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BMC Neurology
Published in: BMC Neurology 1/2010

Open Access 01-12-2010 | Research article

Focused ultrasound-mediated bbb disruption is associated with an increase in activation of AKT: experimental study in rats

Authors: Shahrzad Jalali, Yuexi Huang, Daniel J Dumont, Kullervo Hynynen

Published in: BMC Neurology | Issue 1/2010

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Abstract

Background

The Blood Brain Barrier (BBB) maintains the homeostasis of central nervous system by preventing the free passage of macromolecules from the systemic circulation into the brain. This normal physiological function of the BBB presents a challenge for delivery of therapeutic compounds into the brain. Recent studies have shown that the application of focused ultrasound together with ultrasound contrast agent (microbubbles) temporarily increases the permeability of the BBB. This effect is associated with breakdown of tight junctions, the structures that regulate the paracellular permeability of the endothelial cell layer. The influence of this ultrasound effect on the activation of intracellular signaling proteins is currently not well understood. Therefore, the aim of this study was to investigate the activation of cell survival signaling molecules in response to ultrasound-mediated BBB opening;

Methods

The BBB was disrupted in two four-spot lines (1-1.5 mm spacing) along the right hemisphere of rat brain with ultrasound beams (0.3 MPa, 120 s, 10 ms bursts, repetition frequency = 1 Hz) in the presence Definity microbubbles. Contrast-enhanced MRI images were acquired to assess the extent of BBB opening upon which the animals were sacrificed and the brains removed and processed for biochemical and immunohistochemical analyses;

Results

Immunoblotting of sonicated brain lysates resolved by SDS-PAGE demonstrated an increase in phosphorylation of Akt and its downstream signaling molecule, GSK3β, while the phosphorylation of MAPK remained unchanged. The elevated levels of pAkt and pGSK3β are still evident after 24 hours post-sonication, a time point where the integrity of the BBB is known to be re-established. Furthermore, immunofluoresence staining localized this increase in pAkt and pGSK3β levels to neuronal cells flanking the region of the disrupted BBB;

Conclusions

Our data demonstrates that ultrasound-mediated BBB disruption causes an activation of the Akt signaling pathway in neuronal cells surrounding the disrupted BBB.
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Metadata
Title
Focused ultrasound-mediated bbb disruption is associated with an increase in activation of AKT: experimental study in rats
Authors
Shahrzad Jalali
Yuexi Huang
Daniel J Dumont
Kullervo Hynynen
Publication date
01-12-2010
Publisher
BioMed Central
Published in
BMC Neurology / Issue 1/2010
Electronic ISSN: 1471-2377
DOI
https://doi.org/10.1186/1471-2377-10-114

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