Speciale C, Wu H Q, Cini M, Marconi M, Varasi M, Schwarcz R
Pharmacia & Upjohn, R & D-CNS, Milano, Italy.
Eur J Pharmacol. 1996 Nov 21;315(3):263-7. doi: 10.1016/s0014-2999(96)00613-9.
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.
犬尿喹啉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。我们在此证明，新型强效犬尿氨酸3-羟化酶抑制剂（R,S）-3,4-二氯苯甲酰丙氨酸（FCE 28833A）的全身给药会导致大鼠脑组织中内源性犬尿氨酸和犬尿喹啉酸水平呈剂量依赖性升高。在海马微透析液中，单次口服或腹腔注射400 mg/kg FCE 28833A后，犬尿喹啉酸浓度分别比基础浓度峰值增加了10倍和80倍。腹腔注射FCE 28833A后，细胞外脑犬尿喹啉酸水平至少22小时内仍显著升高，这使得该化合物比先前描述的犬尿氨酸3-羟化酶阻滞剂间硝基苯甲酰丙氨酸更有效地提高犬尿喹啉酸水平。FCE 28833A及类似分子可能对与兴奋性氨基酸受体功能亢进相关的疾病具有治疗价值。
