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Blood-brain barrier functioning as dynamic interface and drug delivery to the brain

血脑屏障充当动态界面和向大脑输送药物

基本信息

批准号：
07457527
负责人：
TSUJI Akira
金额：
$ 4.93万
依托单位：
Kanazawa University
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (B)
财政年份：
1995
资助国家：
日本
起止时间：
1995 至 1996
项目状态：
已结题

项目摘要

The purpose of this research project is to clarify the blood-brain barrier (BBB) functions by regulating carrier-mediated influx and efflux of nutrients and xenobiotics. The following results were obtained by two years term of this research project :1.In transient brain ischemic rats, ATP depletion in the brain resulted in the 17-fold increase of BBB permeability coefficient (PS) of doxorubicin (DOX), whereas no change of PS-value of sucrose by this ischemia. When the ATP content recovered to a normal level by means of cerebral recirculation of blood, the PS-value of DOX recovered to the control PS-value in normal rats. The uptake of DOX by primary cultured bovine brain capillary endothelial cells (BCECs) expressing P-glycoprotein (P-gp) at the luminal membrane was increased significantly by the depletion of ATP level in BCECs. Present evidence for the ATP-dependent transport of DOX and previous results from our laboratory strongly indicate that P-gp in the brain capillaries functions actively as an efflux pump for lipophilic xenobiotics, providing a major mechanism to restrict the transfer of xenobiotics as well as DOX in the brain.2.Secondary active transport system for beta-alanine and taurine, which are transported in sodium and chloride-ion dependent manner, functions at both the luminal and antiluminal membranes of the BBB.The transport system was highly selective for beta-amino acids, such as beta-alanine, taurine and hypotaurine.3.The expression of H^+/monocarboxylate transporter MCT1 in the brain capillaries was clarified by RT-PCR and the nucleotide sequence of the PCR product was confirmed to be the same as that of a part of ratMCT1. This result indicates that MCT1 contributes to pH-dependent and carrier-mediated influx and efflux of monocarboxylic acids at the BBB.4.Peptides were confirmed to be taken up by BCECs via adsorptive-mediated endocytosis which was affected by charge density and/or lipophilicity of peptides.

本研究的目的是通过调节载体介导的营养物质和外来物质的流入和流出来阐明血脑屏障(BBB)的功能。本研究为期两年，结果如下：1.在短暂性脑缺血大鼠，脑内ATP耗竭导致阿霉素(DOX)的血脑屏障通透系数(PS)增加17倍，而蔗糖的PS值无明显变化。经脑血液再循环使ATP含量恢复到正常水平后，正常大鼠DOX的PS值恢复到正常对照组的PS值。原代培养的表达P-糖蛋白(P-gp)的牛脑毛细血管内皮细胞(BCECs)摄取DOX的能力随着BCECs中ATP水平的降低而显著增加。目前有证据表明DOX的转运依赖于ATP，我们实验室的先前结果有力地表明，脑毛细血管中的P-gp积极地作为亲脂性外源生物的外流泵发挥作用，为限制外源物质以及DOX在大脑中的转运提供了一个主要机制。2.β-丙氨酸和牛磺酸的次级主动转运系统，以钠和氯离子依赖的方式转运，在BBB的管腔和反腔膜上发挥作用。该转运系统对β-氨基酸，如β-丙氨酸，具有高度的选择性。3.RT-PCR证实了H~+/单羧酸转运蛋白MCT1在脑毛细血管中的表达，并与部分rATMCT1的核苷酸序列进行了比较。这一结果表明，MCT1参与了单羧酸在BBB上的pH依赖性和载体介导的内流和外流。4多肽被BCEC通过吸附介导的内吞作用摄取，这种内吞作用受多肽的电荷密度和/或亲脂性的影响。