A new chapter opens in anti-inflammatory treatments: The antidepressant bupropion lowers production of tumor necrosis factor-alpha and interferon-gamma in mice
A new chapter opens in anti-inflammatory treatments: The antidepressant bupropion lowers production of tumor necrosis factor-alpha and interferon-gamma in mice
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DOI：
10.1016/j.intimp.2005.12.007
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发表时间：
2006-06-01
影响因子：
5.6
通讯作者：
Soares, M. B. P.
中科院分区：
文献类型：
--
作者：
Brustolim, D.;Ribeiro-dos-Santos, R.;Soares, M. B. P.
在克罗恩病等多种炎症性人类疾病中，病理部分是由肿瘤坏死因子-α (TNF) 或干扰素-γ 等促炎细胞因子介导的。我们在这里展示了一种常用的仿制抗抑郁药安非他酮，十年来在世界范围内广泛用于治疗人类抑郁症，在小鼠脂多糖 (LPS) 诱导的炎症模型中，它可显着降低体内 TNF、干扰素-γ 和白介素-1 β 的水平。接受致命剂量 LPS 攻击的小鼠受到安非他酮的保护，并且抗炎细胞因子白细胞介素 10 的水平增加。先前在啮齿动物和人类中的数据表明，安非他酮的抗抑郁作用是通过其对去甲肾上腺素和多巴胺的微弱再摄取抑制作用介导的。与此一致，在我们的小鼠LPS模型中，安非他酮对TNF的抑制在很大程度上被β-肾上腺素能或多巴胺D1受体拮抗剂消除，但不能被D2拮抗剂消除。 TNF 合成受与细胞内环磷酸腺苷 (cAMP) 成反比关系的控制，刺激 β-肾上腺素受体或 D1 多巴胺能受体会导致 cAMP 增加，但刺激 D2 受体会降低 cAMP。我们得出的结论是，安非他酮可能通过介导 β-肾上腺素受体和 D1 受体信号传导增加来抑制 TNF 合成，从而导致 cAMP 增加，从而抑制 TNF 合成。安非他酮在非精神病人群中也具有良好的耐受性，并且与目前的抗炎、免疫抑制或 TNF 抑制治疗（如泼尼松、硫唑嘌呤、英夫利昔单抗或甲氨蝶呤）相比，长期使用的风险较小。需要新的抗炎治疗。我们相信抗炎、降低肿瘤坏死因子治疗疾病的新篇章已经开启。应探索安非他酮在人类中的用途。 (c) 2006 Elsevier B.V 保留所有权利。
In a wide range of human diseases of inflammatory nature like Crohn's disease, pathology is mediated in part by proinflammatory 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 D I 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. (c) 2006 Elsevier B.V All rights reserved.