(R,S)-3,4-dichlorobenzoylalanine (FCE 28833A) causes a large and persistent increase in brain kynurenic acid levels in rats
(R,S)-3,4-dichlorobenzoylalanine (FCE 28833A) causes a large and persistent increase in brain kynurenic acid levels in rats
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DOI：
10.1016/s0014-2999(96)00613-9
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发表时间：
1996-11-21
影响因子：
5
通讯作者：
Schwarcz, R
中科院分区：
文献类型：
--
作者：
Speciale, C;Wu, HQ;Schwarcz, R
犬尿烯酸是一种内源性兴奋性氨基酸受体拮抗剂，具有神经保护和抗惊厥特性。我们在这里证明，新的和有效的犬尿氨酸3-羟化酶抑制剂（R，S）-3，4-二氯苯甲酰丙氨酸（FCE 28833 A）的全身给药导致大鼠脑组织中内源性犬尿氨酸和犬尿烯酸水平的剂量依赖性升高。在海马微透析液中，400 mg/kg FCE 28833 A单次经口或腹膜内给药后，犬尿烯酸浓度分别比基础浓度增加10倍和80倍。在用FCE 28833 A腹膜内处理后，细胞外脑犬尿烯酸水平保持显著升高至少22小时，使得该化合物成为比先前描述的犬尿氨酸3-羟化酶阻断剂间硝基苯甲酰丙氨酸有效得多的犬尿烯酸水平增强剂。FCE 28833 A和类似分子可能在与兴奋性氨基酸受体功能亢进有关的疾病中具有治疗价值。
Kynurenic acid is an endogenous excitatory amino-acid receptor antagonist with neuroprotective and anticonvulsant properties. We demonstrate here that systemic administration of the new and potent kynurenine 3-hydroxylase inhibitor (R,S)-3,4-dichlorobenzoylalanine (FCE 28833A) causes a dose-dependent elevation in endogenous kynurenine and kynurenic acid levels in rat brain tissue. In hippocampal microdialysates, peak increases of 10- and 80-fold above basal kynurenic acid concentrations, respectively, were obtained after a single oral or intraperitoneal administration of 400 mg/kg FCE 28833A. After intraperitoneal treatment with FCE 28833A, extracellular brain kynurenic acid levels remained significantly elevated for at least 22 h, rendering this compound a far more effective enhancer of kynurenic acid levels than the previously described kynurenine 3-hydroxylase blocker m-nitrobenzoylalanine. FCE 28833A and similar molecules may have therapeutic value in diseases which are linked to a hyperfunction of excitatory amino-acid receptors.