Rosiglitazone‐activated PPARγ induces neurotrophic factor‐α1 transcription contributing to neuroprotection

Brain peroxisome proliferator-activated receptor gamma (PPARγ), a member of the nuclear receptor superfamily of ligand-dependent transcription factors, is involved in neuroprotection. It is activated by the drug rosiglitazone, which then can increase the prosurvival protein BCL-2, to mediate neuroprotection. However, the mechanism underlying this molecular cascade is unknown. Here we show that the neuroprotective protein Neurotrophic Factor-α1 (NF-α1), which also induces the expression of BCL-2, has a promoter that contains PPARγ-binding sites that are activated by rosiglitazone. Treatment of Neuro2a cells and primary hippocampal neurons with rosiglitazone increased endogenous NF-α1 expression and prevented H2O2-induced cytotoxicity. Concomitant with the increase of NF-α1, BCL-2 was also increased in these cells. When siRNA against NF-α1 was used, the induction of BCL-2 by rosiglitazone was prevented, and the neuroprotective effect of rosiglitazone was reduced. These results demonstrate that rosiglitazone-activated PPARγ directly induces the transcription of NF-α1, contributing to neuroprotection in neurons.