Astrocytic TNFα regulates the behavioral response to antidepressants

Duseja, Rachna; Heir, Renu; Lewitus, Gil M.; Altimimi, Haider F.; Stellwagen, David

doi:10.1016/j.bbi.2014.09.012

Cited by 17 publications

(16 citation statements)

References 61 publications

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“…Altered microglial and astrocyte density and pathology associated with depression reflect this imbalance (Cobb et al, 2016; Sanacora and Banasr, 2013; Steiner et al, 2011; Yirmiya et al, 2015). Both astrocyte and microglial Ido1-FL expression appear to be sensitive to antidepressant treatment (Czeh and Di Benedetto, 2013; Duseja et al, 2015), indicating that both aspects of this ‘confusion’ are alleviated by Desip.…”

Section: Discussionmentioning

confidence: 99%

Desipramine decreases expression of human and murine indoleamine-2,3-dioxygenases

Brooks

Janda

Lawson

et al. 2017

Brain, Behavior, and Immunity

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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.

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Section: Discussionmentioning

confidence: 99%

Desipramine decreases expression of human and murine indoleamine-2,3-dioxygenases

Brooks

Janda

Lawson

et al. 2017

Brain, Behavior, and Immunity

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“…Moreover, specific IL-1 genotypes were associated with treatment resistant depression [ 72 ]. In preclinical studies, mice with an astrocyte-specific deletion of TNF-α showed a lack of behavioural response to antidepressant administration [ 73 ].…”

Section: The Relationship Between Cytokines and Depression Antideprementioning

confidence: 99%

Inflammation and Immune Regulation as Potential Drug Targets in Antidepressant Treatment

Schmidt

Kirkby²,

Lichtblau³

2016

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Growing evidence supports a mutual relationship between inflammation and major depression. A variety of mechanisms are outlined, indicating how inflammation may be involved in the pathogenesis, course and treatment of major depression. In particular, this review addresses 1) inflammatory cytokines as markers of depression and potential predictors of treatment response, 2) findings that cytokines interact with antidepressants and non-pharmacological antidepressive therapies, such as electroconvulsive therapy, deep brain stimulation and physical activity, 3) the influence of cytokines on the cytochrome (CYP) p450-system and drug efflux transporters, and 4) how cascades of inflammation might serve as antidepressant drug targets. A number of clinical trials have focused on agents with immunmodulatory properties in the treatment of depression, of which this review covers nonsteroidal anti-inflammatory drugs (NSAIDs), cytokine inhibitors, ketamine, polyunsaturated fatty acids, statins and curcumin. A perspective is also provided on possible future immune targets for antidepressant therapy, such as toll-like receptor-inhibitors, glycogen synthase kinase-3 inhibitors, oleanolic acid analogs and minocycline. Concluding from the available data, markers of inflammation may become relevant factors for more personalised planning and prediction of response of antidepressant treatment strategies. Agents with anti-inflammatory properties have the potential to serve as clinically relevant antidepressants. Further studies are required to better define and identify subgroups of patients responsive to inflammatory agents as well as to define optimal time points for treatment onset and duration.

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“…; Duseja et al . ), although the specific role of astrocyte‐secreted TNF‐α requires further research.…”

Section: Introductionmentioning

confidence: 99%

Role of astrocyte–synapse interactions in CNS disorders

Blanco-Suárez

Caldwell

Allen

2016

The Journal of Physiology

182

114

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Astrocytes comprise half of the cells in the brain. Although astrocytes have traditionally been described as playing a supportive role for neurons, they have recently been recognized as active participants in the development and plasticity of dendritic spines and synapses. Astrocytes can eliminate dendritic spines, induce synapse formation, and regulate neurotransmission and plasticity. Dendritic spine and synapse impairments are features of many neurological disorders, including autism spectrum disorder, schizophrenia, and Alzheimer's disease. In this review we will present evidence from multiple neurological disorders demonstrating that changes in astrocyte-synapse interaction contribute to the pathologies. Genomic analysis has connected altered astrocytic gene expression with synaptic deficits in a number of neurological disorders. Alterations in astrocyte-secreted factors have been implicated in the neuronal morphology and synaptic changes seen in neurodevelopmental disorders, while alteration in astrocytic glutamate uptake is a core feature of multiple neurodegenerative disorders. This evidence clearly demonstrates that maintaining astrocyte-synapse interaction is crucial for normal central nervous system functioning. Obtaining a better understanding of the role of astrocytes at synapses in health and disease will provide a new avenue for future therapeutic targeting.

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Astrocytic TNFα regulates the behavioral response to antidepressants

Cited by 17 publications

References 61 publications

Desipramine decreases expression of human and murine indoleamine-2,3-dioxygenases

Desipramine decreases expression of human and murine indoleamine-2,3-dioxygenases

Inflammation and Immune Regulation as Potential Drug Targets in Antidepressant Treatment

Role of astrocyte–synapse interactions in CNS disorders

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