Effects of gemfibrozil on outcome after permanent middle cerebral artery occlusion in mice

Fibrates are lipid lowering drugs and found as ligands for peroxisome proliferator-activated receptors (PPARs). A clinical study has shown that one type of fibrate gemfibrozil reduces stroke incidence in men. However, it remains unknown whether gemfibrozil improves outcome after stroke. We hypothesized that prophylactic administration of gemfibrozil improves outcome after ischemic stroke. In this study, we measured the impact of gemfibrozil in two permanent middle cerebral artery occlusion (MCAO) models in young adult male mice on normal diet. First, we tested gemfibrozil in a filamentous MCAO model. Pretreatment with gemfibrozil (30 mg/kg) for 7 days moderately but significantly reduced infarct size at 24 h after MCAO. A higher dose (120 mg/kg) did not attenuate infarct size. Rather, it tended to increase brain swelling. Second, we tested in a distal MCAO model. Gemfibrozil (30 mg/kg) for 7 days before and after stroke significantly attenuated cortical lesion size at 7 days after MCAO. Cortical blood flow measured by laser speckle imaging was improved by gemfibrozil in the ischemic hemisphere. In non-stroke animals gemfibrozil also altered gene expression levels of PPARs in both the aorta and brain in organ specific manners; however, endothelial nitric oxide synthase (eNOS) was not significantly affected. These findings suggested the possibility that the observed infarct reductions and cortical blood flow improvements in ischemic brains were not through eNOS-mediated mechanisms. Further investigations may be meritorious to examine whether prophylactic usage of gemfibrozil against stroke is beneficial.