(Arylthio)cyclopentenones derivatives prevent glutamate-induced HT22 cell death through a PPAR gamma-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-gamma (PPAR gamma) antagonist, T0070907. Pull-down assays revealed that biotinylated (arylthio)cyclopentenone (GIF-0643-biotin) and other biotin-bound cyclopentenones bind to PPAR gamma. The results also indicate that the GIF-0643-biotin-PPAR gamma complex is localized to the nucleus. Moreover, retinoid X receptor-alpha (RXR) co-precipitated with the GIF-0643-biotin-PPAR gamma complex, indicating that (arylthio)cyclopentenone can activate PPAR gamma-RXR heterodimers. These findings suggest that (arylthio)cyclopentenone derivatives prevent excitotoxicity by modulating gene expression via activation of the PPAR gamma-RXR hetrodimer.
Shibata
Shoko
S
Department of Biomolecular Science, Faculty of Engineering, Gifu University, Gifu 501-1193, Japan.
Furuta
Kyoji
K
Maeda
Masahide
M
Suzuki
Masaaki
M
Oh-Hashi
Kentaro
K
Kiuchi
Kazutoshi
K
Hirata
Yoko
Y
D000818:Animals; D001549:Benzamides / Q000494:pharmacology; D016923:Cell Death / Q000187:drug effects / Q000502:physiology; D002460:Cell Line; D003517:Cyclopentanes / Q000494:pharmacology*; D018698:Glutamic Acid / Q000633:toxicity*; D006367:HeLa Cells; D006624:Hippocampus / Q000187:drug effects / Q000502:physiology; D006801:Humans; D051379:Mice; D009474:Neurons / Q000187:drug effects* / Q000502:physiology; D018696:Neuroprotective Agents / Q000494:pharmacology*; D009498:Neurotoxins / Q000633:toxicity*; D018384:Oxidative Stress / Q000187:drug effects; D047495:PPAR gamma / Q000037:antagonists & inhibitors / Q000378:metabolism; D047492:Peroxisome Proliferator-Activated Receptors / Q000378:metabolism*; D011725:Pyridines / Q000494:pharmacology; D047490:Retinoid X Receptor alpha / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D013440:Sulfides / Q000494:pharmacology*
D001549:Benzamides; D003517:Cyclopentanes; D018696:Neuroprotective Agents; D009498:Neurotoxins; D047495:PPAR gamma; D047492:Peroxisome Proliferator-Activated Receptors; D011725:Pyridines; D047490:Retinoid X Receptor alpha; D013440:Sulfides; C458508:T 0070907; D018698:Glutamic Acid