Weronika Duda

A new animal model of (chronic) depression induced by repeated and intermittent lipopolysaccharide administration for 4 months

Chronic activation of immune-inflammatory and oxidative and nitrosative stress (O&NS) pathways plays an important role in the pathophysiology of clinical depression. Increased IgA responses directed against LPS of gram-negative bacteria, indicating increased bacterial translocation, may be one of the drivers underpinning these pathways. There is a strong association between signs of bacterial translocation and chronicity of depression and O&NS, but not pro-inflammatory cytokines. The aims of the present study were to: (1) develop a new neurobehavioral model of (chronic) depression (anhedonic behavior) that may reflect chronic LPS stimulation and is associated with increased oxidative stress, and (2) to delineate the effects of fluoxetine on this new depression model. We established that in female mice repeated LPS injections once daily for 5 days (from 750 μg/kg to a maximal dose 1250 μg/kg; increasing doses for the first three days which were then gradually decreased on day 4 and 5) at a one-month interval and this repeated for 4 consecutive months induced chronic anhedonia (estimated by the preference to drink a 1% sucrose) lasting for at least 7 weeks. Chronic LPS administration significantly decreased thymus weight, proliferative activity of splenocytes, production of interferon (IFN)γ and interleukin-(IL)10, and increased superoxide and corticosterone production. Treatment with fluoxetine for 3 weeks abolished the neurobehavioral effects of LPS. The antidepressant effect of fluoxetine was accompanied by increased production of IL-10 and reduced superoxide and corticosterone production. Our results suggest that repeated intermittent LPS injections to female mice may be a useful model of chronic depression and in particular for the depressogenic effects of long standing activation of the toll-like receptor IV complex.

Increased IL-6 trans-signaling in depression: focus on the tryptophan catabolite pathway, melatonin and neuroprogression

Depression has been conceptualized as a disorder driven by immuno-inflammatory pathways and oxidative and nitrosative stress. These factors couple to the induction of neuroregulatory tryptophan catabolites via the activation of indoleamine 2,3-dioxygenase (IDO) and tryptophan 2,3-dioxygenase (TDO). Oxidative damage to neoepitopes increases autoimmune responses, changing the nature of the neural substrate of recurrent depression, which leads to neuroprogression and drives treatment resistance. A number of pro-inflammatory cytokines are linked to these processes. Here, we focus on the role of interleukin (IL)-6 in depression and its associated disorders; we highlight the progress made since the first paper showing increased IL-6 levels was published 20 years ago by Maes and colleagues. When coupled with increased levels of the soluble IL-6 receptor in depression, higher levels of IL-6 may indicate increased IL-6 trans-signaling, whereby IL-6 receptor signaling occurs in cells not normally expressing the IL-6 receptor. It has been suggested that IL-6 is intimately associated with two crucial aspects of depression, as well as central inflammation more broadly. First, the regulation of the local inflammatory response via its interactions with macrophage and glia melatonin production is coupled to local epigenetic modulation via methyl CpG-binding protein 2 (MeCP2). Second, the more systemic regulation of tryptophan availability occurs via the IL-6 induction of IDO. Coupled to its role in the regulation of autoimmune associated T-helper 17 cells and IL-17 production, IL-6 has wide and differential impacts on processes driving depression and a wider range of psychiatric and neurodegenerative conditions.

Inhibitory effect of antidepressant drugs on contact hypersensitivity reaction

BACKGROUND Contact hypersensitivity (CS) reaction in the skin is T-cell mediated immune reaction which plays a major role in the pathogenesis and chronicity of various inflammatory skin disorders and, like other delayed-type hypersensitivity (DTH) reactions, affords immunity against tumor cells and microbes. CS response is a self-limiting reaction, and interleukin (IL)-10 is considered to be a natural suppressant of cutaneous inflammatory response. Recently, it has been demonstrated that major depression is related to activation of the inflammatory response and elevation of some parameters of cell-mediated immunity. It has been suggested that such activation of the immune system may play a role in etiology of depression. If this immunoactivation is involved in etiology of depression, one would expect that antidepressant agents may have negative immunoregulatory effects. To the best of our knowledge, the effect of antidepressants on contact hypersensitivity has not been studied. METHODS The aim of the present study was to establish the effect of prolonged desipramine or fluoxetine treatment on CS reaction to picryl chloride. RESULTS Antidepressants significantly suppressed CS reaction, fluoxetine by 53% whereas desipramine by 47% compared to positive control. Moreover, desipramine and fluoxetine decreased relative weight of auxillary lymph nodes. Desipramine decreased also relative weight of inguinal lymph nodes and spleens whereas desipramine and fluoxetine increased production of IL-10 in comparison to positive control. CONCLUSION The observed effect of antidepressant drugs on CS reaction is consistent with the hypothesis that T-cell mediated immunity is targeted by antidepressants.

Inhibition of 2,4-dinitrofluorobenzene-induced contact hypersensitivity reaction by antidepressant drugs

BACKGROUND Contact hypersensitivity (CHS) induced by a topical application of hapten - 2,4-dinitrofluorobenzene (DNFB), is a T cytotoxic (Tc)1-cell-mediated antigen-specific type of skin inflammation. Recently, it has been shown that antidepressant drugs inhibit the T helper (Th)1-mediated CHS reaction induced by picryl chloride. The aim of present study was to establish the effect of two-week desipramine or fluoxetine administration on the CHS reaction induced by DNFB. METHODS Balb/c (H-2(d)) male mice were divided into six groups: 1) vehicle-treated negative control group; 2) desipramine-treated negative control group; 3) fluoxetine-treated negative control group; 4) vehicle-treated DNFB group (positive control group); 5) desipramine-treated DNFB group; 6) fluoxetine-treated DNFB group. T lymphocytes proliferation was determined by incorporation of [(3)H]-thymidine to DNA of concanavalin A stimulated cells. ELISA test was used for estimation of cytokines production. RESULTS The antidepressants significantly suppressed the CHS reaction mediated by Tc1 cells: desipramine by 55% and fluoxetine by 54% compared to the positive control. Moreover, the antidepressants decreased the proliferative activity of splenocytes and the ability of splenocytes to produce interleukin (IL)-6 and interferon (IFN)-γ and increased IL-10 production by the lymph node (LN) cells of DNFB-treated mice. CONCLUSION The results of the present study show that the Tc1-dependent reactivity to DNFB is significantly suppressed by antidepressant drugs, which suggests their inhibitory effect on Tc1 mediated immunity.

Inhibitory effect of antidepressants on B16F10 melanoma tumor growth.

BACKGROUND Antidepressant drugs, like fluoxetine, a selective serotonin reuptake inhibitor, desipramine, a nonselective noradrenaline reuptake inhibitor, and mirtazapine, an antagonist of noradrenaline α2 auto- and heteroreceptors, are widely used for the treatment of depressive symptoms in cancer patients. Since these antidepressants have different activities targeting the immune system, they might also modulate tumor growth in cancer patients. METHODS In the present study, we investigated the effects of administration of antidepressant drugs: fluoxetine, desipramine and mirtazapine on B16F10 melanoma tumor growth. These drugs were administered intraperitoneally (ip) for 17 days after subcutaneous injection of B16F10 melanoma cells to male C57BL/6J mice. RESULTS Fluoxetine significantly inhibited melanoma solid tumor growth and desipramine tended to decrease this parameter whereas mirtazapine had no effect. CONCLUSION The inhibitory effect of fluoxetine on melanoma growth was associated with an increased mitogen-induced T cell proliferation which may at least partly participate in the mechanism of the antitumor effect of this antidepressant. It appears that the inhibitory effect of fluoxetine on tumor growth is not related with changes in cytokine levels except for IL-10.

Inhibitory effect of antidepressant drugs on contact hypersensitivity reaction is connected with their suppressive effect on NKT and CD8(+) T cells but not on TCR delta T cells.

BACKGROUND Contact hypersensitivity (CHS) reaction induced by a topical application of hapten is a cell-mediated antigen-specific type of skin inflammation mediated by interaction of several subtypes of T cell subpopulations. Recently, it has been shown that antidepressant drugs inhibit CHS reaction, although the mechanism of this effect remains unknown. The aim of the present study was to investigate the effect of 2-week desipramine or fluoxetine administration on the CHS reaction induced by picryl chloride (PCL) application in B10.PL mice and in knock-out mice established on B10.PL background: TCRδ(-/-) mice lacking TCRγδ T lymphocytes; β2m(-/-) mice lacking CD8(+) T lymphocytes and CD1d(-/-) mice lacking CD1d dependent natural killer T (NKT) lymphocytes. METHODS B10.PL, TCRδ(-/-), β2m(-/-) and CD1d(-/-) mice were divided into six groups: 1) vehicle-treated negative control group; 2) desipramine-treated negative control group; 3) fluoxetine-treated negative control group; 4) vehicle and PCL-treated group (positive control group); 5) desipramine and PCL-treated group; and 6) fluoxetine and PCL-treated group. CHS to PCL was tested by evaluation of ear swelling. Metabolic activity of spleen and lymph node cells were estimated by MTT test. RESULTS The antidepressants significantly suppressed the CHS reaction in B10.PL mice: desipramine by 55% and fluoxetine by 42% compared to the positive control. This effect was even stronger in TCRδ(-/-) mice, in which fluoxetine reduced the ear swelling by 73% in comparison with the vehicle-treated positive control group. On the other hand, desipramine and fluoxetine did not inhibit CHS reaction in β2m(-/-) and CD1d(-/-) mice. Moreover, PCL increased metabolic and/or proliferative activity of splenocytes in all four strains of mice whereas the antidepressants decreased this activity of splenocytes in B10.PL, TCRδ(-/-) and CD1d(-/-) mice. CONCLUSION The results of the present study show that lack of CD8(+) T cells or NKT cells abolishes the immunosuppressive effect of antidepressant drugs on PCL-induced CHS reaction in mice. These results suggest that antidepressant drug-induced inhibition of CHS reaction is connected with their inhibitory effect on ability of CD8(+) T cells and NKT cells to induce and/or escalate CHS reaction. TCRγδ cells seem not to be involved in antidepressant-induced suppression of CHS.

Suppression of pro-inflammatory cytokine expression and lack of anti-depressant-like effect of fluoxetine in lipopolysaccharide-treated old female mice

Abstract Some antidepressants show a significantly lower efficacy in elderly patients, particularly in women. Previous studies have shown that antidepressants administered to young animals reduced depression‐like symptoms induced by lipopolysaccharide (LPS). The aim of this study was to find out whether the antidepressant and anti‐inflammatory properties of fluoxetine (FLU) can be observed also in old female C57BL/6J mice. A depression‐like state was evoked by the administration of LPS (100 &mgr;g/kg for 4 consecutive days) which was followed by reduction of sucrose preference (anhedonia) and enhancement of immobility‐time in the forced swim test (FST). Animals, which received FLU (10 mg/kg, 11 days) exhibited a decreased LPS‐induced expression of some inflammatory cytokines in the hippocampus and spleen but this effect was not accompanied by beneficial changes in animals’ behavior. Despite the lack of antidepressant‐properties of FLU in this model, our studies have proven significant profound anti‐inflammatory properties of chronic FLU treatment which may suggest its suitability for fending off inflammatory processes in the elderly. HighlightsFluoxetine did not reduce depressive behavior induced in senescent females by LPS injection.Fluoxetine attenuated LPS‐induced expression of pro‐inflammatory cytokines in the periphery and in the brain.Fluoxetine inhibited of proliferative activity of Con A‐stimulated splenocytes.

Corrigendum to “Inhibition of 2,4-dinitrofluorobenzene-induced contact hypersensitivity reaction by antidepressant drugs” [Pharmacol. Rep. 65 (2013) 1237–1246]

The authors wish to note an incorrectly listed financial support grant. The National Science Centre grant 2011/01/B/NZ6/00300 was inadvertently listed. The authors regret this error. The correct Acknowledgements read as follows.