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

Background and Purpose-The role of the phosphorylated signal transducer and activator of transcription-3 (p-STAT3) after cerebral ischemia by the peroxisome proliferator-activated receptor gamma (PPAR gamma) agonist pioglitazone (PGZ) remains controversial. Whether the increase in p-STAT3 by estrogen is mediated by the estrogen receptor alpha is also obscure. We examined the role of p-STAT3, PPAR gamma, and estrogen receptor alpha 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, PPAR gamma, and p-STAT3 but not estrogen receptor alpha in the pen-infarct area were increased in PGZ-treated compared with vehicle-control rats. The increase in PPAR gamma and p-STAT3 was associated with the transactivation of antiapoptotic and survival genes and the reduction of caspase-3 in this area. Inhibitors of PPAR gamma or STAT3 abolished the PGZ-induced neuroprotection and the increase in p-STAT3. More importantly, p-STAT3 increased by PGZ was bound to PPAR gamma 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 pen-infarct region of p-STAT3 and PPAR gamma by PGZ is essential for neuroprotection after ischemia and that PGZ may be of benefit even in postmenopausal stroke patients. (Stroke. 2012;43:478-483.)