دورية أكاديمية
[Development of Novel Methodology and Its Application for Clarifying the Transport Function of the Blood-brain Barrier].
| العنوان: | [Development of Novel Methodology and Its Application for Clarifying the Transport Function of the Blood-brain Barrier]. |
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| المؤلفون: | Terasaki T; Membrane Transport and Drug Targeing Laboratory, Graduate School of Pharmaceutical Sciences, Tohoku University. |
| المصدر: | Yakugaku zasshi : Journal of the Pharmaceutical Society of Japan [Yakugaku Zasshi] 2021; Vol. 141 (4), pp. 447-462. |
| نوع المنشور: | Journal Article; Review |
| اللغة: | Japanese |
| بيانات الدورية: | Publisher: Nihon Yakugakkai Country of Publication: Japan NLM ID: 0413613 Publication Model: Print Cited Medium: Internet ISSN: 1347-5231 (Electronic) Linking ISSN: 00316903 NLM ISO Abbreviation: Yakugaku Zasshi Subsets: MEDLINE |
| أسماء مطبوعة: | Original Publication: Tokyo : Nihon Yakugakkai |
| مواضيع طبية MeSH: | Biological Transport/*physiology , Blood-Brain Barrier/*metabolism , Brain/*metabolism , Proteomics/*methods, ATP Binding Cassette Transporter, Subfamily B, Member 1/metabolism ; Animals ; Cell Line ; Chromatography, Liquid/methods ; Humans ; Membrane Transport Proteins/metabolism ; Mice ; Neurotransmitter Agents/metabolism ; Proteomics/trends ; Rats ; Tandem Mass Spectrometry/methods ; Xenobiotics/metabolism |
| مستخلص: | The blood-brain barrier (BBB) consists of brain capillary endothelial cells linked by tight junctions and serves to regulate the transfer of endogenous compounds and xenobiotics between the circulating blood and brain interstitial fluid. We have developed a methodology to characterize brain-to-blood efflux transport in vivo, using the Brain Efflux Index and an in vitro culture model of the BBB, i.e., a conditionally immortalized cell line of the neurovascular unit. Employing these methods, we showed that the BBB plays an important role in protecting the brain by transporting neurotransmitters, neuromodulators, metabolites, uremic toxins, and xenobiotics together with atrial natriuretic peptide from the brain interstitial fluid to the circulating blood. We also developed a highly selective, sensitive LC-MS/MS method for simultaneous protein quantification. We found significant species differences in the expression amounts of various BBB transporter proteins among mice, rats, marmosets, cynomolgus monkeys, and humans. Among transporter proteins at the BBB, multidrug resistance protein 1 (Mdr1/Abcb1) is known to generate a concentration gradient of unbound substrate drugs between the blood and brain. Based on measurements of the intrinsic efflux transport rate of Mdr1 and the protein expression amounts of Mdr1 in mouse brain capillaries and Mdr1-expressing cell lines, we predicted the unbound drug concentration gradients of 7 drugs in the mouse brain in vivo. This was the first successful prediction of in vivo drug transport activity from in vitro experimental data and transporter protein concentration in tissues. This methodology and findings should greatly advance central nervous system barrier research. |
| فهرسة مساهمة: | Keywords: Brain Efflux Index method; blood-brain barrier; conditionally immortalized cell line; in vitro blood-brain barrier model; mass spectrometry; pharmacoproteomics |
| المشرفين على المادة: | 0 (ATP Binding Cassette Transporter, Subfamily B, Member 1) 0 (Membrane Transport Proteins) 0 (Neurotransmitter Agents) 0 (Xenobiotics) |
| تواريخ الأحداث: | Date Created: 20210401 Date Completed: 20210702 Latest Revision: 20210702 |
| رمز التحديث: | 20240513 |
| DOI: | 10.1248/yakushi.20-00232 |
| PMID: | 33790111 |
| قاعدة البيانات: | MEDLINE |
| تدمد: | 1347-5231 |
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| DOI: | 10.1248/yakushi.20-00232 |