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 pro-survival protein B-cell lymphoma 2 (BCL-2)， to mediate neuroprotection. However， the mechanism underlying this molecular cascade remains 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 H2 O2 -induced cytotoxicity. Concomitant with the increase in 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. We proposed the following cascade for neuroprotection against oxidative stress by rosiglitazone: Rosiglitazone enters the neuron and binds to peroxisome proliferator-activated receptor gamma (PPARγ) in the nucleus. The PPARγ-rosiglitazone complex binds to the neurotrophic factor-α1 (NF-α1) promoter and activates the transcription of NF-α1 mRNA which is then translated to the protein. NF-α1 is the secreted， binds to a cognate receptor and activates the extracellular signal-regulated kinases (ERK) pathway. This in turn enhances the expression of the pro-survival protein， B-cell lymphoma 2 (BCL-2) and inhibition of caspase 3 (Csp-3) to mediate neuroprotection under oxidative stress. Akt， protein kinase B (PKB).