(Arylthio)cyclopentenones derivatives prevent glutamate-induced HT22 cell death through a PPARγ-dependent pathway

We show that cyclopentenone derivatives, which are synthetic analogs of cyclopentenone prostaglandins, are neuroprotective against glutamate-induced oxidative stress in HT22 cells. This effect was antagonized by a peroxisome proliferator-activated receptor-γ (PPARγ) antagonist, T0070907. Pull-down assays revealed that biotinylated (arylthio)cyclopentenone (GIF-0643-biotin) and other biotin-bound cyclopentenones bind to PPARγ. The results also indicate that the GIF-0643-biotin–PPARγ complex is localized to the nucleus. Moreover, retinoid X receptor-α (RXR) co-precipitated with the GIF-0643-biotin–PPARγ complex, indicating that (arylthio)cyclopentenone can activate PPARγ-RXR heterodimers. These findings suggest that (arylthio)cyclopentenone derivatives prevent excitotoxicity by modulating gene expression via activation of the PPARγ-RXR hetrodimer.