PMID- 29725904 OWN - NLM STAT- MEDLINE DCOM- 20190401 LR - 20200225 IS - 1559-1182 (Electronic) IS - 0893-7648 (Linking) VI - 56 IP - 1 DP - 2019 Jan TI - Chronic Mild Stress Alters Kynurenine Pathways Changing the Glutamate Neurotransmission in Frontal Cortex of Rats. PG - 490-501 LID - 10.1007/s12035-018-1096-7 [doi] AB - Immune stimulation might be involved in the pathophysiology of major depressive disorder (MDD). This stimulation induces indoleamine 2,3-dioxygenase (IDO), an enzyme that reduces the tryptophan bioavailability to synthesize serotonin. IDO products, kynurenine metabolites, exert neurotoxic/neuroprotective actions through glutamate receptors. Thus, we study elements of these pathways linked to kynurenine metabolite activity examining whether antidepressants (ADs) can modulate them. Male Wistar rats were exposed to chronic mild stress (CMS), and some of them were treated with ADs. The expression of elements of the IDO pathway, including kynurenine metabolites, and their possible modulation by ADs was studied in the frontal cortex (FC). CMS increased IDO expression in FC compared to control group, and ADs restored the IDO expression levels to control values. CMS-induced IDO expression led to increased levels of the excitotoxic quinolinic acid (QUINA) compared to control, and ADs prevented the rise in such levels. Neither CMS nor ADs changed significantly the antiexcitotoxic kynurenic acid (KYNA) levels. The QUINA/KYNA ratio, calculated as excitotoxicity risk indicator, increased after CMS and ADs prevented this increase. CMS lowered excitatory amino acid transporter (EAAT)-1 and EAAT-4 expression, and some ADs restored their expression levels. Furthermore, CMS decreased N-methyl-D-aspartate receptor (NMDAR)-2A and 2B protein expression, and ADs mitigated this decrease. Our research examines the link between CMS-induced pro-inflammatory cytokines and the kynurenine pathway; it shows that CMS alters the kynurenine pathway in rat FC. Importantly, it also reveals the ability of classic ADs to prevent potentially harmful situations related to the brain scenario caused by CMS. FAU - Martin-Hernandez, David AU - Martin-Hernandez D AD - Departamento de Farmacologia y Toxicologia, Facultad de Medicina, Universidad Complutense de Madrid, Avda. Complutense s/n, 28040, Madrid, Spain. AD - Centro de Investigacion Biomedica en Red de Salud Mental (CIBERSAM), Avda. Complutense s/n, 28040, Madrid, Spain. AD - Instituto de Investigacion Sanitaria Hospital 12 de Octubre (Imas12), Avda. Complutense s/n, 28040, Madrid, Spain. AD - Instituto Universitario de Investigacion en Neuroquimica UCM, Avda. Complutense s/n, 28040, Madrid, Spain. FAU - Tendilla-Beltran, Hiram AU - Tendilla-Beltran H AD - Laboratorio de Neuropsiquiatria, Instituto de Fisiologia, Benemerita Universidad Autonoma de Puebla, 28040, Puebla, Mexico. FAU - Madrigal, Jose L M AU - Madrigal JLM AD - Departamento de Farmacologia y Toxicologia, Facultad de Medicina, Universidad Complutense de Madrid, Avda. Complutense s/n, 28040, Madrid, Spain. AD - Centro de Investigacion Biomedica en Red de Salud Mental (CIBERSAM), Avda. Complutense s/n, 28040, Madrid, Spain. AD - Instituto de Investigacion Sanitaria Hospital 12 de Octubre (Imas12), Avda. Complutense s/n, 28040, Madrid, Spain. AD - Instituto Universitario de Investigacion en Neuroquimica UCM, Avda. Complutense s/n, 28040, Madrid, Spain. FAU - Garcia-Bueno, Borja AU - Garcia-Bueno B AD - Departamento de Farmacologia y Toxicologia, Facultad de Medicina, Universidad Complutense de Madrid, Avda. Complutense s/n, 28040, Madrid, Spain. AD - Centro de Investigacion Biomedica en Red de Salud Mental (CIBERSAM), Avda. Complutense s/n, 28040, Madrid, Spain. AD - Instituto de Investigacion Sanitaria Hospital 12 de Octubre (Imas12), Avda. Complutense s/n, 28040, Madrid, Spain. AD - Instituto Universitario de Investigacion en Neuroquimica UCM, Avda. Complutense s/n, 28040, Madrid, Spain. FAU - Leza, Juan C AU - Leza JC AD - Departamento de Farmacologia y Toxicologia, Facultad de Medicina, Universidad Complutense de Madrid, Avda. Complutense s/n, 28040, Madrid, Spain. jcleza@med.ucm.es. AD - Centro de Investigacion Biomedica en Red de Salud Mental (CIBERSAM), Avda. Complutense s/n, 28040, Madrid, Spain. jcleza@med.ucm.es. AD - Instituto de Investigacion Sanitaria Hospital 12 de Octubre (Imas12), Avda. Complutense s/n, 28040, Madrid, Spain. jcleza@med.ucm.es. AD - Instituto Universitario de Investigacion en Neuroquimica UCM, Avda. Complutense s/n, 28040, Madrid, Spain. jcleza@med.ucm.es. FAU - Caso, Javier R AU - Caso JR AD - Departamento de Farmacologia y Toxicologia, Facultad de Medicina, Universidad Complutense de Madrid, Avda. Complutense s/n, 28040, Madrid, Spain. jrcaso@med.ucm.es. AD - Centro de Investigacion Biomedica en Red de Salud Mental (CIBERSAM), Avda. Complutense s/n, 28040, Madrid, Spain. jrcaso@med.ucm.es. AD - Instituto de Investigacion Sanitaria Hospital 12 de Octubre (Imas12), Avda. Complutense s/n, 28040, Madrid, Spain. jrcaso@med.ucm.es. AD - Instituto Universitario de Investigacion en Neuroquimica UCM, Avda. Complutense s/n, 28040, Madrid, Spain. jrcaso@med.ucm.es. LA - eng GR - SAF2016-75500-R/Secretaria de Estado de Investigacion, Desarrollo e Innovacion/ GR - FIS13/01102/Instituto de Salud Carlos III/ GR - SAM15PINT1514/Centro de Investigacion Biomedica en Red de Salud Mental/ PT - Journal Article DEP - 20180503 PL - United States TA - Mol Neurobiol JT - Molecular neurobiology JID - 8900963 RN - 0 (Antidepressive Agents) RN - 0 (Cytokines) RN - 0 (Glutamate Plasma Membrane Transport Proteins) RN - 0 (Indoleamine-Pyrrole 2,3,-Dioxygenase) RN - 0 (Inflammation Mediators) RN - 0 (RNA, Messenger) RN - 0 (Receptors, N-Methyl-D-Aspartate) RN - 343-65-7 (Kynurenine) RN - 3KX376GY7L (Glutamic Acid) RN - 8DUH1N11BX (Tryptophan) RN - F6F0HK1URN (Quinolinic Acid) RN - H030S2S85J (Kynurenic Acid) SB - IM MH - Animals MH - Antidepressive Agents/pharmacology/therapeutic use MH - Chronic Disease MH - Cytokines/metabolism MH - Frontal Lobe/drug effects/*pathology/*physiopathology MH - Glutamate Plasma Membrane Transport Proteins/genetics/metabolism MH - Glutamic Acid/*metabolism MH - Indoleamine-Pyrrole 2,3,-Dioxygenase/metabolism MH - Inflammation Mediators/metabolism MH - Kynurenic Acid/metabolism MH - Kynurenine/*metabolism MH - Male MH - Metabolic Networks and Pathways/drug effects MH - Quinolinic Acid/metabolism MH - RNA, Messenger/genetics/metabolism MH - Rats MH - Rats, Wistar MH - Receptors, N-Methyl-D-Aspartate/genetics/metabolism MH - Stress, Psychological/drug therapy/*metabolism/*physiopathology MH - *Synaptic Transmission/drug effects MH - Tryptophan/metabolism OTO - NOTNLM OT - Antidepressants OT - Chronic mild stress OT - Frontal cortex OT - Glutamate neurotransmission OT - Indoleamine 2,3-dioxygenase OT - Kynurenine pathways EDAT- 2018/05/05 06:00 MHDA- 2019/04/02 06:00 CRDT- 2018/05/05 06:00 PHST- 2017/11/22 00:00 [received] PHST- 2018/04/23 00:00 [accepted] PHST- 2018/05/05 06:00 [pubmed] PHST- 2019/04/02 06:00 [medline] PHST- 2018/05/05 06:00 [entrez] AID - 10.1007/s12035-018-1096-7 [pii] AID - 10.1007/s12035-018-1096-7 [doi] PST - ppublish SO - Mol Neurobiol. 2019 Jan;56(1):490-501. doi: 10.1007/s12035-018-1096-7. Epub 2018 May 3.