05-29 |
Medline Journal Info:
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Nlm Unique ID: 7502536 Medline TA: Br J Pharmacol Country: England |
Other Details:
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Languages: eng Pagination: 153-9 Citation Subset: IM |
Affiliation:
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Faculty of Life Sciences, University of Manchester, Manchester, UK. |
Export Citation:
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| MeSH Terms | |
Descriptor/Qualifier:
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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:
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//Biotechnology and Biological Sciences Research Council; //Medical Research Council |
| Chemical | |
Reg. No./Substance:
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0/Interleukin 1 Receptor Antagonist Protein; 0/Neuroprotective Agents; 0/Receptors, Interleukin-1 |
| Comments/Corrections | |
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