Controllable permeability of blood-brain barrier and reduced brain injury through low-intensity pulsed ultrasound stimulation.
Authors: Su WS, Tsai ML, Huang SL, Liu SH, Yang FY
It has been shown that the blood-brain barrier (BBB) can be locally disrupted by focused ultrasound (FUS) in the presence of microbubbles (MB) while sustaining little damage to the brain tissue. Thus, the safety issue associated with FUS-induced BBB disruption (BBBD) needs to be investigated for future clinical applications. This study demonstrated the neuroprotective effects induced by low-intensity pulsed ultrasound (LIPUS) against brain injury in the sonicated brain. Rats subjected to a BBB disruption injury received LIPUS exposure for 5 min after FUS/MB application. Measurements of BBB permeability, brain water content, and histological analysis were then carried out to evaluate the effects of LIPUS. The permeability and time window of FUS-induced BBBD can be effectively modulated with LIPUS. LIPUS also significantly reduced brain edema, neuronal death, and apoptosis in the sonicated brain. Our results show that brain injury in the FUS-induced BBBD model could be ameliorated by LIPUS and that LIPUS may be proposed as a novel treatment modality for controllable release of drugs into the brain.
Introduction
Purpose
Drug delivery with BBB opening
Study Objective
To evaluate whether low-intensity pulsed ultrasound (LIPUS) can modulate focused ultrasound/microbubble-induced blood–brain barrier disruption and reduce associated brain injury in a rat model.
Animal model / Human subject
Rat; Sprague-Dawley; male; 280-300g
Targeted brain region(s)
Hemisphere
Target coordinates
AP: 3 mm posterior to bregma; ML: 2.5 mm lateral to bregma; DV: 5.7 mm below skull surface
Outcomes and Safety
Summary of Outcomes
LPFUS shortened the duration of BBB disruption and reduced edema, hemorrhagem neuron degradation, and apoptosis in the targeted brain.
Duration of biological effect
4 hours
Safety-related matter
FUS/MB-induced BBB disruption can produce adverse effects including erythrocyte extravasation/hemorrhage, increased BBB permeability, brain edema, neuronal degeneration and apoptosis; LIPUS reduced edema, hemorrhage and cell death and was treated as a safe neuroprotective strategy, though LIPUS alone showed a mild nonsignificant increase in EB extravasation and the authors state further studies are needed to fully evaluate safety for clinical application.
Brain Region
Ultrasound Parameters
Ultrasound instrument
Single-element FUS (A392S, Panametrics)
FUS Frequency
1 MHz
FUS Pressure
0.7 Mpa (peak negative pressure)
FUS Mode
pulsed
Focal Characteristics
Focal depth: 5.7 mm; Focal length: None; Aperture size: None
Treatment frequency
single session
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