Department of Pharmaceutics, Graduate School of Medicine and Pharmaceutical Sciences, University of Toyama, 2630 Sugitani, Toyama, 930-0194, Japan.
Fluids Barriers CNS. 2018 Jan 8;15(1):1. doi: 10.1186/s12987-017-0087-9.
para-Tyramine (p-TA) is a biogenic amine which is involved in multiple neuronal signal transductions. Since the concentration of p-TA in dog cerebrospinal fluid (CSF) has been reported to be greater than that in plasma, it is proposed that clearance of cerebral p-TA is important for normal function. The purpose of this study was to examine the role of the blood-brain barrier and blood-cerebrospinal fluid barrier (BCSFB) in p-TA clearance from the brain.
In vivo [H]p-TA elimination from rat cerebral cortex and from CSF was examined after intracerebral and intracerebroventricular administration, respectively. To evaluate BCSFB-mediated p-TA transport, [H]p-TA uptake by isolated rat choroid plexus and conditionally immortalized rat choroid plexus epithelial cells, TR-CSFB3 cells, was performed.
The half-life of [H]p-TA elimination from rat CSF was found to be 2.9 min, which is 62-fold faster than that from rat cerebral cortex. In addition, this [H]p-TA elimination from the CSF was significantly inhibited by co-injection of excess unlabeled p-TA. Thus, carrier-mediated p-TA transport process(es) are assumed to take part in p-TA elimination from the CSF. Since it is known that transporters at the BCSFB participate in compound elimination from the CSF, [H]p-TA transport in ex vivo and in vitro models of rat BCSFB was examined. The [H]p-TA uptake by isolated rat choroid plexus and TR-CSFB3 cells was time-dependent and was inhibited by unlabeled p-TA, indicating carrier-mediated p-TA transport at the BCSFB. The p-TA uptake by isolated choroid plexus and TR-CSFB3 cells was not reduced in the absence of extracellular Na and Cl, and in the presence of substrates of typical organic cation transporters. However, this p-TA uptake was significantly inhibited by cationic drugs such as propranolol, imipramine, amantadine, verapamil, and pyrilamine. Moreover, p-TA uptake by TR-CSFB3 cells took place in an oppositely-directed H gradient manner. Therefore, this suggested that p-TA transport at the BCSFB involves cationic drug-sensitive transport systems which are distinct from typical plasma membrane organic cation transporters.
Our study indicates that p-TA elimination from the CSF is greater than that from the cerebral cortex. Moreover, it is suggested that cationic drug-sensitive transport systems in the BCSFB participate in this p-TA elimination from the CSF.
对苯乙胺（p-TA）是一种生物胺，参与多种神经元信号转导。由于狗脑脊液（CSF）中的 p-TA 浓度大于血浆中的浓度，因此推测大脑中 p-TA 的清除对于正常功能很重要。本研究的目的是研究血脑屏障和血脑脊液屏障（BCSFB）在 p-TA 从大脑清除中的作用。
分别通过脑内和脑室内给药，研究大鼠大脑皮质中 [H]p-TA 的消除和 CSF 中 [H]p-TA 的消除。为了评估 BCSFB 介导的 p-TA 转运，进行了 [H]p-TA 摄取的离体大鼠脉络丛和条件永生大鼠脉络丛上皮细胞，TR-CSFB3 细胞。
发现 [H]p-TA 从大鼠 CSF 中的消除半衰期为 2.9 分钟，比从大鼠大脑皮质中的消除快 62 倍。此外，这种 [H]p-TA 从 CSF 的消除被过量未标记的 p-TA 共同注射显著抑制。因此，假定载体介导的 p-TA 转运过程参与了 p-TA 从 CSF 中的消除。由于已知 BCSFB 上的转运体参与了化合物从 CSF 中的消除，因此检查了大鼠 BCSFB 的离体和体外模型中的 [H]p-TA 转运。[H]p-TA 的摄取与离体大鼠脉络丛和 TR-CSFB3 细胞呈时间依赖性，并被未标记的 p-TA 抑制，表明 BCSFB 上存在载体介导的 p-TA 转运。在不存在细胞外 Na 和 Cl 的情况下，以及在典型的有机阳离子转运体的底物存在的情况下，分离的脉络丛和 TR-CSFB3 细胞的 p-TA 摄取没有减少。然而，这种 p-TA 摄取被诸如普萘洛尔、丙咪嗪、金刚烷胺、维拉帕米和苯海拉明等阳离子药物显著抑制。此外，TR-CSFB3 细胞中的 p-TA 摄取以相反的 H 梯度方式发生。因此，这表明 BCSFB 上的 p-TA 转运涉及不同于典型的质膜有机阳离子转运体的阳离子药物敏感转运系统。
我们的研究表明，CSF 中 p-TA 的消除大于大脑皮质中的消除。此外，推测 BCSFB 中的阳离子药物敏感转运系统参与了 CSF 中 p-TA 的消除。
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