Modulation of blood-brain barrier permeability in mice using synthetic E-cadherin peptide.
The present work characterizes the effects of synthetic E-cadherin peptide (HAV) on blood-brain barrier (BBB) integrity using various techniques including magnetic resonance imaging (MRI) and near-infrared fluorescent imaging (NIRF). The permeability of small molecular weight permeability marker gadolinium diethylenetriaminepentaacetate (Gd-DTPA) contrast agent, the large molecular weight permeability marker, IRDye 800CW PEG, and the P-glycoprotein (P-gp) efflux transporter contrast agent, rhodamine 800 (R800), were examined in the presence and absence of HAV peptide. The results consistently demonstrated that systemic iv administration of HAV peptide resulted in a reversible disruption of BBB integrity and enhanced the accumulation of all the dyes examined. The magnitude of increase ranged from 2-fold to 5-fold depending on the size and the properties of the permeability markers. The time frame for BBB disruption with HAV peptide was rapid, occurring within 3-6 min following injection of the peptide. Furthermore, modulation of BBB permeability was reversible with the barrier integrity being restored within 60 min of the injection. The increased BBB permeability observed following HAV peptide administration was not attributable to changes in cerebral blood flow. These studies support the potential use of cadherin peptides to rapidly and reversibly modulate BBB permeability of a variety of therapeutic agents.
Department of Pharmacology and Therapeutics, University of Manitoba , Winnipeg, Manitoba, Canada.
Ngoc H
NH
On
Paul
P
Kiptoo
Teruna J
TJ
Siahaan
Donald W
DW
Miller
D000818:Animals; D001692:Biological Transport; D001812:Blood-Brain Barrier / Q000187:drug effects* / Q000378:metabolism; D001921:Brain / Q000098:blood supply* / Q000187:drug effects / Q000378:metabolism; D015820:Cadherins / Q000378:metabolism*; D002463:Cell Membrane Permeability / Q000187:drug effects*; D003287:Contrast Media; D005260:Female; D019786:Gadolinium DTPA; D008279:Magnetic Resonance Imaging; D051379:Mice; D008807:Mice, Inbred BALB C; D010446:Peptide Fragments / Q000008:administration & dosage / Q000494:pharmacology*; D019265:Spectroscopy, Near-Infrared
D015820:Cadherins; D003287:Contrast Media; D010446:Peptide Fragments; D019786:Gadolinium DTPA