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 and 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. (c) 2008 John Wiley & Sons, Ltd.
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 and 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. (c) 2008 John Wiley & Sons, Ltd.
Authors: Matthew Campbell; Anh T H Nguyen; Anna-Sophia Kiang; Lawrence C S Tam; Oliviero L Gobbo; Christian Kerskens; Sorcha Ni Dhubhghaill; Marian M Humphries; G-Jane Farrar; Paul F Kenna; Peter Humphries Journal: Proc Natl Acad Sci U S A Date: 2009-10-12 Impact factor: 11.205
Authors: Richard F Keep; Anuska V Andjelkovic; Jianming Xiang; Svetlana M Stamatovic; David A Antonetti; Ya Hua; Guohua Xi Journal: J Cereb Blood Flow Metab Date: 2018-05-08 Impact factor: 6.200
Authors: Lawrence C S Tam; Anna-Sophia Kiang; Matthew Campbell; James Keaney; G Jane Farrar; Marian M Humphries; Paul F Kenna; Pete Humphries Journal: Hum Mol Genet Date: 2010-09-02 Impact factor: 6.150
Authors: Matthew Campbell; Finnian Hanrahan; Oliviero L Gobbo; Michael E Kelly; Anna-Sophia Kiang; Marian M Humphries; Anh T H Nguyen; Ema Ozaki; James Keaney; Christoph W Blau; Christian M Kerskens; Stephen D Cahalan; John J Callanan; Eugene Wallace; Gerald A Grant; Colin P Doherty; Peter Humphries Journal: Nat Commun Date: 2012-05-22 Impact factor: 14.919