Differential Transport of a Secretin Analog across the Blood-Brain and Blood-Cerebrospinal Fluid Barriers of the Mouse
- 1 September 2002
- journal article
- Published by American Society for Pharmacology & Experimental Therapeutics (ASPET) in Journal of Pharmacology and Experimental Therapeutics
- Vol. 302 (3), 1062-1069
- https://doi.org/10.1124/jpet.102.036129
Abstract
Secretin is a gastrointestinal peptide belonging to the vasoactive intestinal peptide (VIP)/glucagon/pituitary adenylate cyclase-activating polypeptide (PACAP) family recently suggested to have therapeutic effects in autism. A direct effect on brain would require secretin to cross the blood-brain barrier (BBB), an ability other members of the VIP/PACAP family have. Herein, we examined whether a secretin analog (SA) radioactively labeled with 131I (I-SA) could cross the BBB of 4-week-old mice. We found I-SA was rapidly cleared from serum with fragments not precipitating with acid appearing in brain and serum. Levels of radioactivity were corrected to reflect only intact I-SA as estimated by acid precipitation. After i.v. injection, I-SA was taken up by brain at a modest rate of 0.9 to 1.5 μl/g-mm. Capillary depletion, brain perfusion, and high-performance liquid chromatography were used to confirm the passage of intact I-SA across the BBB. I-SA entered every brain region, with the highest uptake into the hypothalamus and cerebrospinal fluid (CSF). Unlabeled SA (10 μg/mouse) did not inhibit uptake by brain but did inhibit clearance from blood and uptake by the CSF, colon, kidney, and liver. The decreased clearance of I-SA from blood increased the percentage of the i.v. injected dose taken up per brain (%Inj/g) from about 0.118 to 0.295%Inj/g. In conclusion, SA crosses the vascular barrier by a nonsaturable process and the choroid plexus by a saturable process in amounts that for other members of its family produce central nervous system (CNS) effects. This passage provides a pathway through which peripherally administered SA could affect the CNS.Keywords
This publication has 28 references indexed in Scilit:
- Effect of secretin on children with autism: a randomized controlled trialDevelopmental Medicine and Child Neurology, 2000
- Secretin and autism: a two-part clinical investigation.Journal of Autism and Developmental Disorders, 2000
- MRI volumes of amygdala and hippocampus in non–mentally retarded autistic adolescents and adultsNeurology, 1999
- Demonstration of a Direct Interaction between Residue 22 in the Carboxyl-terminal Half of Secretin and the Amino-terminal Tail of the Secretin Receptor Using Photoaffinity LabelingPublished by Elsevier ,1999
- Intracerebroventricular secretin enhances pancreatic volume and bicarbonate response in ratsSurgery, 1996
- Peptides and the blood-brain barrier: Lipophilicity as a predictor of permeabilityBrain Research Bulletin, 1985
- Secretin modulation of behavioral and physiological functions in the ratPeptides, 1983
- Secretin: specific binding to rat brain membranesJournal of Neuroscience, 1983
- A microsphere study on the effects of somatostatin and secretin on regional blood flow in anesthetized dogsRegulatory Peptides, 1982
- The mechanism of pancreatic secretionThe Journal of Physiology, 1902