Relationships between methoxyindole and kynurenine pathway metabolites in plasma and urine in children suffering from febrile and epileptic seizures.
OBJECTIVE
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.


METHODS
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).


METHODS
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.


RESULTS
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.


CONCLUSIONS
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.
Muñóz-Hoyos
A
A
Departamento de Pediatría, Hospital Universitario, Granada, Spain.
Molina-Carballo
A
A
Rodríguez-Cabezas
T
T
Uberos-Fernández
J
J
Ruiz-Cosano
C
C
Acuña-Castroviejo
D
D
D015095:3-Hydroxyanthranilic Acid / Q000378:metabolism; D002648:Child; D002675:Child, Preschool; D002940:Circadian Rhythm; D004827:Epilepsy / Q000378:metabolism*; D005260:Female; D006801:Humans; D007223:Infant; D007736:Kynurenic Acid / Q000652:urine; D007737:Kynurenine / Q000378:metabolism* / Q000652:urine; D008297:Male; D008550:Melatonin / Q000097:blood / Q000378:metabolism / Q000652:urine; D003294:Seizures, Febrile / Q000378:metabolism*; D014364:Tryptophan / Q000378:metabolism*; D014977:Xanthurenates / Q000652:urine
D014977:Xanthurenates; D015095:3-Hydroxyanthranilic Acid; D007737:Kynurenine; C028330:xanthurenic acid; D014364:Tryptophan; D007736:Kynurenic Acid; D008550:Melatonin