In vivo and in vitro evidence of blood-brain barrier transport of a novel cationic arginine-vasopressin fragment 4-9 analog.
In vivo and in vitro evidence of blood-brain barrier transport of a novel cationic arginine-vasopressin fragment 4-9 analog.
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新型阳离子精氨酸-加压素片段 4-9 类似物的血脑屏障转运的体内和体外证据。
DOI：
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发表时间：
1999
影响因子：
3.5
通讯作者：
Tetsuya Terasaki
中科院分区：
文献类型：
--
作者：
S. Tanabe;Y. Shimohigashi;Yasuhisa Nakayama;Takashi Makino;Tsugumi Fujita;T. Nose;Gozoh Tsujimoto;Teruo Yokokura;Mikihiko Naito;Takashi Tsuruo;Tetsuya Terasaki
本文研究了一种新的精氨酸加压素片段4-9 [AVP（4-9），等电点（pI）= 9.2]类似物，即阳离子AVP（4 -9）（C-AVP（4 - 9），PI = 9.8）在体内和体外血脑屏障（BBB）中的转运和代谢。在小鼠静脉注射给药后45分钟，（35）S标记AVP（4-9）和（125）I标记C-AVP（4-9）的大脑-血浆浓度比分别为0.103和0.330 ml/g大脑，BBB渗透清除率分别为1.47 × 10（-4）和3.10 × 10（-4）ml/min/g大脑。在使用通过SV 40感染永生化的小鼠脑毛细血管内皮细胞（MBEC 4）的体外研究中，在120分钟时，（35）S-标记的AVP（4-9）和（125）I-标记的C-AVP（4-9）与MBEC 4的耐酸结合值分别为0.93和1.95微升/mg蛋白（作为细胞/培养基比）。（35）S-标记的AVP（4-9）显示出双相饱和的耐酸结合，其半饱和常数（K（D））为3.8 nM（高亲和力）和45.7 μ M（低亲和力）。（125）I标记的C-AVP（4-9）显示单相饱和耐酸结合，K（D）值为16.4 μ M。（125）I标记的C-AVP（4-9）的抗酸结合显著依赖于温度和介质渗透压。（125）I标记的C-AVP（4-9）的抗酸结合被丹酰尸胺、氧化苯胂（内吞抑制剂）、2，4-二硝基苯酚（代谢抑制剂）和AVP（4-9）、聚（L-赖氨酸）和鱼精蛋白（阳离子物质）抑制，但不被聚（L-谷氨酸）（阴离子肽）和V（1）和V（2）加压素受体拮抗剂抑制。此外，通过HPLC和质谱法证实脑匀浆中C-AVP（4 -9）转化为AVP（4-9）。目前的结果表明，C-AVP（4-9）通过吸收介导的内吞作用比AVP（4-9）更有效地转运通过BBB，并且C-AVP（4-9）在大脑中转化为神经活性母体肽AVP（4-9）。
The blood-brain barrier (BBB) transport and metabolism of a novel arginine-vasopressin fragment 4-9 [AVP(4-9), isoelectric point; (pI) = 9.2] analog, that is, cationic AVP(4-9) (C-AVP(4-9), PI = 9.8), were examined in vivo and in vitro. At 45 min after an i.v. administration to mice, the cerebrum-to-plasma concentration ratios of (35)S-labeled AVP(4-9) and (125)I-labeled C-AVP(4-9) were 0.103 and 0.330 ml/g cerebrum, respectively, and the BBB permeation clearances were 1.47 x 10(-4) and 3.10 x 10(-4) ml/min/g cerebrum, respectively. In the in vitro study using mouse brain capillary endothelial cells immortalized by SV40 infection (MBEC4), the acid-resistant binding values of (35)S-labeled AVP(4-9) and (125)I-labeled C-AVP(4-9) to MBEC4 at 120 min were 0.93 and 1.95 microliter/mg protein (as the cell/medium ratios), respectively. (35)S-labeled AVP(4-9) showed two-phase saturable acid-resistant binding, and its half-saturation constants (K(D)) were 3.8 nM (high affinity) and 45.7 microM (low affinity). (125)I-labeled C-AVP(4-9) showed single-phase saturable acid-resistant binding, with a K(D) value of 16.4 microM. The acid-resistant binding of (125)I-labeled C-AVP(4-9) was significantly dependent on temperature and medium osmolarity. The acid-resistant binding of (125)I-labeled C-AVP(4-9) was inhibited by dancylcadaverine, phenylarsine oxide (endocytosis inhibitors), 2,4-dinitrophenol (a metabolic inhibitor), and AVP(4-9), poly(L-lysine), and protamine (cationic substances), but not by poly(L-glutamic acid) (an anionic peptide) and the V(1) and V(2) vasopressin receptor antagonists. In addition, the conversion of C-AVP(4-9) to AVP(4-9) in the cerebral homogenate was confirmed by HPLC and mass spectrometry. The present results demonstrate that C-AVP(4-9) is transported through the BBB more effectively than AVP(4-9), via absorptive-mediated endocytosis, and that C-AVP(4-9) is converted to the neuroactive parent peptide, AVP(4-9), in the cerebrum.
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