Differential transport of a secretin analog across the blood-brain and blood-cerebrospinal fluid barriers of the mouse.
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 (131)I (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 microl/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 microg/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.
Banks
William A
WA
Geriatric Research, Education, and Clinical Center, St. Louis University School of Medicine, 915 N. Grand Boulevard, St. Louis, MO 63106, USA. bankswa@slu.edu
Goulet
Martin
M
Rusche
James R
JR
Niehoff
Michael L
ML
Boismenu
Richard
R
D000465:Algorithms; D000818:Animals; D001812:Blood-Brain Barrier / Q000502:physiology*; D002199:Capillary Permeability; D002851:Chromatography, High Pressure Liquid; D007275:Injections, Intravenous; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D012044:Regression Analysis; D012633:Secretin / Q000031:analogs & derivatives* / Q000134:cerebrospinal fluid / Q000493:pharmacokinetics*; D012995:Solubility; D012997:Solvents; D014018:Tissue Distribution
D012997:Solvents; D012633:Secretin