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New insight into the antidepressants action: modulation of kynurenine pathway by increasing the kynurenic acid/3-hydroxykynurenine ratio

  • Basic Neurosciences, Genetics and Immunology - Original Article
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Abstract

Altered function of kynurenine pathway has emerged recently as one of the factors contributing to the pathogenesis of depression. Neuroprotective kynurenic acid (KYNA) and neurotoxic 3-hydroxykynurenine (3-HK) are two immediate metabolites of l-kynurenine. Here, we aimed to assess the hypothesis that antidepressant drugs that may change brain KYNA/3-HK ratio. In primary astroglial cultures, fluoxetine, citalopram, amitriptyline and imipramine (1–10 μM) increased de novo production of KYNA and diminished 3-HK synthesis (24 and 48, but not 2 h). RT-PCR studies revealed that Kat1, Kat2 and kynurenine-3-monooxygenase (Kmo) gene expressions were not altered after 2 h. At 24 h, the expression of Kat1 and Kat2 genes was enhanced by all studied drugs, whereas Kmo expression was diminished by citalopram, fluoxetine and amitriptyline, but not imipramine. After 48 h, the expression of Kat1 and Kat2 was further up-regulated, and Kmo expression was down-regulated by all antidepressants. The ratio KYNA/3-HK was increased by fluoxetine, citalopram, amitriptyline and imipramine in a time-dependent manner—the effect was not observed after 2 h, modest after 24 h and robust after 48 h incubation time. Our findings indicate that the action of antidepressants may involve re-establishing of the beneficial ratio between KYNA and 3-HK. Shift in the kynurenine pathway, observed after prolonged exposure to antidepressant drugs, may partly explain their delayed therapeutic effectiveness.

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Acknowledgments

This study was supported by the grants from Medical University in Lublin no.: DS. 450/10, 450/11, 452/09, 452/10 and 452/11. RT-PCR equipment in the Department of Genetics was sponsored by Medical University in Lublin and European Fund, Development of Eastern Poland 2007–2013, Priority Axis I Modern Economy, Operations I.3 Innovation Promotion.

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Authors and Affiliations

  1. Department of Experimental and Clinical Pharmacology, Medical University, Jaczewskiego 8, 20-090, Lublin, Poland

    Tomasz Kocki, Sebastian Wnuk, Renata Kloc & Ewa M. Urbanska

  2. Department of Genetics, Medical University, Lublin, Poland

    Janusz Kocki

  3. Department of Clinical Neuroscience, Section of Psychiatry, Karolinska University Hospital Huddinge, Karolinska Institutet, Stockholm, Sweden

    Björn Owe-Larsson

  4. Department of Toxicology, Institute of Agricultural Medicine, Lublin, Poland

    Ewa M. Urbanska

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  1. Tomasz Kocki
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  2. Sebastian Wnuk
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  3. Renata Kloc
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  4. Janusz Kocki
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  6. Ewa M. Urbanska
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Correspondence to Ewa M. Urbanska.

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Kocki, T., Wnuk, S., Kloc, R. et al. New insight into the antidepressants action: modulation of kynurenine pathway by increasing the kynurenic acid/3-hydroxykynurenine ratio. J Neural Transm 119, 235–243 (2012). https://doi.org/10.1007/s00702-011-0668-8

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