Tachikawa Masanori, Kasai Yasuyuki, Yokoyama Reiji, Fujinawa Jun, Ganapathy Vadivel, Terasaki Tetsuya, Hosoya Ken-ichi
Department of Pharmaceutics, Graduate School of Medicine and Pharmaceutical Sciences, University of Toyama, Toyama, Japan.
J Neurochem. 2009 Oct;111(2):499-509. doi: 10.1111/j.1471-4159.2009.06332.x. Epub 2009 Aug 17.
Although the cerebral accumulation of guanidinoacetate (GAA) contributes to neurological complications in S-adenosylmethionine:guanidinoacetate N-methyltransferase (GAMT) deficiency, how GAA is abnormally distributed in the brain remains unknown. The purpose of this study was to investigate the transport of GAA across the blood-brain barrier (BBB) and in brain parenchymal cells in rats. [(14)C]GAA microinjected into the rat cerebrum was not eliminated from the brain, implying the negligible contribution of GAA efflux transport across the BBB. In contrast, in vivo analysis and an uptake study by TR-BBB cells, a rat in vitro BBB model, revealed that GAA was transported from the circulating blood across the BBB most likely via a creatine transporter (CRT). Although CRT at the BBB is almost saturated by endogenous creatine under physiological conditions, the creatine level in the blood significantly decreases in GAMT deficiency. This might lead to the increase of CRT-mediated blood-to-brain transport of GAA at the BBB. Furthermore, [(14)C]GAA was taken up by brain parenchymal cells in a concentrative manner most likely via taurine transporter and CRT. These characteristics of GAA transport across the BBB and in the brain parenchymal cells could be the key factors that facilitate GAA accumulation in the brains of patients with GAMT deficiency.
尽管胍基乙酸（GAA）在大脑中的蓄积会导致S-腺苷甲硫氨酸：胍基乙酸N-甲基转移酶（GAMT）缺乏症的神经并发症，但GAA在大脑中异常分布的机制仍不清楚。本研究的目的是研究GAA在大鼠血脑屏障（BBB）和脑实质细胞中的转运情况。向大鼠大脑微量注射[(14)C]GAA后，其并未从大脑中清除，这意味着GAA通过BBB的外流转运作用可忽略不计。相反，体内分析以及利用大鼠体外BBB模型TR-BBB细胞进行的摄取研究表明，GAA最有可能通过肌酸转运体（CRT）从循环血液转运穿过BBB。尽管在生理条件下，BBB处的CRT几乎被内源性肌酸饱和，但在GAMT缺乏症中，血液中的肌酸水平会显著降低。这可能导致BBB处CRT介导的GAA从血液到大脑的转运增加。此外，[(14)C]GAA最有可能通过牛磺酸转运体和CRT以浓缩方式被脑实质细胞摄取。GAA在BBB和脑实质细胞中的这些转运特性可能是导致GAMT缺乏症患者大脑中GAA蓄积的关键因素。
