Controlled modulation of BBB permeability using the bradykinin agonist, RMP-7

Area of Science:

• Neuroscience
• Pharmacology
• Biomedical Engineering

Background:

• The blood-brain barrier (BBB) restricts drug entry into the brain.
• Bradykinin agonist RMP-7 activates B2 receptors to permeabilize the BBB.
• RMP-7 shows enhanced effects on the blood-brain tumor barrier (BBTB).

Purpose of the Study:

• To investigate RMP-7's effect on BBB and BBTB permeability.
• To compare RMP-7's efficacy with different drug properties and tumor proximity.
• To explore BBB restoration dynamics and tachyphylaxis after RMP-7 administration.

Main Methods:

• Quantitative autoradiography and intracarotid infusions of RMP-7 in animal models.
• Comparison of RMP-7's effect on [14C]carboplatin, [14C]dextran, and [14C]BCNU permeability.
• Studies in different rat strains and tumor models, assessing BBB closure and desensitization.

Main Results:

• RMP-7 increased permeability to hydrophilic carboplatin and dextran, with greater effects on the BBTB.
• The topographic effect was more pronounced for larger molecules like dextran.
• RMP-7 had no effect on lipophilic BCNU permeability.
• BBB closure occurred within minutes of RMP-7 withdrawal.
• Continuous RMP-7 infusion led to spontaneous barrier restoration and desensitization.

Conclusions:

• RMP-7 effectively enhances BBB and BBTB permeability for hydrophilic drugs, especially near tumors.
• RMP-7's effects are dependent on drug properties and proximity to the tumor.
• The BBB rapidly recovers after RMP-7 administration, and tachyphylaxis can occur.
• Findings support RMP-7's potential for improving drug delivery across the BBB.