Dataset Information

Diminished Expression of P-glycoprotein Using Focused Ultrasound Is Associated With JNK-Dependent Signaling Pathway in Cerebral Blood Vessels.

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.

SUBMITTER: Choi H

PROVIDER: S-EPMC6928061 | biostudies-literature | 2019

REPOSITORIES: biostudies-literature

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Diminished Expression of P-glycoprotein Using Focused Ultrasound Is Associated With JNK-Dependent Signaling Pathway in Cerebral Blood Vessels.

Choi HyoJin H Lee Eun-Hee EH Han Mun M An Sang-Hyun SH Park Juyoung J

Frontiers in neuroscience 20191217

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 mec ...[more]

PMID: 31920511

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Project description:BackgroundCerebral cavernous malformations (CCM) are vascular lesions within the central nervous system, consisting of dilated and hemorrhage-prone capillaries. CCMs can cause debilitating neurological symptoms, and surgical excision or stereotactic radiosurgery are the only current treatment options. Meanwhile, transient blood-brain barrier opening (BBBO) with focused ultrasound (FUS) and microbubbles is now understood to exert potentially beneficial bioeffects, such as stimulation of neurogenesis and clearance of amyloid-β. Here, we tested whether FUS BBBO could be deployed therapeutically to control CCM formation and progression in a clinically-representative murine model.MethodsCCMs were induced in mice by postnatal, endothelial-specific Krit1 ablation. FUS was applied for BBBO with fixed peak-negative pressures (PNPs; 0.2-0.6 MPa) or passive cavitation detection-modulated PNPs. Magnetic resonance imaging (MRI) was used to target FUS treatments, evaluate safety, and measure longitudinal changes in CCM growth after BBBO.ResultsFUS BBBO elicited gadolinium accumulation primarily at the perilesional boundaries of CCMs, rather than lesion cores. Passive cavitation detection and gadolinium contrast enhancement were comparable in CCM and wild-type mice, indicating that Krit1 ablation does not confer differential sensitivity to FUS BBBO. Acutely, CCMs exposed to FUS BBBO remained structurally stable, with no signs of hemorrhage. Longitudinal MRI revealed that FUS BBBO halted the growth of 94% of CCMs treated in the study. At 1 month, FUS BBBO-treated lesions lost, on average, 9% of their pre-sonication volume. In contrast, non-sonicated control lesions grew to 670% of their initial volume. Lesion control with FUS BBBO was accompanied by a marked reduction in the area and mesenchymal appearance of Krit mutant endothelium. Strikingly, in mice receiving multiple BBBO treatments with fixed PNPs, de novo CCM formation was significantly reduced by 81%. Mock treatment plans on MRIs of patients with surgically inaccessible lesions revealed their lesions are amenable to FUS BBBO with current clinical technology.ConclusionsOur results establish FUS BBBO as a novel, non-invasive modality that can safely arrest murine CCM growth and prevent their de novo formation. As an incisionless, MR image-guided therapy with the ability to target eloquent brain locations, FUS BBBO offers an unparalleled potential to revolutionize the therapeutic experience and enhance the accessibility of treatments for CCM patients.

Project description:BACKGROUND:The systemic low-frequency oscillation (sLFO) functional (f)MRI signals extracted from the internal carotid artery (ICA) and the superior sagittal sinus (SSS) are found to have valuable physiological information. PURPOSE:1) To further develop and validate a method utilizing these signals to measure the delay times from the ICAs and the SSS. 2) To establish the delay time as an effective perfusion biomarker that associates with cerebral circulation time (CCT). 3) To explore within subject variations, and the effects of gender and age on the delay times. STUDY TYPE:Prospective. SUBJECTS:In all, 100 healthy adults (Human Connectome Project [HCP], age range 22-36 years, 54 females and 46 males), 56 healthy children (Adolescent Brain Cognitive Development project) were included. FIELD STRENGTH/SEQUENCE:Echo planar imaging (EPI) sequence at 3T. ASSESSMENT:The sLFO fMRI signals from the ICAs and the SSSs were extracted from the resting state fMRI data. The maximum cross-correlation coefficients and their corresponding delay times were calculated. The gender and age differences of delay times were assessed statistically. STATISTICAL TESTS:T-tests were conducted to measure the gender differences. The Kruskal-Wallis test was used to detect age differences. RESULTS:Consistent and robust results were found from 80% of the 400 HCP scans included. Negative correlations (-0.67) between the ICA and the SSS signals were found with the ICA signal leading the SSS signal by ?5 sec. Within subject variation was 2.23 sec at the 5% significance level. The delay times were not significantly different between genders (P = 0.9846, P = 0.2288 for the left and right ICA, respectively). Significantly shorter delay times (4.3 sec) were found in the children than in the adults (P < 0.01). DATA CONCLUSION:We have shown that meaningful perfusion information (ie, CCT) can be derived from the sLFO fMRI signals of the large blood vessels. LEVEL OF EVIDENCE:1 Technical Efficacy Stage: 1 J. Magn. Reson. Imaging 2019;50:1504-1513.

Dataset Information

Diminished Expression of P-glycoprotein Using Focused Ultrasound Is Associated With JNK-Dependent Signaling Pathway in Cerebral Blood Vessels.

Publications

Diminished Expression of P-glycoprotein Using Focused Ultrasound Is Associated With JNK-Dependent Signaling Pathway in Cerebral Blood Vessels.

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