Desipramine decreases expression of human and murine indoleamine-2,3-dioxygenases
| Autor: | Marcus A. Lawson, Alexandra K. Brooks, Jennifer L. Rytych, Robin A. Smith, Cecilia Ocampo-Solis, Tiffany M. Janda, Robert H. McCusker |
|---|---|
| Rok vydání: | 2016 |
| Předmět: |
0301 basic medicine
Male Kynurenine pathway Serotonin reuptake inhibitor Immunology Biology Pharmacology Article 03 medical and health sciences Behavioral Neuroscience chemistry.chemical_compound Interferon-gamma Mice Young Adult 0302 clinical medicine In vivo Desipramine medicine Animals Humans Indoleamine-Pyrrole 2 3 -Dioxygenase Neurotransmitter Microglia Adrenergic Uptake Inhibitors Endocrine and Autonomic Systems 030104 developmental biology medicine.anatomical_structure chemistry Leukocytes Mononuclear Female 030217 neurology & neurosurgery Ex vivo Kynurenine medicine.drug |
| Zdroj: | Brain, behavior, and immunity. 62 |
| ISSN: | 1090-2139 |
| Popis: | Abundant evidence connects depression symptomology with immune system activation, stress and subsequently elevated levels of kynurenine. Anti-depressants, such as the tricyclic norepinephrine/serotonin reuptake inhibitor desipramine (Desip), were developed under the premise that increasing extracellular neurotransmitter level was the sole mechanism by which they alleviate depressive symptomologies. However, evidence suggests that anti-depressants have additional actions that contribute to their therapeutic potential. The Kynurenine Pathway produces tryptophan metabolites that modulate neurotransmitter activity. This recognition identified another putative pathway for anti-depressant targeting. Considering a recognized role of the Kynurenine Pathway in depression, we investigated the potential for Desip to alter expression of rate-limiting enzymes of this pathway: indoleamine-2,3-dioxygenases (Ido1 and Ido2). Mice were administered lipopolysaccharide (LPS) or synthetic glucocorticoid dexamethasone (Dex) with Desip to determine if Desip alters indoleamine-dioxygenase (DO) expression in vivo following a modeled immune and stress response. This work was followed by treating murine and human peripheral blood mononuclear cells (PBMCs) with interferon-gamma (IFNγ) and Desip. In vivo: Desip blocked LPS-induced Ido1 expression in hippocampi, astrocytes, microglia and PBMCs and Ido2 expression by PBMCs. Ex vivo: Desip decreased IFNγ-induced Ido1 and Ido2 expression in murine PBMCs. This effect was directly translatable to the human system as Desip decreased IDO1 and IDO2 expression by human PBMCs. These data demonstrate for the first time that an anti-depressant alters expression of Ido1 and Ido2, identifying a possible new mechanism behind anti-depressant activity. Furthermore, we propose the assessment of PBMCs for anti-depressant responsiveness using IDO expression as a biomarker. |
| Databáze: | OpenAIRE |
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