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.
Footnotes
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This study was supported by in part by VA Merit Review, R01 NS41863, R01 AA12743, and by Repligen Corporation.
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DOI: 10.1124/jpet.102.036129
- Abbreviations:
- PACAP
- pituitary adenylate cyclase-activating polypeptide
- BBB
- blood-brain barrier
- CNS
- central nervous system
- SA
- secretin analog
- HPLC
- high-performance liquid chromatography
- I-SA
- secretin analog radioactively labeled with 131I
- T-Alb
- albumin radioactively labeled with 99mTc
- Ki
- unidirectional influx rate
- Vi
- initial volume of distribution within brain
- %Inj/g
- percentage of the intravenously injected dose present in 1 g of brain
- PE
- polyethylene
- CSF
- cerebrospinal fluid
- Received March 15, 2002.
- Accepted May 8, 2002.
- U.S. Government
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