Intact blood-brain barrier transport of small molecular drugs in animal models of amyloid beta and alpha-synuclein pathology
Intact blood-brain barrier transport of small molecular drugs in animal models of amyloid beta and alpha-synuclein pathology
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DOI：
10.1016/j.neuropharm.2017.08.002
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发表时间：
2018-01-01
影响因子：
4.7
通讯作者：
Syvanen, Stina
中科院分区：
文献类型：
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作者：
Gustafsson, Sofia;Lindstrom, Veronica;Syvanen, Stina
神经血管单元的病理生理学损伤，包括血脑屏障（BBB）的完整性和动态性，已被认为是神经退行性疾病的原因和后果。对 BBB 药物输送的病理影响也存在争议。本研究的目的是通过测定老年 A β PP 转基因小鼠、α-突触核蛋白转基因小鼠和野生型小鼠中未结合的脑与血浆浓度比（K-p、K-uu、K-脑）来研究 BBB 药物转运。给小鼠服用一盒包含五种化合物的药物，包括地高辛、左氧氟沙星（1 mg/kg，皮下注射）、帕潘立酮、羟考酮和地西泮（0.25 mg/kg，皮下注射）。给药后0.5、1或3小时收集脑和血液。使用 LC-MS/MS 测量药物浓度。计算总脑与血浆浓度比，并使用平衡透析来确定所有化合物在脑和血浆中未结合药物的分数。这三个测量值一起用于确定 Kp,uu,brain 值。尽管当前动物模型中存在 A β 或 α-突触核蛋白病理学，但与野生型动物相比，对于所研究的任何化合物，药物跨 BBB 转运的程度没有观察到差异。因此，本研究表明，在估计药物转运至大脑时，必须谨慎解释神经退行性疾病中渗漏屏障的概念。尽管存在病理学现象，但高度动态的血脑屏障调节大脑药物暴露的能力似乎仍然完好无损。 (C) 2017 年作者。由爱思唯尔有限公司出版
Pathophysiological impairment of the neurovascular unit, including the integrity and dynamics of the blood-brain barrier (BBB), has been denoted both a cause and consequence of neurodegenerative diseases. Pathological impact on BBB drug delivery has also been debated. The aim of the present study was to investigate BBB drug transport, by determining the unbound brain-to-plasma concentration ratio (K-p,K-uu,K-brain), in aged A beta PP-transgenic mice, alpha-synuclein transgenic mice, and wild type mice.Mice were dosed with a cassette of five compounds, including digoxin, levofloxacin (1 mg/kg, s.c.), paliperidone, oxycodone, and diazepam (0.25 mg/kg, s.c.). Brain and blood were collected at 0.5,1, or 3 h after dosage. Drug concentrations were measured using LC-MS/MS. The total brain-to-plasma concentration ratio was calculated and equilibrium dialysis was used to determine the fraction of unbound drug in brain and plasma for all compounds. Together, these three measures were used to determine the Kp,uu,brain value.Despite A beta or alpha-synuclein pathology in the current animal models, no difference was observed in the extent of drug transport across the BBB compared to wild type animals for any of the compounds investigated. Hence, the present study shows that the concept of a leaking barrier within neurodegenerative conditions has to be interpreted with caution when estimating drug transport into the brain. The capability of the highly dynamic BBB to regulate brain drug exposure still seems to be intact despite the presence of pathology. (C) 2017 The Authors. Published by Elsevier Ltd.