title: The antidepressant-like effects of pioglitazone in a chronic mild stress mouse model are associated with PPARγ-mediated alteration of microglial activation phenotypes.
abstract: Discoveries 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.
  
  
  
  Chronic 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.
  
  
  
  It 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.
  
  
  
  We 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.
authors.affiliation: School of Life Science and Technology, Center for Informational Biology, University of Electronic Science and Technology of China, Chengdu, 610054, China.
authors.forename: Qiuying
authors.initials: Q
authors.lastname: Zhao
authors.affiliation: School of Life Science and Technology, Center for Informational Biology, University of Electronic Science and Technology of China, Chengdu, 610054, China.
authors.forename: Xiaohui
authors.initials: X
authors.lastname: Wu
authors.affiliation: School of Life Science and Technology, Center for Informational Biology, University of Electronic Science and Technology of China, Chengdu, 610054, China.
authors.forename: Shuo
authors.initials: S
authors.lastname: Yan
authors.affiliation: State Key Laboratory Breeding Base of Systematic Research, Development and Utilization of Chinese Medicine Resources, Pharmacy College, Chengdu University of Traditional Chinese Medicine, Chengdu, 6111376, China.
authors.forename: Xiaofang
authors.initials: X
authors.lastname: Xie
authors.affiliation: School of Life Science and Technology, Center for Informational Biology, University of Electronic Science and Technology of China, Chengdu, 610054, China.
authors.forename: Yonghua
authors.initials: Y
authors.lastname: Fan
authors.affiliation: School of Life Science and Technology, Center for Informational Biology, University of Electronic Science and Technology of China, Chengdu, 610054, China.
authors.forename: Jinqiang
authors.initials: J
authors.lastname: Zhang
authors.affiliation: State Key Laboratory Breeding Base of Systematic Research, Development and Utilization of Chinese Medicine Resources, Pharmacy College, Chengdu University of Traditional Chinese Medicine, Chengdu, 6111376, China. pengchengchengdu@126.com.
authors.forename: Cheng
authors.initials: C
authors.lastname: Peng
authors.affiliation: School of Life Science and Technology, Center for Informational Biology, University of Electronic Science and Technology of China, Chengdu, 610054, China. youzili@uestc.edu.cn.
authors.forename: Zili
authors.initials: Z
authors.lastname: You
mesh_terms: D000818:Animals; D000928:Antidepressive Agents / Q000494:pharmacology / Q000627:therapeutic use*; D001835:Body Weight / Q000187:drug effects; D002461:Cell Line, Transformed; D002908:Chronic Disease; D016207:Cytokines / Q000235:genetics / Q000378:metabolism; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D005518:Food Preferences / Q000187:drug effects / Q000523:psychology; D019417:Hindlimb Suspension; D008124:Locomotion / Q000187:drug effects; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D017628:Microglia / Q000187:drug effects* / Q000378:metabolism; D047495:PPAR gamma / Q000378:metabolism*; D000077205:Pioglitazone; D015398:Signal Transduction / Q000187:drug effects; D013315:Stress, Psychological / Q000188:drug therapy* / Q000473:pathology*; D013395:Sucrose / Q000008:administration & dosage; D013550:Swimming / Q000523:psychology; D045162:Thiazolidinediones / Q000494:pharmacology / Q000627:therapeutic use*
chemical_list: D000928:Antidepressive Agents; D016207:Cytokines; D047495:PPAR gamma; D045162:Thiazolidinediones; D013395:Sucrose; D000077205:Pioglitazone
keywords: Alternative activation; Antidepressant; CMS; Cytokine; Microglia; PPARγ; Pioglitazone