Abstract
MRI-guided focused ultrasound (MRgFUS) combined with microbubbles (MBs) is a promising technology that can facilitate drug delivery through a temporarily disrupted blood-brain barrier (BBB) and induce the down-regulation of P-glycoprotein (P-gp) expression on the blood vessels. Despite the increasing evidence regarding the down-regulation of P-gp expression after MRgFUS BBB disruption (BBBD), its underlying molecular events remain unclear. The aim of this study was to evaluate the underlying mechanism of FUS BBBD-mediated P-gp down-regulation. While our results showed down-regulation of P-gp at 24 h post-BBBD in transcriptional and translational levels, restoration to the normal expression appeared at different time points for transcriptional (72 h) and translational (120 h) levels. In addition, the signaling molecule, JNK, was significantly activated in the cerebral blood vessels at 24 h post-BBBD. Although P-gp levels were significantly decreased, the expression levels of proteins involved in the integrity of blood vessels, such as Glut1, ZO-1 and occludin, were not decreased at 24 h post-BBBD. Our study suggests that the JNK signaling pathway is involved in the regulation of FUS-induced P-gp expression, without affecting vessel integrity, and a detailed regulatory mechanism can provide the basis for clinical application of FUS to the treatment of neurological disease.
Highlights
The blood-brain barrier (BBB) is a physical barrier that comprises impermeable brain capillaries, supported by microvascular endothelial cells, pericytes, astrocytes, tight junctions (TJs), and a basal membrane
We found that TJ protein expression levels in the BBB-disrupted blood vessels were not decreased 24 h after focused ultrasound (FUS), suggesting that the JNK signaling can be attributed to distinct pathways that differ from those regulating the TJ proteins
To the best of our knowledge, this is the first report of a regulation mechanism of P-gp following MRI-guided focused ultrasound (MRgFUS) combined with microbubbles in cerebral blood vessels
Summary
The blood-brain barrier (BBB) is a physical barrier that comprises impermeable brain capillaries, supported by microvascular endothelial cells, pericytes, astrocytes, tight junctions (TJs), and a basal membrane. It plays an essential role in maintaining homeostasis in the nervous system. The endothelial cells of the BBB have highly selective transporters as functional barriers, limiting free pJNK-Dependent P-gp Downregulation by FUS diffusion (Abbott, 2013). It presents a major challenge in terms of drug delivery for the treatment of neurological disorders. The underlying mechanism for the temporary reduction of P-gp expression remains largely elusive
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