THE KYNURENINE PATHWAY: A MISSING PIECE IN THE PUZZLE OF VALPROATE ACTION?
THE KYNURENINE PATHWAY: A MISSING PIECE IN THE PUZZLE OF VALPROATE ACTION?
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DOI：
10.1016/j.neuroscience.2012.12.052
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发表时间：
2013-03-27
期刊：
影响因子：
3.3
通讯作者：
Plaznik, A.
中科院分区：
文献类型：
--
作者：
Maciejak, P.;Szyndler, J.;Plaznik, A.
本研究旨在确定犬尿氨酸途径（KP）在丙戊酸（VPA）作用机制中的作用。因此，我们研究了给予 VPA（腹腔注射 50、250 和 500 mg/kg）后大脑和血浆中色氨酸 (TRP)、犬尿酸 (KYNA) 和犬尿氨酸 (KYN) 浓度的变化。我们研究中最重要的发现是，VPA 给药使 KYNA、KYN 和 TRP 的中心浓度逐渐强劲增加。同时，血浆中TRP水平下降，而血浆中KYNA的外周升高较海马更弱且发生更早。考虑到观察到的效果可能是 VPA 诱导的 TRP 从其与血浆白蛋白的结合位点发生强烈位移的结果，我们检查了布洛芬 (IBU) 给药（一种用于研究药物与血清白蛋白结合的原型药物）对 KP 的影响。我们发现 IBU 引起的 KP 活性变化模式与 VPA 类似。这些新发现表明存在一种机制，可以在 VPA 给药后刺激大脑中 KYNA 的产生，并可能部分促进 VPA 的作用机制。我们的实验结果表明，通过施用不同的药物（包括 VPA、IBU 或短链脂肪酸），TRP 从其在血浆白蛋白上的结合位点移位，可以实现大脑 KYNA 水平的增加，从而产生重要的临床后果。 (c) 2013 年国际广播组织。由爱思唯尔有限公司出版。保留所有权利。
The present study was designed to determine the role of the kynurenine pathway (KP) in the mechanism of action of valproate (VPA). Therefore, we investigated changes in the concentrations of tryptophan (TRP), kynurenic acid (KYNA), and kynurenine (KYN) in the brain and plasma following VPA administration (50, 250 and 500 mg/kg i.p.). The most important findings of our study were that VPA administration produced a progressive and strong increase in the central concentrations of KYNA, KYN and TRP. Simultaneously, the TRP level in plasma declined, while the peripheral increase of KYNA in plasma was weaker and occurred earlier than in the hippocampus. Bearing in mind that the observed effect may be a result of a strong VPA-induced displacement of TRP from its binding sites to plasma albumin, we checked the effect of ibuprofen (IBU) administration (a prototypic drug used to study drug binding to serum albumin) on the KP. We found that IBU evoked a similar pattern of change in the KP activity as VPA. These new findings indicate the existence of a mechanism that could stimulate the production of KYNA in the brain after VPA administration, and may partially contribute to the mechanisms of VPA action. The results of our experiment indicate that an increase in the brain's KYNA level may be achieved by TRP displacement from its binding site on plasma albumin with the administration of different drugs, including VPA, IBU, or short-chain fatty acids, with important clinical consequences. (c) 2013 IBRO. Published by Elsevier Ltd. All rights reserved.