期刊
PHARMACOLOGICAL RESEARCH
卷 121, 期 -, 页码 114-121出版社
ACADEMIC PRESS LTD- ELSEVIER SCIENCE LTD
DOI: 10.1016/j.phrs.2017.04.028
关键词
Major depressive disorder; Antidepressants; NLRP3-inflammasome; Autophagy
资金
- Grupo de Investigacion Junta de Andalucia [CTS113]
- Consejeria de Salud of the Junta de Andalucia [PI-0036-2014]
- MRC-UK PET Methodology Programme [G1100809/1]
Major Depressive Disorder (MDD, ICD-10: F-33) is a prevalent illness in which the pathogenic mechanism remains elusive. Recently an important role has been attributed to neuro-inflammation, and specifically the NLRP3-inflammasome complex, in the pathogenesis of MDD. This suggests a key role for immunomodulation as a key pathway in the treatment of this disorder. This study evaluates the involvement of nine common antidepressants in the NLRP3-inflammasome complex (fluoxetine, paroxetine, mianserin, mirtazapine, venlafaxine, desvenlafaxine, amitriptyline, imipramine and agomelatine), both in in vitro THP-1 cells stimulated by ATP, and in a stress-induced depressive animal or MDD patients. Antidepressant treatment induced inflammasome inhibition was observed by decreased serum levels of IL-1 and IL-18 and decrease of NLRP3 and IL-1 beta (p17) protein expression. This was also observed under stress induced depressive behaviour and inflammasome activation in C57Bl/6 mice in vivo. Deletion of key autophagy mediator Atg5 in embryonic fibroblasts (MEF cells) showed an autophagy dependent-NLRP3-inflammasome inhibition by antidepressant treatment. These results suggest the NLRP3-inflammasome could be a biomarker for antidepressant treatment response in MDD patients, and therefore the monitoring of NLRP3 expression levels and/or IL-1 beta/IL-18 release may have clinical value in drug selection. Existing evidence suggests an anti-inflammatory effect of some antidepressants shown by IL-1 beta, IL-6 and TNF-alpha. Our data have shown that antidepressant-mediated autophagy may have a role in restoration of certain metabolic and immunological pathways in MDD patients. (C) 2017 Elsevier Ltd. All rights reserved.
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