Controllable permeability of blood-brain barrier and reduced brain injury through low-intensity pulsed ultrasound stimulation.

Wei-Shen Su,Feng-Yi Yang,Min-Lan Tsai,Sin-Luo Huang,Shing-Hwa Liu

doi:10.18632/oncotarget.5978

Abstract

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.

Highlights

The blood-brain barrier (BBB) is a rate-limiting factor in terms of the brain’s permeability to drugs
After sonications, Evans Blue (EB) extravasation significantly decreased in the focused ultrasound (FUS)/MB-sonicated brains followed by FUS (2.86 W) or low-intensity pulsed ultrasound (LIPUS) (0.51 W) application compared to the FUS in the presence of MB (FUS/MB) group (Fig. 1B)
This study shows for the first time that LIPUS stimulation after FUS/MB-induced BBB disruption (BBBD) modulates the duration of BBB and reduces cerebral edema

Summary

Introduction

The blood-brain barrier (BBB) is a rate-limiting factor in terms of the brain’s permeability to drugs. Many promising studies have demonstrated that focused ultrasound (FUS) with microbubbles (MB) can non-invasively deliver therapeutic agents to a specific region of interest in the brain through local BBB disruption (BBBD) [1,2,3]. Ultrasound interacts with MB to produce cavitation, which releases drugs, and causes brain injury, including mild hemorrhage, edema, or apoptosis [4, 5]. Several studies have shown that FUS-induced BBBD does not cause observable histological brain damage [6, 7]. Treatment safety depends wholly on the selection of appropriate treatment parameters relatively little brain damage occurs at optimum ultrasound parameters capable of FUS-induced BBBD, no investigation has showed a complete lack of brain injury when using this non-invasive technique. Investigations aimed at providing an effective method for neuroprotection against brain injury following FUS-induced BBBD are necessary

Methods

Results

Conclusion