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Title

Antidepressants induce autophagy dependent-NLRP3-inflammasome inhibition in Major depressive disorder

AuthorsAlcocer-Gómez, Elísabet; Casas-Barquero, Nieves; Bullón, Pedro; Sánchez-Alcázar, José Antonio CSIC ORCID CVN ; Cordero, Mario D. CSIC ORCID
KeywordsNLRP3-inflammasome
Antidepressants
Autophagy
Major depressive disorder
Issue Date2017
PublisherElsevier
CitationPharmacological Research 121: 114-121 (2017)
AbstractMajor 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-1β and IL-18 and decrease of NLRP3 and IL-1β (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-1β/IL-18 release may have clinical value in drug selection. Existing evidence suggests an anti-inflammatory effect of some antidepressants shown by IL-1β, IL-6 and TNF-α. Our data have shown that antidepressant-mediated autophagy may have a role in restoration of certain metabolic and immunological pathways in MDD patients.
Descriptionet al.
URIhttp://hdl.handle.net/10261/163453
DOI10.1016/j.phrs.2017.04.028
Identifiersdoi: 10.1016/j.phrs.2017.04.028
e-issn: 1096-1186
issn: 1043-6618
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