A new chapter opens in anti-inflammatory treatments:The antidepressant bupropion lowers production of tumor necrosis factor-alpha and interferon-gamma in mice

Abstract

In a wide range of human diseases of inflammatory nature like Crohn's disease, pathology is mediated in part by pro-inflammatory cytokines like tumor necrosis factor-alpha (TNF) or interferon-gamma. We show here that a commonly used generic antidepressant bupropion, in wide use worldwide to treat depression in humans for a decade now, profoundly lowers levels of TNF, interferon-gamma, and interleukin-1 beta in vivo, in a mouse lipopolysaccharide (LPS) induced inflammation model. Mice challenged with an otherwise lethal dose of LPS were protected by bupropion and levels of the anti-inflammatory cytokine interleukin-10 were increased. Previous data in rodents and humans indicate antidepressant effects of bupropion are mediated by its weak reuptake inhibition of norepinephrine and dopamine. Concordant with this, TNF suppression by bupropion in our mouse LPS model was largely abrogated by beta-adrenergic or dopamine D1 receptor antagonists but not by a D2 antagonist. TNF synthesis is controlled by an inverse relationship with intracellular cyclic adenosine monophosphate (cAMP) and stimulation of either beta-adrenoreceptors or D1 dopaminergic receptors result in increased cAMP but stimulation of D2 receptors lowers cAMP. We conclude that bupropion may suppress TNF synthesis by mediating increased signaling at beta-adrenoreceptors and D1 receptors, resulting in increased cAMP that inhibits TNF synthesis. Bupropion is well tolerated also in non-psychiatric populations and has less risk with long term use than current anti-inflammatory, immunosuppressive or TNF suppressive treatments such as prednisone, azathioprine, infliximab, or methotrexate. New anti-inflammatory treatments are needed. We believe a new chapter in antiinflammatory, TNF lowering treatment of disease has been opened. Bupropion's use for this in humans should be explored.

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“…While we attempted to overcome this limitation by evaluating the effects of the common antidepressant fluox etine on KP metabolites in rats, different classes of antidepres sant medications may have affected the present results. [59][60][61] Other variables known to affect inflammatory markers, such as body mass index, were not available for statistical corrections. While our histopathological analysis revealed no major signs of activated M1 amoeboid microglia, other microglial abnormal ities, particularly at the neurovascular interface, could not be adequately quantified in the present study.…”

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“…Therefore, the synergistic effects of Suc and Cp may not only affect adipose tissue but also peripheral macrophages. Furthermore, Brustolim et al (50) reported that the antidepressant bupropion, which is a norepinephrine and dopamine weak reuptake inhibitor, may suppress TNF-α synthesis by mediating increased signaling β-adrenoreceptors and dopamine type 1 receptors, resulting in increased cAMP that inhibits TNF-α synthesis. In addition, Cloëz-Tayarani et al (51) reported that serotonin inhibited TNF-α production human peripheral blood mononuclear cells.…”