Drugs with antidepressant properties affect tryptophan metabolites differently in rodent models with depression-like behavior.
Amanda Eskelund,Yan Li,David P. Budac,Heidi Kaastrup Müller,Maria Gulinello,Connie Sanchez,Gregers Wegener +6 more
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Sustained vortioxetine and fluoxetine administration decreased QUIN independent of species, while ketamine was ineffective and supported the hypothesis that modulating tryptophan metabolism may be part of the mechanism of action for some antidepressants.Abstract:
The metabolism of tryptophan through kynurenine and serotonin pathways is linked to depression. Here, effects of different drugs with antidepressant properties (vortioxetine, fluoxetine and ketamine) on various tryptophan metabolites in different brain regions and plasma were examined using tandem mass spectrometry (LC-MS/MS), in Flinders Sensitive Line (FSL) rats, a genetic rat model of depression, and its controls: Flinders Resistant Line (FRL) and Sprague-Dawley (SD) rats. Protein levels of kynurenine pathway enzymes were measured in the brains and livers of these rat strains. Furthermore, effects of vortioxetine on tryptophan metabolites were assessed in the cortical regions of lupus mice (MRL/MpJ-FasIpr), a murine model of increased depression-like behavior associated with inflammation. Sustained vortioxetine or fluoxetine (at doses aimed to fully occupy serotonin transporter via food or drinking water for at least 14 days) reduced levels of the excitotoxin quinolinic acid (QUIN) in various brain regions in all rats. Furthermore, chronic vortioxetine reduced levels of QUIN in MRL/MpJ-FasIpr mice. Acute i.p. administration of fluoxetine (10 mg/kg) or vortioxetine (10 mg/kg) led to reduced brain 5-HIAA in SD rats (2, 4, 6 and 8 hours) and a similar trend was evident in FSL and FRL rats after 4 hours. In contrast, single or repeated administration of ketamine (15 mg/kg i.p.) did not induce significant changes in metabolite levels. In conclusion, sustained vortioxetine and fluoxetine administration decreased QUIN independent of species, while ketamine was ineffective. These results support the hypothesis that modulating tryptophan metabolism may be part of the mechanism of action for some antidepressants.
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Kynurenine pathway in depression: A systematic review and meta-analysis
Kamiyu Ogyu,Kaoruhiko Kubo,Yoshihiro Noda,Yusuke Iwata,Sakiko Tsugawa,Yuki Omura,Masataka Wada,Ryosuke Tarumi,Eric Plitman,Sho Moriguchi,Takahiro Miyazaki,Hiroyuki Uchida,Ariel Graff-Guerrero,Masaru Mimura,Shinichiro Nakajima,Shinichiro Nakajima +15 more
TL;DR: This meta‐analysis revealed that patients with depression had decreased level of KYNA and KYN, whereas antidepressant‐free patients showed increased level of QUIN, and further research is clearly needed given the heterogeneity among their sample characteristics.
Journal ArticleDOI
Microglia: An Interface between the Loss of Neuroplasticity and Depression.
Gaurav Singhal,Bernhard T. Baune +1 more
TL;DR: It is clear that all molecular pathways to depression are linked through microglia-associated neuroinflammation and hippocampal degeneration, and the various molecular pathways associated with the microglial role in depression are critically analyzed.
Journal ArticleDOI
Age- and Disease-Specific Changes of the Kynurenine Pathway in Parkinson's and Alzheimer's Disease
Freek J. H. Sorgdrager,Yannick Vermeiren,Yannick Vermeiren,Martijn van Faassen,Claude van der Ley,Ellen A. A. Nollen,Ido P. Kema,Peter Paul De Deyn,Peter Paul De Deyn +8 more
TL;DR: It is hypothesized that the combination of age‐ and disease‐specific changes in cerebral Kyn pathway activity could contribute to reduced neurogenesis and increased excitotoxicity in neurodegenerative disease.
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Neuroinflammation and the Kynurenine Pathway in CNS Disease: Molecular Mechanisms and Therapeutic Implications.
Mustafa N. Mithaiwala,Danielle Santana-Coelho,Grace A. Porter,Jason C. O'Connor,Jason C. O'Connor +4 more
TL;DR: In this paper, the authors provide a thorough overview of the different branches of the kynurenine pathway pertinent to CNS disease pathology that have therapeutic implications for the development of selected and efficacious treatment strategies.
Journal ArticleDOI
The kynurenine pathway and bipolar disorder: intersection of the monoaminergic and glutamatergic systems and immune response.
Bashkim Kadriu,Cristan Farmer,Peixiong Yuan,Lawrence Park,Zhi-De Deng,Ruin Moaddel,Ioline D. Henter,Bridget Shovestul,Elizabeth D. Ballard,Cristoph Kraus,Philip W. Gold,Rodrigo Machado-Vieira,Rodrigo Machado-Vieira,Carlos A. Zarate +13 more
TL;DR: The results suggest that, in addition to having rapid and sustained antidepressant effects in BD participants, ketamine also impacts key components of the KYN pathway.
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