Role of the blood-cerebrospinal fluid barrier transporter as a cerebral clearance system for prostaglandin E2 produced in the brain.
Role of the blood-cerebrospinal fluid barrier transporter as a cerebral clearance system for prostaglandin E2 produced in the brain.
复制标题
血脑脊液屏障转运蛋白作为脑内产生的前列腺素 E2 的脑清除系统的作用。
DOI：
10.1111/jnc.12018
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发表时间：
2012
期刊：
影响因子：
4.7
通讯作者：
Tachikawa M
中科院分区：
文献类型：
--
作者：
Eskilsson A.;Tachikawa M.;Hosoya K.;Blomqvist A.;Tachikawa M;Tachikawa M
前列腺素e2水平的升高参与了缺血和细菌感染引起的神经炎症的进展。尽管在这些病理条件下pge2的产生和清除率的不平衡似乎会影响脑脊液（CSF）中pge2的浓度，但其调控系统仍不完全清楚。本研究的目的是研究通过微粒体PGE2合成酶- 1 （mPGES - 1）、可诱导的PGE2生成酶和通过血- CSF屏障（BCSFB）从脑脊液中清除PGE2的细胞系统。免疫组织化学分析显示，mPGES‐1在星形胶质细胞、硬脑膜和脑血管内皮细胞的体细胞和血管周围层中表达，表明这些细胞是脑脊液中pge2的局部产生位点。它们体内对脑脊液中opge2的清除能力是甘露醇的8倍，甘露醇被认为反映了脑脊液的体积流量。同时注射未标记的pge2和β -内酰胺类抗生素，如青霉素、头孢唑林和头孢曲松，可以抑制这一过程，这些抗生素是有机阴离子转运蛋白3 （OAT3）的底物和/或抑制剂。离体脉络膜丛对pge2的摄取特征至少部分与OAT3一致。OAT3介导pge2的输运，Michaelis-Menten常数为4.24 μM。这些发现表明，脑脊液中调节PGE2水平的系统涉及脉络丛上皮细胞对OAT3介导的PGE2摄取，通过局部产生PGE2的BCSFB作为脑清除途径。
An increasing level of prostaglandin (PG) E2is involved in the progression of neuroinflammation induced by ischemia and bacterial infection. Although an imbalance in the rates of production and clearance of PGE2under these pathological conditions appears to affect the concentration of PGE2in the cerebrospinal fluid (CSF), the regulatory system remains incompletely understood. The purpose of this study was to investigate the cellular system of PGE2production via microsomal PGE synthetase‐1 (mPGES‐1), the inducible PGE2‐generating enzyme, and PGE2elimination from the CSF via the blood–CSF barrier (BCSFB). Immunohistochemical analysis revealed that mPGES‐1 was expressed in the soma and perivascular sheets of astrocytes, pia mater, and brain blood vessel endothelial cells, suggesting that these cells are local production sites of PGE2in the CSF. Thein vivoPGE2elimination clearance from the CSF was eightfold greater than that ofd‐mannitol, which is considered to reflect CSF bulk flow. This process was inhibited by the simultaneous injection of unlabeled PGE2and β‐lactam antibiotics, such as benzylpenicillin, cefazolin, and ceftriaxone, which are substrates and/or inhibitors of organic anion transporter 3 (OAT3). The characteristics of PGE2uptake by the isolated choroid plexus were at least partially consistent with those of OAT3. OAT3 was able to mediate PGE2transport with a Michaelis–Menten constant of 4.24 μM. These findings indicate that a system regulating the PGE2level in the CSF involves OAT3‐mediated PGE2uptake by choroid plexus epithelial cells, acting as a cerebral clearance pathway via the BCSFB of locally produced PGE2.