Muñóz-Hoyos A, Molina-Carballo A, Rodríguez-Cabezas T, Uberos-Fernández J, Ruiz-Cosano C, Acuña-Castroviejo D
Departamento de Pediatría, Hospital Universitario, Granada, Spain.
Clin Endocrinol (Oxf). 1997 Dec;47(6):667-77. doi: 10.1046/j.1365-2265.1997.2991136.x.
The methoxyindole pathway metabolite, melatonin (aMT), and the kynurenine pathway metabolites, kynurenic acid (KYNA), xanturenic acid (XA) and 3-hydroxyantranilic acid (3HANA) are anticonvulsants, whereas the kynurenine pathway metabolites, L-kynurenine (KYN) and 3-hydroxykynurenine (3HK), are proconvulsants. It is thought that alterations in the concentrations of these compounds may be responsible for the excitotoxic aspect of human seizures. The aim of this study was to determine whether alterations in tryptophan metabolism might be related to the occurrence and type (febrile or non-febrile) of seizures in children.
One hundred and eighteen children from the University of Granada Hospital were studied. They were divided into two main groups (febrile or epileptic convulsive) depending upon their clinical diagnosis. An age-, weight- and gender-matched control group was also studied. Each group was then divided into two subgroups of patients sampled between 0900 h and 2100 h (diurnal groups) and patients sampled between 2100 h and 0900 h (nocturnal groups).
Plasma melatonin was measured in samples obtained from both the diurnal and nocturnal groups. Urinary excretion of melatonin and kynurenine metabolities were measured in an aliquot of 12-h urine samples collected from both the diurnal and nocturnal groups.
Besides the typical circadian rhythm of melatonin we also found diurnal/nocturnal differences in the concentrations of all the kynurenines, which reached significantly higher levels during the day. In normal humans the production of methoxyindoles is lower during the day and rises at night, whereas the production of kynurenines is higher during the day and decreases at night. In patients suffering from febrile and epileptic convulsions, however, there was a significant increase in the nocturnal production of KYN, 3HK, KYNA and XA. Thus we found the circadian rhythm of kynurenines to be altered in convulsive patients. Furthermore, while the various kynurenine metabolites increased by the same amount during the night in febrile convulsive children, in epileptic children the increase in KYN and 3HK was significantly lower than the increase in KYNA and XA. During the day the proconvulsant KYN decreased significantly and the anticonvulsant XA increased in both convulsive groups. Moreover, plasma aMT increased during the day in febrile convulsive group and also during the night in both febrile and epileptic groups although showing no significant change in their urinary excretion levels.
Our results point to the existence of an imbalance in the tryptophan metabolite pathways during convulsions, blunting the normal diurnal-nocturnal rhythm of kynurenines. They also support the idea of a difference in the production of tryptophan metabolites between febrile and epileptic patients, suggesting that the tryptophan pathways follow different routes depending upon the type and duration of the convulsion.
甲氧基吲哚途径代谢产物褪黑素（aMT）以及犬尿氨酸途径代谢产物犬尿喹啉酸（KYNA）、黄尿酸（XA）和3-羟基邻氨基苯甲酸（3HANA）具有抗惊厥作用，而犬尿氨酸途径代谢产物L-犬尿氨酸（KYN）和3-羟基犬尿氨酸（3HK）则具有促惊厥作用。人们认为这些化合物浓度的改变可能是人类癫痫发作兴奋性毒性方面的原因。本研究的目的是确定色氨酸代谢的改变是否可能与儿童癫痫发作的发生及类型（热性或非热性）有关。
研究了来自格拉纳达大学医院的118名儿童。根据临床诊断将他们分为两个主要组（热性或癫痫性惊厥组）。还研究了一个年龄、体重和性别匹配的对照组。然后将每组分为在09:00至21:00采样的患者亚组（日间组）和在21:00至09:00采样的患者亚组（夜间组）。
在从日间组和夜间组获得的样本中测量血浆褪黑素。在从日间组和夜间组收集的12小时尿液样本的等分试样中测量褪黑素和犬尿氨酸代谢产物的尿排泄量。
除了褪黑素典型的昼夜节律外，我们还发现所有犬尿氨酸的浓度存在日间/夜间差异，白天的浓度显著更高。在正常人中，甲氧基吲哚的产生在白天较低，夜间升高，而犬尿氨酸的产生在白天较高，夜间降低。然而，在热性和癫痫性惊厥患者中，KYN、3HK、KYNA和XA的夜间产生显著增加。因此，我们发现惊厥患者中犬尿氨酸的昼夜节律发生了改变。此外，在热性惊厥儿童中，各种犬尿氨酸代谢产物在夜间增加的量相同，而在癫痫儿童中，KYN和3HK的增加显著低于KYNA和XA的增加。在白天，两个惊厥组中促惊厥的KYN显著降低，抗惊厥的XA增加。此外，热性惊厥组白天血浆aMT增加，热性和癫痫组夜间血浆aMT也增加，但其尿排泄水平无显著变化。
我们的结果表明惊厥期间色氨酸代谢途径存在失衡，使犬尿氨酸正常的昼夜节律减弱。它们还支持热性和癫痫患者色氨酸代谢产物产生存在差异的观点，表明色氨酸途径根据惊厥的类型和持续时间遵循不同的途径。
