Acute neuroprotection by pioglitazone after mild brain ischemia without effect on long-term outcome

Peroxisome proliferator-activated receptor-gamma (PPAR-gamma) agonists (thiazolidinediones) have anti-inflammatory effects and improve endothelium function. Here, we analyzed the effects of pioglitazone on short- and longer-term outcome after mild transient brain ischemia. 129/SV mice were subjected to 30 min filamentous middle cerebral artery occlusion (MCAo), followed by reperfusion. Post event, animals were treated with daily intraperitoneal (i.p.) pioglitazone (20 mg/kg body weight) or vehicle. Pioglitazone given acutely after transient brain ischemia/reperfusion reduced lesion size and the number of Iba1-expressing microglia in the ischemic striatum at three days. In vitro, pioglitazone attenuated migration and proliferation of primary mouse microglia. However, analysis at 6 weeks after MCAo/reperfusion no longer yielded an effect of pioglitazone on either lesion size or Iba1+ cell counts. Regarding functional longer-term outcome, we also did not detect a beneficial effect of pioglitazone on motor function measured either on the pole test or the wire hanging test or on learning and memory in the Morris water maze. Our study thus underscores the importance of extending experimental stroke studies to an analysis of longer-term outcome.