Neuroprotective effects of peroxisome proliferator-activated receptor γ agonist through activation of Akt and signal transducers and activators of transcription 3 in transient forebrain ischemia.

Peroxisome proliferator-activated receptor gamma (PPARgamma) belongs to the nuclear hormone receptor family and is a ligand-modulated transcriptional factor. Pioglitazone, a PPARgamma ligand of the thiazolidinedione class, exerts several pleiotropic effects including neuroprotection in addition to reducing blood glucose and insulin resistance; however, its mechanism remains obscure. In this study, we examined the PPARgamma expression and the protective effects of pioglitazone after transient forebrain ischemia. We focused on Akt and signal transducers and activators of transcription 3 (STAT3), key pathways of prosurvival signaling in ischemic neuronal injury as the mechanisms of pioglitazone's effects. Male Sprague-Dawley rats were given daily oral administration of pioglitazone (0.2, 2 and 20 mg/kg/d) or the vehicle, and transient forebrain ischemia was induced by 5-minute occlusion of bilateral common carotid arteries with hypotension. Western blot and immunohistochemistry revealed that PPARgamma expression in the hippocampal CA1 subregion was upregulated 1-8 h after forebrain ischemia, which was observed mainly in pyramidal neurons. Most CA1 neurons were positive for TUNEL staining 5 days after ischemia, and pioglitazone administration reduced TUNEL-positive cells in a dose-dependent manner, with a significant difference in the 20 mg/kg/d group compared with the vehicle. Phosphorylation of Akt (Ser473) and its target, glycogen synthase kinase-3beta (Ser9), was increased after ischemia, and 20 mg/kg/d dose of pioglitazone significantly increased phosphorylation of these proteins. Furthermore, pioglitazone treatment enhanced phosphorylation of STAT3 (Tyr705) after ischemia. These results indicate that pioglitazone attenuates neuronal ischemic injury through the activation of Akt and STAT3 pathways.