Article

The Role of Caveolin-1 in Blood–Brain Barrier Disruption Induced by Focused Ultrasound Combined with Microbubbles

Department of Neurosurgery, Second Affiliated Hospital, Chongqing Medical University, Chongqing, China.
Journal of Molecular Neuroscience (Impact Factor: 2.76). 08/2011; 46(3):677-87. DOI: 10.1007/s12031-011-9629-9
Source: PubMed

ABSTRACT This research was designed to determine whether disrupting the blood-brain barrier (BBB) in rats by applying focused ultrasound (FUS) combined with microbubbles induced changes in the density of caveolae and/or the expression of the structural protein caveolin-1. To this end, two approaches were utilized. First, using enhanced magnetic resonance imaging, characteristics of BBB disruption induced by our specific FUS parameters and dose of microbubble were recorded, and the time after treatment when the BBB was the most permeable was determined. Second, rats were treated with FUS or microbubbles alone, both or neither, and a combination of Evans blue (EB) BBB permeability assays, streptavidin-peroxidase (SP) immunohistochemistry, western blot, and transmission electron microscopy (TEM) was employed to detect any changes in caveolae density and caveolin-1 expression at the previously determined time point when the BBB was the most permeable. The first set of studies revealed that our specific FUS parameters and dose of microbubbles were able to induce a transient, targeted, and reversible BBB opening in rats, and that the BBB was the most permeable 1 h after treatment with FUS and microbubbles. In the second set of experiments, the results of the SP immunohistochemistry, western blot, and TEM, taken together, revealed that caveolae and caveolin-1 were primarily localized in the brain microvascular endothelial cells of all of the rats regardless of treatment, and that caveolin-1 expression was highest in the rats treated with both FUS and microbubbles. In summary, treatment with FUS, in combination with a dose of microbubbles, can enhance BBB permeability through a caveolae-mediated transcellular approach by upregulating the expression level of caveolin-1 and, consequently, the amount of caveolae. This caveolin-1-mediated transcellular transport pathway may cooperate with other transport pathways to induce opening of the BBB. This research sheds light on the mechanism of a transient, targeted, and reversible opening of the BBB induced by FUS combined with microbubbles.

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    • "In a study investigating caveolae density it was found that caveolae and caveolin-1 were primarily localized in the brain microvascular endothelial cells of all the animals tested (rats) regardless of treatment, and that caveolin-1 expression was the highest in the rats treated with both FUS and microbubbles. The authors concluded that caveolin-1-mediated transcellular transport pathway may cooperate with other transport pathways (e.g., tight junctional disruption) to induce opening of the BBB [60]. "
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    • "Recently, it has been demonstrated that focused ultrasound in combination with ultrasound contrast agents (UCA) can lead to a transient disruption of the BBB without relevant neuronal damage.3,4,5,6 As an underlying molecular mechanism of ultrasonographic BBB opening, both a transient disintegration of tight junctional complexes7 and an increased caveolae-mediated transcellular transport have been discussed.8 By this means, macromolecules such as antibodies9 or plasmid DNA for nonviral gene therapy10 have successfully been delivered in rodents. "
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