Intact noradrenaline transporter is needed for the sympathetic fine-tuning of cytokine balance

Earlier studies demonstrated that cytokine production is under the tonic control of noradrenaline. As the level and/or the duration of noradrenaline action is regulated by the noradrenaline transporter (NET), which is also a target of antidepressant treatment, we studied its role in the regulation of the cytokine response during inflammation. The endotoxin-evoked tumour necrosis factor-alpha (TNF-alpha) and interleukin-10 response was studied in genetically produced noradrenaline transporter-deficient (NET-KO) mice and by treatment with desipramine, a monoamine uptake-blocker antidepressant. NET-KO mice responded to endotoxin with significantly lower TNF-alpha and interleukin-10 production in comparison to their wild-type counterparts. Functional involvement of both alpha- and beta-adrenoceptors could be demonstrated in our model systems, using 7,8-methylenedioxy-14 alpha-hydroxy-alloberbane.HCl (CH-38083) and propranolol; however, the differences between the two phenotypes remained, suggesting a limited role of alpha-adrenoceptors in the observed changes. Acute treatment of both wild-type and NET-KO mice with desipramine significantly decreased the TNF-alpha response and significantly increased interleukin-10 production, indicating the role of an intact noradrenaline transporter in anti-inflammatory responses.     

Neuropharmacology of antidepressants that modify central noradrenergic and serotonergic function: a short review

The first generation of antidepressants largely act as ‘dual’ action drugs in that they facilitate both noradrenergic and serotonergic activity either by blocking the reuptake of noradrenaline and serotonin (tricyclic antidepressants) or by inhibiting the catabolism of these amines (monoamine oxidase inhibitors). Largely as a consequence of their unacceptable side effects, these drugs have been partly replaced by the second generation drugs that showed selectivity of either the noradrenaline (viloxazine, maprotiline, reboxetine) or serotonin (fluoxetine, sertraline, etc.) transporter. While these second generation drugs have undoubted advantages in terms of their safety and tolerability, there is growing evidence that the efficacy of some of these selective uptake inhibitors (e.g. SSRIs) in the treatment of the more severe forms of depression is less than that of the TCAs. This has led to the view that ‘dual action’ antidepressants may offer superiority in the treatment of severe depression. Two groups of novel antidepressants have been developed to meet the need of combining increased efficacy with safety. These include the mixed amine reuptake inhibitors such as lofepramine, venlafaxine and milnacipran and the novel tetracyclic antidepressant mirtazepine that facilitates the functional activity of both noradrenaline and serotonin without affecting the reuptake sites. Copyright © 1999 John Wiley & Sons, Ltd.     

Comparative study of the effects of desipramine and reboxetine on locus coeruleus neurons in rat brain slices

Several studies have suggested that the locus coeruleus may play an important role in the pathophysiology of depression. The aim of this study was to characterize, using single-unit extracellular recordings, the in vitro effects of the noradrenaline reuptake inhibitors desipramine and reboxetine, on locus coeruleus neurons from control rats and from those chronically treated with desipramine. Bath application of desipramine (1-100 microM) and reboxetine (0.1-10 microM) decreased the firing rate of locus coeruleus neurons in a concentration-dependent manner and the alpha(2)-adrenoceptor antagonist RX 821002 (10 microM) reversed these effects. In addition, reserpine (5 mg/kg, 3 h before the experiment) almost completely blocked the inhibitory effect of desipramine. Both drugs (1 microM desipramine and 0.1 microM reboxetine) potentiated the inhibitory effect of noradrenaline (10 microM). A 7-day treatment with desipramine (3 mg/kg/12 h, i.p.) caused a decrease in sensitivity to the alpha(2)-adrenoceptor agonist bromoxidine (EC(50) increased by 3.3-fold), but not to noradrenaline or reboxetine. In contrast, this treatment potentiated the inhibitory effect of desipramine with respect to control. Moreover, 14-day treatment with desipramine (3 mg/kg/12 h, i.p.) or reboxetine (10 mg/kg/12 h, i.p.) also potentiated the in vitro effect of desipramine without modifying the in vitro effect of reboxetine. These results show that desipramine and reboxetine modulate the activity of locus coeruleus neurons by noradrenaline acting on alpha(2)-adrenoceptors, and reveal that alpha(2)-adrenoceptor-independent mechanisms may also underlie the action of noradrenaline uptake inhibitors.     

Anti-Inflammatory effects of antidepressants through suppression of the interferon-gamma/interleukin-10 production ratio

There is some evidence that major depression--in particular, treatment-resistant depression (TRD)--is accompanied by activation of the inflammatory response system and that proinflammatory cytokines may play a role in the etiology of depression. This study was carried out to examine the effects of antidepressive agents, i.e., imipramine, venlafaxine, L-5-hydroxytryptophan, and fluoxetine on the production of interferon-gamma (IFN-gamma), a proinflammatory cytokine, and interleukin-10 (IL-10), a negative immunoregulatory cytokine. Diluted whole blood of fluoxetine-treated patients with TRD (mean age, 50.6+/-3.9 years) and age-matched healthy controls (mean age, 51.6+/-1.7 years) and younger healthy volunteers (mean age, 35.4+/-9.6 years) was stimulated with phytohemagglutinin (1 microg/mL) and lipopolysaccharide (5 microg/mL) for 48 hours with and without incubation with the antidepressants at 10-6 M and 10(-5) M. IFN-gamma and IL-10 were quantified by means of enzyme-linked immunoassays. The ratio of IFN-gamma to IL-10 production by immunocytes was computed because this ratio is of critical importance in determining the capacity of immunocytes to activate or inhibit monocytic and T-lymphocytic functions. All four antidepressive drugs significantly increased the production of IL-10. Fluoxetine significantly decreased the production of IFN-gamma. All four antidepressants significantly reduced the IFN-gamma/IL-10 ratio. There were no significant differences in the antidepressant-induced changes in IFN-gamma or IL-10 between younger and older healthy volunteers and TRD patients. Tricyclic antidepressants, selective serotonin reuptake inhibitors, and serotonin-noradrenaline reuptake inhibitors, as well as the immediate precursor of serotonin, have a common, negative immunoregulatory effect by suppressing the IFN-gamma/IL-10 production ratio. It is suggested that the therapeutic efficacy of antidepressants may be related to their negative immunoregulatory effects.     

In vitro immunoregulatory effects of antidepressants in healthy volunteers

Major depression is accompanied by an activation of the inflammatory response system (IRS) and antidepressants may have immunoregulatory activities. This study was carried out to compare the effect of imipramine, mianserin and lithium on the in vitro production of Th1-like cytokines, such as IL-2, IFN-gamma, lymphotoxin and Th2-like cytokines such as IL-4, IL-10 as well as IL-12 and TGF-beta. Peripheral blood mononuclear cells (PBMC) of 16 healthy volunteers were stimulated with polyclonal activators (phytohemagglutinin with lipopolysaccharide PHA + LPS) with or without incubation with imipramine, mianserin (1 microM) or lithium (1 mM). Imipramine and mianserin exhibited similar activities enhancing unstimulated IFN-gamma and IL-10 production. In PHA + LPS-stimulated PBMC both antidepressants inhibited IFN-gamma, IL-2 and lymphotoxin production (Th1-like cytokines) as well as IL-12 and IL-4 production. Under the same in vitro conditions, both antidepressants stimulated production of negative immunoregulatory cytokines such as IL-10 and TGF-beta. Lithium differed significantly from imipramine and mianserin, as it enhanced IL-2, IFN-gamma, IL-10 and TGF-beta production and inhibited only IL-4. All three examined antidepressants reduced IFN-gamma/IL-10 ratio. None of the antidepressants at the used concentrations induced apoptosis in PBMC so those changes in cytokine production were not the result of selective killing of certain cell subpopulations. Imipramine and mianserin at high concentrations negatively influenced reactive oxygen species (ROS) production in neutrophils, however, at concentrations in the therapeutical range none of the antidepressants used influenced "oxidative burst" in neutrophils. The results indicate that antidepressants exert immunoregulatory effects on human leukocyte functions, especially on cytokine production.     

The role of noradrenaline and selective noradrenaline reuptake inhibition in depression.

Depression is a common disorder that impacts on all aspects of a person's life. For the past 10 years, clinicians have focused on serotonin in their treatment of depression. This is largely due to the growing acceptance of the efficacy and safety of the selective serotonin reuptake inhibitors (SSRIs) in comparison with older tricyclic antidepressants (TCAs). However, evidence for a role of noradrenaline in depression has been accumulating for some time, beginning with the discovery that drugs which either caused or alleviated depression acted to alter noradrenaline metabolism. Until recently, the role of noradrenaline in depression was predicted from clinical experience with noradrenergic TCAs (desipramine, nortriptyline and protriptyline) and selective serotonin and noradrenaline reuptake inhibitors (venlafaxine, milnacipran). The licensing of reboxetine, a selective noradrenaline reuptake inhibitor now allows the role of noradrenaline in depression to be investigated directly. This review presents key data from the literature that support a role for noradrenaline in depression taking into account neurophysiology, psychopharmacology and clinical trial data.     

Chronic treatment with duloxetine is necessary for an anxiolytic-like response in the mouse zero maze: the role of the serotonin transporter

Rationale Monoamine transporter inhibitor antidepressants have anxiolytic efficacy in man. However, preclinical data poorly reflect this, either because (1) few studies assess chronic antidepressant treatment in animal models, (2) antidepressants are anxiogenic after acute treatment; and (3) animal models of anxiety are insensitive to antidepressants. Objective We address issues (1) and (2) and ascertain potential mechanisms mediating anxiolytic effects demonstrated. Methods The effect of acute treatment with seven antidepressants covering the classes selective serotonin reuptake inhibitors, serotonin–noradrenaline reuptake inhibitors, noradrenaline reuptake inhibitors and tricyclic antidepressants were compared with the benzodiazepine, chlordiazepoxide, on the mouse zero maze, an unconditioned model of anxiety. Furthermore, citalopram, duloxetine, reboxetine and amitriptyline were assessed after chronic administration (10 mg/kg p.o., 21 days, twice daily) in this model. In mice treated chronically, (a) the hypothermic response to serotonin (5-HT)_1A and 5-HT_1B receptor ligands, 8-hydroxy-2-(di-n-propylamino)tetralin (8-OHDPAT) and m-chlorophenyl piperazine (mCPP), respectively, was assessed and (b) serotonin transporter (SERT) and noradrenaline transporter (NET) densities in the cortex and hippocampus, respectively, were determined. Results None of the antidepressants were anxiolytic after acute treatment, although reboxetine, duloxetine and amitriptyline were anxiogenic. Only chronic treatment with duloxetine induced an anxiolytic effect, which was dissociable from nonspecific motor effects. Duloxetine reduced SERT density in the cortex by ∼75% compared to control, with no effect on NET density in the hippocampus. Citalopram and amitriptyline significantly reduced SERT density by ∼20%, whereas reboxetine selectively reduced NET density. All drugs reduced the hypothermic response to 8-OHDPAT and mCPP. Conclusion Duloxetine was anxiolytic after chronic but not acute treatment, reflecting clinical experience with antidepressants in general. Duloxetine's anxiolytic-like profile may be ascribed to the considerable reduction in the density of the SERT in the cortex.     

人参皂苷-Ro促进小鼠脾细胞增殖及调节小鼠脾细胞Th1/Th2细胞因子的产生

目的研究人参皂苷-Ro对小鼠脾细胞增殖及细胞因子产生的影响。方法［³H］ TdR参入法检测人参皂苷-Ro对小鼠脾淋巴细胞增殖的影响；酶联免疫吸附法检测人参皂苷-Ro对小鼠脾淋巴细胞产生细胞因子白介素-2、干扰素-γ和白介素-4的影响；逆转录聚合酶链式反应分析法研究人参皂苷-Ro对小鼠脾淋巴细胞中干扰素-γ、白介素-4 mRNA表达的影响。结果人参皂苷-Ro在1-10 μmol·L^-1显著促进Con A诱导的小鼠脾淋巴细胞增殖及小鼠脾淋巴细胞白介素-2的产生；在2-10 μmol·L^-1促进Con A诱导的小鼠脾淋巴细胞产生和表达Th2细胞因子白介素-4, 而降低Con A诱导的小鼠脾淋巴细胞产生和表达Th1细胞因子干扰素-γ。结论人参皂苷-Ro通过调节脾细胞内Th1型和Th2型细胞因子的转录和表达发挥免疫调节作用。     

Concurrent electroconvulsive therapy in patients receiving reboxetine

There are few studies of the potential interaction between antidepressants and electroconvulsive therapy (ECT), although there is a theoretical risk of serotonin syndrome when ECT is used in patients receiving selective serotonin reuptake inhibitors. There may also be an increased cardiovascular risk during ECT therapy in patients receiving tricyclic antidepressants. Reboxetine is a novel selective noradrenaline reuptake inhibitor, with actions specific to the noradrenergic system and negligible affinity for other neurotransmitter receptors. Here we report two cases in which ECT was used in patients receiving reboxetine. In both cases the episodes of ECT appeared uncomplicated by the concomitant administration of reboxetine. We suggest that the combined use of ECT with reboxetine is well tolerated. Copyright © 1999 John Wiley & Sons, Ltd.     

Expanding the horizons of depression: beyond the monoamine hypothesis

The monoamine hypothesis has dominated our understanding of depression and of pharmacological approaches to its management and it has produced several generations of antidepressant agents, ranging from the monoamine oxidase inhibitors (MAOIs), through tricyclics (TCAs) and selective serotonin reuptake inhibitors (SSRIs), to the recently introduced selective noradrenaline reuptake inhibitor (NARI), reboxetine. Greater receptor selectivity has improved tolerability, but not efficacy, when newer compounds are compared with the original tricyclic antidepressants (TCAs) and monoamine oxidase inhibitors. Essentially, the newer antidepressants have the same distinguishing feature as older ones, i.e. acute enhancement of monoaminergic neurotransmission. The monoamine hypothesis cannot conclusively link the acute biochemical action of antidepressants on monoamine levels with their delayed clinical effect of 10-14 days, nor can it explain the mode of action of antidepressants that are effective despite being very weak inhibitors of monoaminergic transmission (e.g. iprindole) or, incongruously, enhancing monoamine uptake (e.g. tianeptine). Compared with other fields of medicine, there has been a lack of progress in understanding the pathophysiology of depression and producing truly novel antidepressant agents. Other biological approaches to depression, such as overactivity of the hypothalamic-pituitary-adrenal axis, hippocampal neural plasticity in response to stress, and the link between the inflammatory response and depression, offer new approaches to finding pharmacological agents, aided by improved techniques for visualising the human brain, better animal models, and increased knowledge of human markers of depression. Copyright 2001 John Wiley & Sons, Ltd.     

Cytokines: abnormalities in major depression and implications for pharmacological treatment

The role of cytokines in depression was first considered when the cytokine interferon resulted in "sickness behaviour", the symptoms of which are similar to those of major depression. The latter is associated with an increase in pro-inflammatory cytokines such as interleukin-1 (IL-1), interleukin-6 (IL-6) and tumour necrosis factor alpha (TNF-alpha). These cytokines are potent modulators of corticotropin-releasing hormone (CRH) which produces heightened hypothalamic-pituitary-adrenal axis (HPA) activity characterized by increases in ACTH and cortisol, both of which are reported elevated in major depression. Antidepressant treatment has immunomodulatory effects with increases in the production of IL-10, which is an anti-inflammatory cytokine. This review based on a Medline search from 1980-2003, focuses on the evidence available of cytokine changes in acute stress, chronic stress and major depression. It examines the effects of antidepressant treatment on immune parameters in both animal models and clinical trials. We suggest that future antidepressants may target the immune system by either blocking the actions of pro-inflammatory cytokines or increasing the production of anti-inflammatory cytokines.     

Inhibitory effect of antidepressants on B16F10 melanoma tumor growth

BackgroundAntidepressant 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.MethodsIn 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.ResultsFluoxetine significantly inhibited melanoma solid tumor growth and desipramine tended to decrease this parameter whereas mirtazapine had no effect.ConclusionThe 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.     

Differential effect of betulin and betulinic acid on cytokine production in human whole blood cell cultures

Betulin and betulinic acid, plant-derived triterpenoid compounds, have been described to possess anti-inflammatory activity. In this paper, we examine the ability of both compounds to induce and modulate cytokine production in human whole blood cell cultures. The results indicate that betulin is a modest TNF-alpha inducer and also an enhancer of mitogen-induced TNF-alpha production. In contrast to betulin, betulinic acid is a modulator of cytokine production by Th1/Th2 cell subpopulations which slightly enhances IL-10 formation and inhibits IFN-gamma production, reducing IFN-gamma/IL-10 ratio from 3.6 to 2.6.     

Moclobemide exerts anti-inflammatory effect in lipopolysaccharide-activated primary mixed glial cell culture

An increasing body of evidence indicates that glial activation and neuroinflammation play an important role in the pathogenesis of psychiatric and neurodegenerative diseases. Activated glial cells secrete various cytokines that influence neurotransmission, hypothalamus–pituitary–adrenal axis activity, neuronal plasticity and neurogenesis. It has been suggested that alterations in cytokine networks are involved in the mechanism of action of antidepressant drugs. Until now, only a few studies demonstrated that some tricyclic antidepressants and selective serotonin reuptake inhibitors reduced production of pro-inflammatory cytokines in brain glia cells. We have investigated for the first time whether the antidepressant, moclobemide (a reversible selective inhibitor of monoamine oxidase-A) has an influence on pro-inflammatory cytokines [interleukin (IL)-1β and tumor necrosis factor (TNF)-α] and anti-inflammatory cytokine (IL-10) in primary rat mixed glial cell cultures stimulated by lipopolysaccharide (LPS). Our results showed that moclobemide used in a wide range of concentrations diminished LPS-stimulated IL-1β and TNF-α mRNAs expression in cellular extracts and remarkably reduced the levels of both pro-inflammatory cytokines in culture medium. In opposite to this, the drug had no influence on IL-10 mRNA and slightly reduced IL-10 concentration. Moreover, moclobemide decreased LPS-stimulated translocation of NFκB p65 subunit into cellular nuclei. These results suggest that moclobemide exerts anti-inflammatory effect in the central nervous system because it affects the balance between pro- and anti-inflammatory cytokines (IL-1β, TNF-α/IL-10) in primary mixed glial cell cultures.     

Interaction of the human plasma membrane monoamine transporter (hPMAT) with antidepressants and antipsychotics

Monoamine neurotransmission is efficiently terminated through synaptic reuptake of released neurotransmitters by high-affinity Na⁺- and Cl⁻-dependent neuronal monoamine transporters of the SLC6A family located in the plasma membrane of presynaptic nerve terminals. Recently, a low-affinity, high-capacity Na⁺- and Cl⁻-independent plasma membrane monoamine transporter (PMAT) belonging to the SLC29 solute carrier family has been cloned. PMAT was shown to transport monoamine neurotransmitters as well as organic cations such as 1-phenyl-4-methyl-pyridinium (MPP⁺). Thus, the PMAT which is highly expressed in the human brain may be involved in the modulation of central monoaminergic neurotransmission and it may be a target for drugs used to treat depression and schizophrenia, i.e., dysregulations of the monoamine homeostasis in the central nervous system (CNS). Therefore, we examined in transfected cells the influence on [³H]-MPP⁺ transport by the human PMAT (hPMAT) of nine monoamine transport inhibiting antidepressants (ADs) belonging to pharmacologically diverse classes (imipramine, desipramine, amitriptyline, bupropion, fluoxetine, sertraline, paroxetine, reboxetine, and venlafaxine), of the atypical ADs tianeptine and trimipramine and of five antipsychotics (levomepromazine, haloperidol, clozapine, olanzapine, and risperidone). All examined drugs inhibited the hPMAT; however, half-maximum inhibition (IC₅₀) was observed at concentrations which were much higher than reported clinical plasma concentrations of these drugs. Thus, inhibition of the hPMAT by these CNS drugs may not (or only marginally) contribute to their therapeutic effects.     

An assessment of the acute effects of the serotonin releasers methylenedioxymethamphetamine, methylenedioxyamphetamine and fenfluramine on immunity in rats

The purpose of the present study was to examine the effect of the serotonin releasing amphetamine derivatives methylenedioxymethamphetamine (MDMA), methylenedioxyamphetamine (MDA) and fenfluramine (FEN) on immunity in rats. Similar to MDA and MDMA, FEN reduced the number of circulating lymphocytes, provoked a suppression of Con A-stimulated lymphocyte proliferation and total IFN-gamma and IL-10 production in diluted whole blood cultures. Thus the non-psychostimulant amphetamine derivative FEN, shares the ability of the psychostimulant methylenedioxy-substituted amphetamine derivatives to alter these indices of immune function in the rat. However, when Con A-stimulated cytokine production was normalised for the number of lymphocytes in culture in order to examine cytokine production at a cellular level, the effect of the amphetamine derivatives begins to diverge. FEN shares with MDMA and MDA the ability to suppress production of the Th2 type cytokine IL-10. However the effect of these drugs on Th1 type cytokine secretion was much more complex. While the methylendioxy-substituted amphetamines increases the secretion of the Th1 type cytokine IL-2 without altering the related Th1 type cytokine IFN-gamma, FEN did not alter IL-2 secretion, but suppressed IFN-gamma secretion. In addition to these effects on T-cell responses, all three drugs inhibited LPS-induced TNF-alpha secretion from diluted whole blood cultures suggesting that macrophage activity is impaired following treatment. In all, these data extend our previous findings concerning the effects of MDMA on the immune system and demonstrate that the related serotonin releasers MDA and FEN also provoke immunological changes in rats.     

Measuring T cell cytokines in allergic upper and lower airway inflammation: can we move to the clinic?

Recent insights regarding the development of allergic diseases such as allergic rhinitis, asthma and atopic eczema are based on the functional diversity of T helper (Th)1 and Th2 lymphocytes. Th2 cells (secreting Interleukin (IL)-4, IL-5, IL-9 and IL-13) are considered to be responsible for the induction and for many of the manifestations of atopic diseases. Local overproduction of Th2 cytokines at the site of allergic inflammation, and an intrinsic defect in the production of IFN-gamma by Th1 cells in atopic individuals, have now been reported by several authors. Both IFN-gamma and IL-10 have been suggested to play a modulatory role in the induction and maintenance of allergen-specific tolerance in healthy individuals. However, recent studies indicate that Th1 cells, secreting IFN-gamma might cause severe airway inflammation. On the other hand, 'inflammatory T cells' or Th17 cells, producing IL-17, could represent a link between T cell inflammation and granulocytic influx as observed in allergic airway inflammation. We focus in this review on local (at the side of inflammation) T cell cytokine production and cytokine production by circulating T cells (after in vitro restimulation) from individuals with allergic airway disease, rhinitis and/or asthma. We furthermore review the changes in local T cell cytokine production and/or cytokine production by circulating T cells (after restimulation in vitro) from allergic/asthmatic individuals after treatment with anti-inflammatory agents or immunotherapy. Finally, we discuss whether measuring these T cell cytokines in the airways might be of diagnostic importance or could help to follow-up patients with allergy/asthma.     

Possible involvement of GABAB receptors in action of antidepressants]

Antidepressants are divided into several groups such as monoamine oxidase inhibitors, serotonin reuptake inhibitors, noradrenaline reuptake inhibitors and alpha-adrenoceptor antagonists. Antidepressants show, however, a common clinical profile: their clinical actions occur after a chronic treatment. It is, therefore, suggested that antidepressants have a common pharmacological profile. We reviewed possible involvement of gamma-aminobutyric acid (GABA)B receptors in action of antidepressants. Our data in combination with previous ones from other laboratories suggest that antidepressants suppress the activity of presynaptic 5-hydroxytryptamine3 receptors on GABA neurons, resulting in the reduction of GABA release. It is likely that the decrease in GABA release attenuates GABAB receptor-mediated neurotransmission, thereby upregulating GABAB receptors.