In Vivo Transport of a Dynorphin-like Analgesic Peptide,E-2078, Through the Blood–Brain Barrier: An Application of Brain Microdialysis |
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Authors: | Tetsuya Terasaki Yoshiharu Deguchi Hitoshi Sato Ken-ichi Hirai Akira Tsuji |
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Institution: | (1) Department of Pharmaceutics, Faculty of Pharmaceutical Sciences, Kanazawa University, Takara-machi, Kanazawa, 920, Japan |
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Abstract: | In vivo transport through the blood–brain barrier (BBB) has been demonstrated for a dynorphin-like analgesic peptide, CH3-125I]Tyr-Gly-Gly-Phe-Leu-Arg-CH3Arg-D-Leu-NHC2H5 (125I]E-2078). A remarkable time-dependent increase in the distribution volume of 125I]E-2078 in the brain parenchyma separated from blood vessels and capillaries was observed during a brain perfusion. The distribution volume of 125I]E-2078 in the brain parenchyma after 20 min of perfusion was 2.18 ± 0.09 µl/g brain (mean ± SE) and was significantly greater than the distribution volume of 3H]inulin (0.994 ± 0.138 (µl/g brain), providing in vivo evidence for the penetration of 125I]E-2078 into the brain parenchyma. Brain microdialysis was carried out to collect directly the brain interstitial fluid (ISF) during the brain perfusion of 125I]E-2078. No metabolite of 125I]E-2078 in the brain ISF was found by high-performance liquid chromatographic analysis of the brain dialysate. The concentrations of 125I]E-2078 and 14C]sucrose in the brain ISF were estimated based on an in vitro evaluation of dialysis clearance. The concentration ratio of 125I]E-2078 between the brain ISF and the brain perfusate was determined to be 2.92 × 10–l ± 0.50 × 10–l and was approximately 100 times higher than that of 14C]sucrose (2.71 × 10–3 ± 1.43 × 10–3), demonstrating transport of 125I]E-2078 through the BBB in vivo. On the other hand, no remarkable difference in the cerebrospinal fluid (CSF)-to-perfusate concentration ratios of 125I]E-2078 and 14C]sucrose was observed, indicating little contribution of the blood–CSF barrier (BCSF barrier) transport to the penetration of 125I]E-2078 into the brain. |
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Keywords: | brain microdialysis dynorphin-like analgesic peptide basic peptide blood– brain barrier (BBB) transport brain perfusion brain interstitial fluid blood– cerebrospinal fluid (BCSF) barrier absorptive-mediated endocytosis |
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