Rosiglitazone-activated PPAR[gamma] induces neurotrophic factor-[alpha]1 transcription contributing to neuroprotection

Brain peroxisome proliferator-activated receptor gamma (PPAR[gamma]), 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-[alpha]1 (NF-[alpha]1), which also induces the expression of BCL-2, has a promoter that contains PPAR[gamma]-binding sites that are activated by rosiglitazone. Treatment of Neuro2a cells and primary hippocampal neurons with rosiglitazone increased endogenous NF-[alpha]1 expression and prevented H2O2-induced cytotoxicity. Concomitant with the increase in NF-[alpha]1, BCL-2 was also increased in these cells. When siRNA against NF-[alpha]1 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 PPAR[gamma] directly induces the transcription of NF-[alpha]1, 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 (PPAR[gamma]) in the nucleus. The PPAR[gamma]-rosiglitazone complex binds to the neurotrophic factor-[alpha]1 (NF-[alpha]1) promoter and activates the transcription of NF-[alpha]1 mRNA which is then translated to the protein. NF-[alpha]1 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).