Fenofibrate Increases Heme Oxygenase 1 Expression and Astrocyte Proliferation While Limits Neuronal Injury During Intracerebral Hemorrhage

Peroxisome proliferator-activated receptors alpha (PPAR alpha) is a therapy target in atherosclerosis and cardiovascular diseases. However, anti-inflammatory effects of PPARa in intracerebral hemorrhage (ICH) remain unknown. We investigated the anti-inflammatory effects of fenofibrate, a ligand of PPAR alpha, in ICH rat model. We found that engagement of fenofibrate increased nissl body and astrocytes, and reduced the neuronal damage, which was observed in paraffin section of ICH rat brain. Fenofibrate also promoted the proliferation of astrocytes that were isolated from adult rat brain. Fenofibrate significantly upregulated heme oxygenase 1 (HO-1) at protein and mRNA levels in human glioblastoma LN-18 cells and rat brain astrocytes respectively, but nuclear factor kappa-light- chain-enhancer of activated B cells (NF kappa B) was downregulated after fenofibrate treatment. Results showed that fenofibrate-induced upregulation of HO-1 expression were inhibited after LN-18 cells were transfected with 50nM small interfering RNA (siRNAs) for 48 hours to knockdown PPAR alpha. Further studies in rat astrocytes confirmed the rescue effects of PPARa silence against fenofibrate induced upregulation of HO-1 expression. Our data indicated that fenofibrate benefits neuronal protection through increasing HO-1 expression level and decreasing NF kappa B expression in PPAR alpha-dependent manner. In conclusion, PPARa and HO-1 may function as significant targets to protect the brain during ICH.