Brain-transportable dipeptides across the blood-brain barrier in mice

• Published in: Scientific reports Vol. 9; no. 1; p. 5769
• Main Authors: Tanaka, Mitsuru, Dohgu, Shinya, Komabayashi, Genki, Kiyohara, Hayato, Takata, Fuyuko, Kataoka, Yasufumi, Nirasawa, Takashi, Maebuchi, Motohiro, Matsui, Toshiro
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 08-04-2019; Nature Publishing Group
• Subjects: 101/58; 631/1647/245/2160; 631/443/319; Animals; Blood-brain barrier; Blood-Brain Barrier - metabolism; Cerebellum; Cerebellum - metabolism; Cerebral cortex; Cerebral Cortex - metabolism; Dipeptides - chemistry; Dipeptides - pharmacokinetics; Hippocampus - metabolism; Humanities and Social Sciences; Hypothalamus; Hypothalamus - metabolism; Male; Mice; Mice, Inbred ICR; multidisciplinary; Neostriatum; Neuroimaging; Nutrients; Parenchyma; Peptides; Perfusion; Rodents; Science; Science (multidisciplinary); Tissue Distribution
• ISSN: 2045-2322; 2045-2322
• DOI: 10.1038/s41598-019-42099-9

Apart from nutrients required for the brain, there has been no report that naturally occurring peptides can cross the blood-brain barrier (BBB). The aim of this study was to identify the BBB-transportable peptides using
in situ
mouse perfusion experiments. Based on the structural features of Gly-
N
-methylated Gly (Gly-Sar), a reported BBB-transportable compound, 18 dipeptides were synthesized, and were perfused in the mouse brain for two minutes. Among the synthesized dipeptides, Gly-Sar, Gly-Pro, and Tyr-Pro were transported across the BBB with
K
i
values of 7.60 ± 1.29, 3.49 ± 0.66, and 3.53 ± 0.74 µL/g·min, respectively, and accumulated in the mouse brain parenchyma. Additionally, using MALDI-MS/MS imaging analysis of Tyr-Pro-perfused brain, we provide evidence for Tyr-Pro accumulation in the hippocampus, hypothalamus, striatum, cerebral cortex, and cerebellum of mouse brain.