Modulation of the inflammatory response in rats chronically treated with the antidepressant agomelatine
Modulation of the inflammatory response in rats chronically treated with the antidepressant agomelatine
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DOI：
10.1016/j.euroneuro.2013.03.008
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发表时间：
2013-11-01
影响因子：
5.6
通讯作者：
Riva, Marco A.
中科院分区：
文献类型：
--
作者：
Molteni, Raffaella;Macchi, Flavia;Riva, Marco A.
越来越多的证据表明，炎症/免疫系统的激活有助于抑郁症的发病机制，这一假设可能具有很强的临床意义。事实上，超过30%的抑郁症患者未能达到缓解，这就有必要确定可能代表药物新靶点的系统。因此，本研究的目的是评价抗抑郁药阿戈美拉汀在脂多糖（LPS）炎症激发后调节大鼠脑中免疫应答特定组分的能力。为此，成年雄性大鼠在末次给药后16 h用LPS急性激发前，用阿戈美拉汀长期给药。在激发后2、6或24小时处死大鼠，并通过使用实时PCR或ELISA研究炎症反应的几个组分。我们发现阿戈美拉汀显著降低了LPS诱导的大鼠脑内和外周水平促炎细胞因子白细胞介素-1 β和白细胞介素-6的上调。在中枢水平，这些作用与抑制NF-κ B易位以及改变负责小胶质细胞活化的机制有关。此外，我们发现阿戈美拉汀还能够改变与犬尿氨酸途径相关的酶的表达，这些酶被认为是炎症相关抑郁症的重要介质。这些数据揭示了可能有助于阿戈美拉汀治疗效果的新特性，为免疫/炎症系统的特定组分在抗抑郁反应中的关键作用提供了证据，从而在抑郁症发病机制中发挥了关键作用。(C)2013 Elsevier B.V.和ECNP。All rights reserved.
Growing evidence suggests that the activation of the inflammatory/immune system contributes to depression pathogenesis, a hypothesis that might hold strong clinical implication. Indeed more than 30% of depressed patients fail to achieve remission, which poses the necessity to identify systems that may represent novel targets for medications. Accordingly, goal of this study was to evaluate the ability of the antidepressant agomelatine to modulate specific components of the immune response in the rat brain following an inflammatory challenge with lipopolysaccharide (LPS). To this aim, adult male rats were chronically treated with agomelatine before being acutely challenged with LPS 16 h after the last drug administration. Rats were sacrificed 2, 6, or 24 h after the challenge and several components of the inflammatory response have been investigated by using real-time PCR or ELISA. We found that agomelatine significantly reduced the LPS-induced up-regulation of the pro-inflammatory cytokines interleukin-1 beta and interleukin-6 in the rat brain as well as at peripheral level. At central level, these effects are associated to the inhibition of NF-kappa B translocation as well as to alterations of mechanisms responsible for microglia activation. In addition, we found that agomelatine was also able to alter the expression of enzymes related to the kynurenine pathway that are thought to represent important mediators to inflammation-related depression. These data disclose novel properties that may contribute to the therapeutic effect of agomelatine providing evidence for a crucial role of specific components of the immune/inflammatory system in the antidepressant response and thereby in depression etiopathology. (C) 2013 Elsevier B.V. and ECNP. All rights reserved.