title: Activation of signal transducer and activator of transcription-3 by a peroxisome proliferator-activated receptor gamma agonist contributes to neuroprotection in the peri-infarct region after ischemia in oophorectomized rats.
abstract: OBJECTIVE
  The role of the phosphorylated signal transducer and activator of transcription-3 (p-STAT3) after cerebral ischemia by the peroxisome proliferator-activated receptor γ (PPARγ) agonist pioglitazone (PGZ) remains controversial. Whether the increase in p-STAT3 by estrogen is mediated by the estrogen receptor α is also obscure. We examined the role of p-STAT3, PPARγ, and estrogen receptor α against ischemic brain damage after PGZ treatment.
  
  
  METHODS
  Female Wistar rats subjected or not subjected to bilateral oophorectomy were injected with 1.0 or 2.5 mg/kg PGZ 2 days, 1 day, and 1 hour before 90-minute middle cerebral artery occlusion-reperfusion and compared with vehicle-control rats.
  
  
  RESULTS
  The cortical infarct size was larger in ovariectomized than in nonovarietomized rats; it was reduced by PGZ treatment. Inversely with the reduction of the infarct size, PPARγ, and p-STAT3 but not estrogen receptor α in the peri-infarct area were increased in PGZ-treated compared with vehicle-control rats. The increase in PPARγ and p-STAT3 was associated with the transactivation of antiapoptotic and survival genes and the reduction of caspase-3 in this area. Inhibitors of PPARγ or STAT3 abolished the PGZ-induced neuroprotection and the increase in p-STAT3. More importantly, p-STAT3 increased by PGZ was bound to PPARγ and the complex translocated to the nucleus to dock to the response element through p-STAT3.
  
  
  CONCLUSIONS
  Our findings suggest that the activation in the peri-infarct region of p-STAT3 and PPARγ by PGZ is essential for neuroprotection after ischemia and that PGZ may be of benefit even in postmenopausal stroke patients.
authors.affiliation: Department of Neurosurgery, Institute of Health Biosciences, The University of Tokushima Graduate School, 3-18-15, Kuramoto-cho, Tokushima 770-8503, Japan. k-tomoya@xg8.so-net.ne.jp
authors.forename: Tomoya
authors.initials: T
authors.lastname: Kinouchi
authors.forename: Keiko T
authors.initials: KT
authors.lastname: Kitazato
authors.forename: Kenji
authors.initials: K
authors.lastname: Shimada
authors.forename: Kenji
authors.initials: K
authors.lastname: Yagi
authors.forename: Yoshiteru
authors.initials: Y
authors.lastname: Tada
authors.forename: Nobuhisa
authors.initials: N
authors.lastname: Matsushita
authors.forename: Manabu
authors.initials: M
authors.lastname: Sumiyoshi
authors.forename: Junichiro
authors.initials: J
authors.lastname: Satomi
authors.forename: Teruyoshi
authors.initials: T
authors.lastname: Kageji
authors.forename: Shinji
authors.initials: S
authors.lastname: Nagahiro
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000235:genetics; D001479:Basal Ganglia / Q000473:pathology; D001921:Brain / Q000473:pathology; D002545:Brain Ischemia / Q000188:drug therapy* / Q000473:pathology; D053148:Caspase 3 / Q000378:metabolism; D002467:Cell Nucleus / Q000378:metabolism; D002544:Cerebral Infarction / Q000188:drug therapy* / Q000473:pathology; D004247:DNA / Q000235:genetics; D047628:Estrogen Receptor alpha / Q000378:metabolism; D005260:Female; D018696:Neuroprotective Agents; D010052:Ovariectomy; D047495:PPAR gamma / Q000819:agonists*; D000077205:Pioglitazone; D021381:Protein Transport; D051381:Rats; D017208:Rats, Wistar; D020218:Response Elements; D050796:STAT3 Transcription Factor / Q000235:genetics* / Q000378:metabolism*; D045162:Thiazolidinediones / Q000627:therapeutic use*; D015533:Transcriptional Activation / Q000187:drug effects
chemical_list: D047628:Estrogen Receptor alpha; D018696:Neuroprotective Agents; D047495:PPAR gamma; D050796:STAT3 Transcription Factor; C494088:Stat3 protein, rat; D045162:Thiazolidinediones; D004247:DNA; D053148:Caspase 3; D000077205:Pioglitazone