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 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).
Section on Cellular Neurobiology, Program on Developmental Neuroscience, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland, USA.
Erwan
E
Thouennon
Section on Cellular Neurobiology, Program on Developmental Neuroscience, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland, USA.
Yong
Y
Cheng
Section on Cellular Neurobiology, Program on Developmental Neuroscience, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland, USA.
Vida
V
Falahatian
Section on Cellular Neurobiology, Program on Developmental Neuroscience, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland, USA.
Niamh X
NX
Cawley
Section on Cellular Neurobiology, Program on Developmental Neuroscience, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland, USA.
Yoke Peng
YP
Loh
D000818:Animals; D015153:Blotting, Western; D043423:Carboxypeptidase H / Q000378:metabolism*; D005786:Gene Expression Regulation; D051379:Mice; D009474:Neurons / Q000187:drug effects / Q000378:metabolism*; D018696:Neuroprotective Agents / Q000494:pharmacology*; D018384:Oxidative Stress; D047495:PPAR gamma / Q000378:metabolism*; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000096:biosynthesis; D051381:Rats; D060888:Real-Time Polymerase Chain Reaction; D000077154:Rosiglitazone; D045162:Thiazolidinediones / Q000494:pharmacology*; D014158:Transcription, Genetic
D018696:Neuroprotective Agents; D047495:PPAR gamma; D019253:Proto-Oncogene Proteins c-bcl-2; D045162:Thiazolidinediones; D000077154:Rosiglitazone; D043423:Carboxypeptidase H
BCL-2; hippocampus; neuroprotection; neurotrophic factor-α1; rosiglitazone