CANADIAN SOCIETY OF PHARMACOLOGY AND THERAPEUTICS 2014 SCIENTIFIC MEETING PROGRAM

Abstract

Objectives:

To examine th e effects of a cyclic cadherin peptide, containing the Ala - Asp - Thr (cADT) sequence, on BBB integrity.

Methods:

The effect of cADT peptide on BBB permeability was examined in Balb/c mice specifically focusing on both the time frame for modulation of BBB per meability and the magnitude of BBB disruption. Blood - brain barrier permeability was assessed with gadolinium contrast agent (Gd - DTPA; a small hydrophilic permeability marker), under control conditions and following exposure to cADT (0.1 - using magnetic resonance imaging (MRI). Administration of imaging agents and cadherin peptide was done through bolus tail vein injections.

Results:

Under control conditions, very little Gd - DTPA entered the brain. Mice treated with cADT displayed a dose - dependent increase in BBB permeability as assessed with Gd - DTPA minimal effect on enhancement (4 - fold) and 32 mol/kg producing maximal increases (14 - fold) in Gd - DTPA entry into the brain. The increase in BBB permeabil ity was rapid, occurring within 6 - 9 minutes following the administration of the cadherin peptide. While there were regional differences in baseline BBB permeability, the cADT peptide produced similar increases in BBB permeability throughout all regions exa mined. The cADT peptide produced increases in BBB permeability that lasted for more than 2 hrs following the injection of the peptide. Complete restoration of BBB integrity was observed within 4 - 6 hrs of cadherin peptide administration.

Conclusions:

The cyclized cadherin peptide produced a rapid and reversible increase in BBB permeability. The use of the cadherin peptides in combination with therapeutic agents can enhance drug delivery to the brain.