The antidepressant-like effects of pioglitazone in a chronic mild stress mouse model are associated with PPARγ-mediated alteration of microglial activation phenotypesReportar como inadecuado

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Journal of Neuroinflammation

, 13:259

First Online: 04 October 2016Received: 29 January 2016Accepted: 21 September 2016


BackgroundDiscoveries that microglia-mediated neuroinflammation is involved in the pathological process of depression provided a new strategy for novel antidepressant therapy. Peroxisome proliferator-activated receptor γ PPARγ is a nuclear receptor regulating inflammation and microglial polarization and, therefore, a potential target for resolving depressive disorders. Our hypothesis was that antidepressant effects could be achieved through anti-inflammatory and neuroprotective activities by PPARγ-dependent microglia-modulating agents.

MethodsChronic mild stress CMS treatment was performed on C57BL-6 mice for 6 weeks. After 3 weeks with the CMS procedure, depressive-like behaviors were evaluated by sucrose preference SP, tail suspension test TST, forced swimming test FST, and locomotor activity. Pioglitazone was administered intragastrically once per day for 3 weeks at different doses. Neuroinflammatory cytokines were determined by real time-PCR RT-PCR, enzyme-linked immunosorbent assay ELISA, and western blot. The activated microglial state was confirmed by immunohistochemistry. N9 microglial cells were subjected to lipopolysaccharide, pioglitazone, and GW9662 to discuss the phenotype of activated microglia by RT-PCR, ELISA, and western blot.

ResultsIt was demonstrated that the PPARγ agonist pioglitazone 2.5 mg-kg ameliorated depression-like behaviors in CMS-treated mice, as indicated by body weight BW, the SP test, the FST, and the TST. The amelioration of the depression was blocked by the PPARγ antagonist GW9662. The expression of M1 markers IL-1β, IL-6, TNFα, iNOS, and CCL2 increased, and the gene expression of M2 markers Ym1, Arg1, IL-4, IL-10, and TGFβ decreased in the hippocampus of the stress-treated mice. Pioglitazone significantly inhibited the increased numbers and morphological alterations of microglia in the hippocampus, reduced the elevated expression of microglial M1 markers, and increased the downgraded expression of microglial M2 markers in C57BL-6 mice exposed to CMS. In an in vitro experiment, pioglitazone reversed the imbalance of M1 and M2 inflammatory cytokines, which is correlated with the inhibition of nuclear factor kB activation and is expressed in LPS-stimulated N9 microglial cells.

ConclusionsWe showed that pioglitazone administration induce the neuroprotective phenotype of microglia and ameliorate depression-like behaviors in CMS-treated C57BL-6 mice. These data suggested that the microglia-modulating agent pioglitazone present a beneficial choice for depression.

KeywordsPioglitazone PPARγ Antidepressant CMS Microglia Alternative activation Cytokine AbbreviationsANOVAAnalysis of variance


BWBody weight

CMSChronic mild stress

CNSCentral nervous system

FSTForced swimming test


Iba1Ionized calcium-binding adaptor protein-1

IkBInhibitor of NF-kB


M1Classical activation

M2Alternative activation

MAOIsMonoamine oxidase inhibitors

MDDMajor depressive disorder

NF-kBNuclear factor kB

OBOlfactory bulbectomised


PBSPhosphate-buffered saline

PPARγPeroxisome proliferator-activated receptor γ

RT-PCRReal time-PCR

SPSucrose preference

SSRIsSelective serotonin reuptake inhibitors

TNFαTumor necrosis factor-α

TSTTail suspension test

Electronic supplementary materialThe online version of this article doi:10.1186-s12974-016-0728-y contains supplementary material, which is available to authorized users.

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Autor: Qiuying Zhao - Xiaohui Wu - Shuo Yan - Xiaofang Xie - Yonghua Fan - Jinqiang Zhang - Cheng Peng - Zili You


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