INHIBITORS OF KYNURENINE HYDROXYLASE AND KYNURENINASE INCREASE CEREBRAL FORMATION OF KYNURENATE AND HAVE SEDATIVE AND ANTICONVULSANT ACTIVITIES
INHIBITORS OF KYNURENINE HYDROXYLASE AND KYNURENINASE INCREASE CEREBRAL FORMATION OF KYNURENATE AND HAVE SEDATIVE AND ANTICONVULSANT ACTIVITIES
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DOI：
10.1016/0306-4522(94)90227-5
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发表时间：
1994-07-01
期刊：
影响因子：
3.3
通讯作者：
MATTOLI, L
中科院分区：
文献类型：
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作者：
CARPENEDO, R;CHIARUGI, A;MATTOLI, L
Kynurenate 是离子型谷氨酸受体的内源性拮抗剂。它是由犬尿氨酸（一种色氨酸代谢物）合成的，其大脑浓度的显着增加可能对病理情况有用。我们试图通过改变犬尿氨酸分解代谢来增加其新合成。合成了几种犬尿氨酸类似物并测试它们作为犬尿氨酸羟化酶 (E.C.1.14.13.9) 和犬尿氨酸酶 (E.C.3.7.1.3) 的抑制剂，这两种酶催化犬尿氨酸转化为兴奋毒素喹啉酸盐。在这些类似物中，我们观察到烟碱基丙氨酸（一种其药理特性先前已被报道的化合物）作为犬尿氨酸羟化酶抑制剂的IC50为900+/-180μM，作为犬尿氨酸酶抑制剂的IC50为800+/-120μM。在寻找更有效的分子时，我们注意到间硝基苯甲酰丙氨酸作为犬尿氨酸羟化酶抑制剂的IC50为0.9+/-0.1μM，作为犬尿氨酸酶抑制剂的IC50为100+/-12μM。当给大鼠施用间硝基苯甲酰丙氨酸（400 mg/kg）时，大脑中犬尿氨酸（高达 10 倍）和犬尿酸盐（高达 5 倍）的浓度显着增加。在血液和肝脏中也获得了类似的结果。此外，通过微透析技术评估，间硝基苯甲酰丙氨酸以剂量依赖性、持久（最多13倍和最多4小时）的方式增加海马细胞外液中犬尿酸盐的浓度。这种增加与运动活动的减少以及大鼠免受最大电击诱发的癫痫发作或 DBA/2 小鼠的听源性癫痫发作的保护有关。本研究得出的结论是：（i）间硝基苯甲酰丙氨酸是犬尿氨酸羟化酶的有效抑制剂，也影响犬尿氨酸酶； (ii)这些酶的抑制导致犬尿酸盐的脑细胞外浓度显着增加； (iii)这种增加与镇静和抗惊厥作用相关，表明兴奋性氨基酸受体的功能性拮抗作用。
Kynurenate is an endogenous antagonist of the ionotropic glutamate receptors. It is synthesized from kynurenine, a tryptophan metabolite, and a significant increase in its brain concentration could be useful in pathological situations. We attempted to increase its neosynthesis by modifying kynurenine catabolism. Several kynurenine analogues were synthesized and tested as inhibitors of kynurenine hydroxylase (E.C.1.14.13.9) and of kynureninase (E.C.3.7.1.3), the two enzymes which catalyse the conversion of kynurenine to excitotoxin quinolinate. Among these analogues we observed that nicotinylalanine, a compound whose pharmacological properties have previously been reported, had an IC50 of 900 +/- 180 mu M as inhibitor of kynurenine hydroxylase and of 800 +/- 120 mu M as inhibitor of kynureninase. In the search for more potent molecules we noticed that meta-nitrobenzoylalanine had an IC50 of 0.9 +/- 0.1 mu M as inhibitor of kynurenine hydroxylase and of 100 +/- 12 mu M as inhibitor of kynureninase. When administered to rats meta-nitrobenzoylalanine (400 mg/kg) significantly increased the concentration of kynurenine (up to 10 times) and kynurenate (up to five times) in the brain. Similar results were obtained in the blood and in the liver. Furthermore meta-nitrobenzoylalanine increased in a dose dependent, long lasting (up to 13 times and up to 4 h) manner the concentration of kynurenate in the hippocampal extracellular fluid, as evaluated with a microdialysis technique. This increase was associated with a decrease in the locomotor activity and with protection from maximal electroshock-induced seizures in rats or from audiogenic seizures in DBA/2 mice.The conclusions drawn from the present study are: (i) meta-nitrobenzoylalanine is a potent inhibitor of kynurenine hydroxylase also affecting kynureninase; (ii) the inhibition of these enzymes causes a significant increase in the brain extracellular concentration of kynurenate; (iii) this increase is associated with sedative and anticonvulsant actions, suggesting a functional antagonism of the excitatory amino acid receptors.