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.
Geriatric Research, Education, and Clinical Center, St. Louis University School of Medicine, 915 N. Grand Boulevard, St. Louis, MO 63106, USA. bankswa@slu.edu
William A
WA
Banks
Martin
M
Goulet
James R
JR
Rusche
Michael L
ML
Niehoff
Richard
R
Boismenu
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