Blood-brain barrier disruption induced by diagnostic ultrasound combined with microbubbles in mice

Area of Science:

• Neuroscience
• Biomedical Engineering
• Pharmacology

Background:

• The blood-brain barrier (BBB) restricts the passage of most molecules into the brain.
• Non-invasive methods for controlled BBB opening are crucial for targeted brain therapies.
• Diagnostic ultrasound combined with microbubbles (MBs) offers a potential strategy for BBB modulation.

Purpose of the Study:

• To determine how microbubble dose, mechanism index (MI), and sonication duration affect ultrasound-induced BBB disruption.
• To explore the molecular mechanisms underlying BBB changes.
• To assess the safety and efficacy of this technique for potential therapeutic applications.

Main Methods:

• Blood-brain barrier disruption was assessed using Evans blue (EB) staining and EB extravasation measurements.
• Histological examination evaluated potential tissue damage.
• Western blotting and immunohistofluorescence analyzed tight junction (TJ) protein expression (ZO-1, occludin, claudin-5).
• Transmission electron microscopy examined TJ ultrastructure changes.

Main Results:

• BBB disruption extent positively correlated with MB dose, MI, and sonication duration.
• Optimal parameters achieved significant BBB disruption with minimal tissue damage.
• Reduced expression of ZO-1, occludin, and claudin-5 was observed, correlating with BBB disruption.
• Lanthanum nitrate tracer confirmed paracellular passage across the disrupted BBB.

Conclusions:

• Ultrasound-mediated microbubble administration is a viable method for controlled BBB opening.
• This technique facilitates the delivery of diagnostic and therapeutic agents to the brain.
• It holds significant potential for advancing the diagnosis and treatment of brain diseases.