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ABSORPTION, DISTRIBUTION, METABOLISM, AND EXCRETION

Characterization of Blood-Brain Barrier Permeability to PYY_3-36 in the Mouse

Oral Anatomy, School of Dentistry, Showa University, Tokyo, Japan (N.N.); First Anatomy, School of Medicine, Showa University, Tokyo, Japan (N.N., S.S.); Geriatric Research, Education, and Clinical Center, Veterans Affairs Medical Center-St. Louis and Division of Geriatrics, Department of Internal Medicine, St. Louis University School of Medicine, St. Louis, Missouri (N.N., M.L.N., W.A.B.)

Peptide YY_3-36 (PYY) has emerged as an important signal in the gut-brain axis, with peripherally administered PYY affecting feeding and brain function. For these effects to be direct, PYY would have to cross the blood-brain barrier (BBB). Here, we determined the permeability of the BBB to PYY radioactively labeled with ¹³¹I (I-PYY). Multiple-time regression analysis showed the unidirectional influx rate (K_i) from blood-to-brain for I-PYY to be 0.49 ± 0.19 µl/g-min, a rate similar to that previously measured for leptin. Influx was not inhibited by 1 µg/mouse of unlabeled PYY, suggesting PYY crosses the BBB by transmembrane diffusion. About 0.176% of the i.v.-injected dose of I-PYY was taken up by brain, an amount similar to that for other peptides important in gut-brain communication. Capillary depletion showed that 69% of I-PYY crossed the BBB to enter the parenchymal space of the brain, and high-performance liquid chromatography demonstrated that the radioactivity in this space represented intact I-PYY. After intracerebroventricular injection, I-PYY crossed from brain to blood by the mechanism of bulk flow. We conclude that PYY crosses in both the blood-to-brain and brain-to-blood directions by nonsaturable mechanisms. Passage across the BBB provides a mechanism by which blood-borne PYY can affect appetite and brain function.

Address correspondence to: Dr. William A. Banks, Geriatric Research, Education, and Clinical Center, Veterans Affairs Medical Center, John Cochran Division, 915 N. Grand Blvd., St. Louis, MO 63106. E-mail: bankswa{at}slu.edu

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