期刊
JOURNAL OF GENE MEDICINE
卷 10, 期 8, 页码 930-947出版社
JOHN WILEY & SONS LTD
DOI: 10.1002/jgm.1211
关键词
blood-brain barrier; tight junctions; RNA interference; claudin-5; drug delivery
资金
- Wellcome Trust
- Fighting Blindness Ireland
- Enterprise Ireland
- European Union Evi-GenoRet [LSHG-CT-2005-512036]
- European Union [MRTN-CT-2003-504003]
- British RP Society
- Health Research Board of Ireland
Background The blood-brain barrier (BBB) contains tight junctions (TJs) which reduce the space between adjacent endothelial cells lining the fine capillaries of the microvasculature of the brain to form a selective and regulatable barrier. Methods Using a hydrodynamic approach, we delivered siRNA targeting the TJ protein claudin-5 to the endothelial cells of the BBB in mice. Results We have shown a significant decrease in claudin-5 mRNA levels 24 and 48 hours post-delivery of siRNA, with levels of protein expression decreasing up to 48 hours post-injection compared to uninjected, phosphate-buffered saline (PBS)-injected End non-targeting siRNA-injected mice. We observed increased permeability at the BBB to molecules up to 742 Da, but not 4400 Da, using tracer molecule perfusion and MRI analysis. To illustrate the functional efficacy of size-selective and transient barrier opening, we have shown that enhanced delivery of the small neuropeptide thyrotropin-releasing hormone (TRH) (MW 360 Da) to the brains of mice 48 hours post-injection of siRNA targeting claudin-5 significantly modifies behavioural output. Conclusions These data demonstrate that it is now possible to transiently and size-selectively open the BBB in mice, allowing in principle the delivery of a wide range of agents for the establishment and treatment of experimental mouse models of neurodegenerative, neuropsychiatric and malignant diseases. Copyright (c) 2008 John Wiley & Sons, Ltd.
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