期刊
BRITISH JOURNAL OF PHARMACOLOGY
卷 160, 期 1, 页码 153-159出版社
WILEY
DOI: 10.1111/j.1476-5381.2010.00684.x
关键词
brain penetration; interleukin-1 receptor antagonist; cerebral ischaemia; inflammation; neuroprotection
资金
- Biotechnology and Biological Sciences Research Council
- Integrative Mammalian Biology initiative
- Medical Research Council
- MRC [G0801296, G0801040] Funding Source: UKRI
- Medical Research Council [G0801296, G0801040] Funding Source: researchfish
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 naive or exposed to middle cerebral artery occlusion (MCAo)] were given a single s.c. dose of IL-1RA (100 mg center dot 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 naive. 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.
作者
我是这篇论文的作者
点击您的名字以认领此论文并将其添加到您的个人资料中。
推荐
暂无数据