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Chronic Mild Stress Alters Kynurenine Pathways Changing the Glutamate Neurotransmission in Frontal Cortex of Rats

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Abstract

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.

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Funding

Funding for this study was provided by the Instituto de Salud Carlos III (PI13/01102) and Fondos Europeos de Desarrollo Regional (FEDER) and the Ministerio de Economía, Industria y Competitividad (MINECO; SAF2016-75500-R), and CIBERSAM to JCL, including an Intramural Translational Project awarded to JRC from the CIBERSAM (SAM15PINT1514). BGB and JRC are postdoctoral Ramón y Cajal fellows (MINECO). HTB was funded by the CONACYT (Consejo Nacional de Ciencia y Tecnología, Mexico).

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Authors and Affiliations

  1. Departamento de Farmacología y Toxicología, Facultad de Medicina, Universidad Complutense de Madrid, Avda. Complutense s/n, 28040, Madrid, Spain

    David Martín-Hernández, José L. M. Madrigal, Borja García-Bueno, Juan C. Leza & Javier R. Caso

  2. Centro de Investigación Biomédica en Red de Salud Mental (CIBERSAM), Avda. Complutense s/n, 28040, Madrid, Spain

    David Martín-Hernández, José L. M. Madrigal, Borja García-Bueno, Juan C. Leza & Javier R. Caso

  3. Instituto de Investigación Sanitaria Hospital 12 de Octubre (Imas12), Avda. Complutense s/n, 28040, Madrid, Spain

    David Martín-Hernández, José L. M. Madrigal, Borja García-Bueno, Juan C. Leza & Javier R. Caso

  4. Instituto Universitario de Investigación en Neuroquímica UCM, Avda. Complutense s/n, 28040, Madrid, Spain

    David Martín-Hernández, José L. M. Madrigal, Borja García-Bueno, Juan C. Leza & Javier R. Caso

  5. Laboratorio de Neuropsiquiatría, Instituto de Fisiología, Benemérita Universidad Autónoma de Puebla, 28040, Puebla, Mexico

    Hiram Tendilla-Beltrán

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  1. David Martín-Hernández
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  2. Hiram Tendilla-Beltrán
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  3. José L. M. Madrigal
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  4. Borja García-Bueno
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  5. Juan C. Leza
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Correspondence to Juan C. Leza or Javier R. Caso.

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Dr. Javier R. Caso is the first corresponding author and Dr. Juan C.Leza is the co-corresponding author.

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Martín-Hernández, D., Tendilla-Beltrán, H., Madrigal, J.L.M. et al. Chronic Mild Stress Alters Kynurenine Pathways Changing the Glutamate Neurotransmission in Frontal Cortex of Rats. Mol Neurobiol 56, 490–501 (2019). https://doi.org/10.1007/s12035-018-1096-7

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