THE EFFECTS OF ACUTE PSYCHOLOGICAL STRESS ON ENZYMES REGULATING THE KYNURENINE PATHWAY
Notice bibliographique
Résumé
INTRODUCTION An emerging body of literature recognizes the relationship between stress and inflammation. The kynurenine pathway is particularly relevant because it accounts for the majority of tryptophan’s metabolism [1]. Activation of the kynurenine pathway depletes the tryptophan pool for serotonin, and has been associated with the emergence of depressive-like symptoms and “sickness behaviour” (anhedonia, anxiety, and sleep disturbances) in animals [1]. The first and rate limiting step of the kynurenine pathway converts tryptophan to kynurenine and can be catalyzed by tryptophan 2,3-dioxygenase (TDO), which operates under basal conditions, or by indoleamine 2,3-dioxygenase 1 (IDO1), which predominates under inflammatory states [2]. Indeed, previous research has shown that IDO1 can be induced by cytokines, such as tumor necrosis factor alpha (TNFα) [1,2]. Recent data from our lab indicates that TNFα protein is increased in the amygdala 4 h after exposure to an acute stressor. Hence, this investigation attempted to determine the effects of acute stress on mRNA levels of enzymes regulating the kynurenine pathway. METHODS Adult, male, Sprague Dawley rats ( N =48) were subjected to 120 minutes of restraint stress and rapidly decapitated 1 h, 2 h, 4 h, 6 h, or 24 h later. Trunk blood was collected and analyzed for circulating corticosterone and TNFα levels. Brains were extracted and excised into amygdalae, hypothalami, prefrontal cortices, and hippocampi. RNA was isolated, followed by cDNA synthesis, and quantitative PCR (qPCR) to quantify mRNA levels of IDO1, TDO, kynurenine aminotransferase 1 (KAT1), kynurenine 3-monooxygenase (KYNM), kynureninase (KYNU), and 3-hydroxyanthranilate 3,4-dioxygenase. RESULTS Results indicated that plasma corticosterone levels were elevated 2 h after the acute stressor, while circulating levels of TNFα were increased at the 1 h and the 2 h post stress time points. Analysis of amygdalar qPCR data indicated an upregulation of IDO1 mRNA at the 1 h time point, and increased KYNM and KYNU mRNA at the 4 h time point. There were no amygdalar mRNA changes in the other genes. Regarding hypothalamic data, there was an increase in TDO mRNA at the 4 h time point and KYNU mRNA at the 1 h time point. DISCUSSION AND CONCLUSIONS Increases in expression of kynurenine pathway enzymes in the amygdala occurred in a time dependent manner. Taken together, the data is concordant with previous reports, which indicate that IDO1 and TDO can be induced by TNFα and corticosterone, respectively [1,2]. The result of increased amygdalar KYNM and KYNU mRNA following acute stress represents a novel finding and suggests that stress shifts the kynurenine pathway towards neurotoxic metabolites, such as 3-hyroxykynurenine and quinolinic acid, which may aggravate the symptoms of inflammation-induced depression. Follow up work on this study would investigate mRNA changes in other brain regions, such as the prefrontal cortex and the hippocampus. In addition, plasma and brain concentrations of tryptophan, kynurenine, kynurenic acid, and quinolinic acid would be determined to see if they are in accordance with the mRNA data. Ultimately, the present study highlights the kynurenine pathway as a potential therapeutic target for inflammation-induced depression.
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Comment cette classification a été obtenuedéplier
Prédiction machine sur la base complète
Imitation des enseignantsNi prévalence calibrée, ni vérité terrain. Validation humaine à venir. Le volet Gemma est une étiquette directe du modèle pour chaque travail de la base, lue sur la notice réduite au titre. Le volet Codex est un classifieur appris des 10 348 étiquettes directes de Codex et calibré sur les taux pondérés de l'échantillon; les champs sans appui suffisant ne portent aucun appel Codex. Le mode candidate est l'union des deux volets; le consensus est leur intersection. Ces sorties portent le statut machine_predicted_unvalidated et ne sont pas des étiquettes humaines.
Scores du classifieur distillé par catégorie (deux têtes)
| Catégorie | Codex | Gemma |
|---|---|---|
| Métarecherche | 0,000 | 0,000 |
| Méta-épidémiologie (sens strict) | 0,000 | 0,000 |
| Méta-épidémiologie (sens large) | 0,000 | 0,000 |
| Bibliométrie | 0,000 | 0,000 |
| Études des sciences et des technologies | 0,000 | 0,000 |
| Communication savante | 0,000 | 0,000 |
| Science ouverte | 0,000 | 0,000 |
| Intégrité de la recherche | 0,000 | 0,001 |
| Charge utile insuffisante (le modèle a refusé de juger) | 0,002 | 0,000 |
Scores machine (provisoires)
Les deux têtes enseignantes du modèle étudiant, lues sur ce travail. Un score ordonne la base pour la relecture; il n'affirme jamais une catégorie, et le statut de validation accompagne chaque rangée tel quel.
Scores de référence d'un modèle non mature (critères de maturité non atteints, 7 itérations). Un score ordonne; il n'affirme jamais une catégorie.
score_only:v0-immature-baseline · tel quel depuis la passe de notation : score_only signifie que le nombre peut ordonner les travaux, et qu'aucune étiquette de catégorie n'en découleClassification
machine, non validéePrédiction automatique; un appel candidat d’une seule source (Gemma direct ou Codex distillé), pas un consensus.
Le détail, modèle par modèle et score par score, se trouve en fin de page sous « Comment cette classification a été obtenue ».