Ketamine and Active Ketamine Metabolites Regulate STAT3 and the Type I Interferon Pathway in Human Microglia: Molecular Mechanisms Linked to the Antidepressant Effects of Ketamine
Ketamine and Active Ketamine Metabolites Regulate STAT3 and the Type I Interferon Pathway in Human Microglia: Molecular Mechanisms Linked to the Antidepressant Effects of Ketamine
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DOI：
10.3389/fphar.2019.01302
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发表时间：
2019-11-05
影响因子：
5.6
通讯作者：
Weinshilboum, Richard M.
中科院分区：
文献类型：
--
作者：
Ho, Ming-Fen;Zhang, Cheng;Weinshilboum, Richard M.
炎症是一个重要的生物过程，会增加抑郁症的风险，部分原因是促炎细胞因子的产生和谷氨酸能神经传递的改变。氯胺酮具有抗炎特性，这可能有助于其抗抑郁作用。本研究旨在阐明氯胺酮及其活性代谢物（2R,6R;2S,6S）-羟基去甲氯胺酮 (HNK) 的作用机制，该代谢物似乎在氯胺酮的快速抗抑郁作用中也发挥着重要作用。使用 HMC3 人类小胶质细胞系作为模型系统来测试氯胺酮在免疫反应调节中的可能作用，这可能有助于其抗抑郁作用。我们的结果强调了这样一个事实：氯胺酮及其两种活性代谢物可以至少部分地通过信号转导器和转录 3 (STAT3) 的激活来调节 I 型干扰素通路，而转录 3 在免疫反应中发挥着重要作用。具体来说，受氯胺酮或其活性代谢物调节的 STAT3 下游基因在“对 I 型干扰素的反应”途径中富集。我们的数据还表明，STAT3 可能在氯胺酮的抗抑郁作用中发挥作用，至少部分通过真核延伸因子 2 (EEF2) 介导，导致脑源性神经营养因子 (BDNF) 表达增加，并促进突触蛋白突触后密度蛋白 95 (PSD95) 和突触蛋白 I (SYN1) 的合成。
Inflammation is an important biological process which contributes to risk for depression, in part as a result of the production of proinflammatory cytokines and of alterations in glutamatergic neurotransmission. Ketamine has anti-inflammatory properties which might contribute to its antidepressant effects. This study was designed to clarify mechanisms of action for ketamine and its active metabolites, (2R,6R;2S,6S)-hydroxynorketamine (HNK), which also appear to play a major role in ketamine's rapid antidepressant effects. An HMC3 human microglial cell line was used as a model system to test a possible role for ketamine in immune response regulation that might contribute to its antidepressant effects. Our results highlight the fact that ketamine and its two active metabolites can regulate the type I interferon pathway mediated, at least partially, through signal transducer and activation of transcription 3 (STAT3) which plays a major role in the immune response. Specifically, STAT3 downstream genes that were modulated by either ketamine or its active metabolites were enriched in the "response to type I interferon" pathway. Our data also suggest that STAT3 might play a role in ketamine's antidepressant effects, mediated, at least in part, through eukaryotic elongation factor 2 (EEF2), resulting in the augmentation of brain-derived neurotropic factor (BDNF) expression and promoting the synthesis of synaptic proteins postsynaptic density protein 95 (PSD95) and synapsin I (SYN1).