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Abstract
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 Ki 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.
Highlights
The physiological preference of peptide uptake has been demonstrated in human and animal studies
It has been reported that cell penetrating peptides (CPP) mostly composed of >10 amino acids possessing cationic, amphipathic or hydrophobic properties can enter the central nervous system (CNS) by energy-independent passive penetration or energy-dependent endocytosis penetration pathways[9], there are no studies showing the intact transport of small hydrophilic peptides beyond the blood-brain barrier (BBB) system
The transport of Gly-Sar across mouse BBB was determined in brain homogenates by using 2,4,6-trinitrobenzensulfonate (TNBS) aided-liquid chromatography-time-of-flight (LC-TOF)/mass spectrometry (MS) technique described previousely[17], wherein the target peptide was derivatized with TNBS to form a trinitrophenyl (TNP)-peptide
Summary
The physiological preference of peptide uptake has been demonstrated in human and animal studies. No studies report the intact absorption of dipeptides beyond the blood-brain barrier (BBB). It has been reported that cell penetrating peptides (CPP) mostly composed of >10 amino acids possessing cationic, amphipathic or hydrophobic properties can enter the central nervous system (CNS) by energy-independent passive penetration or energy-dependent endocytosis penetration pathways[9], there are no studies showing the intact transport of small hydrophilic peptides (i.e., di-/tripeptides) beyond the BBB system. In the BBB system, the transporters of PepT2 and peptide/histidine transporter 1 (PHT1), but not PepT1, were expressed at the blood-cerebrospinal fluid (CSF)-barrier composed of the choroid plexus epithelium[7]. An in vivo pharmacokinetic study using Pht1-null mice[11] revealed that PHT1 is expressed throughout the brain including choroid plexus, and preferably recognizes histidines. We performed a mass spectrometry (MS)-visualization experiment with phytic acid-aided matrix assisted laser desorption ionization (MALDI)– MS/MS imaging[15] to provide a direct evidence of the accumulation of dipeptides in the brain
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