title: Neuroprotective cyclopentenone prostaglandins up-regulate neurotrophic factors in C6 glioma cells.
abstract: In a previous study, we developed newly synthesized arylthio derivatives of cyclopentenone prostaglandins (GIF-0642, GIF-0643, GIF-0644, GIF-0745 and GIF-0747), which are neuroprotective against both manganese toxicity in PC12 cells and glutamate toxicity in HT22 cells. In the present study, we showed that these compounds and their lead compound, NEPP11, are potent inducers of glial cell line-derived neurotrophic factor (GDNF) expression in C6 glioma cells and primary astrocytes. These neuroprotective cyclopentenone prostaglandins also induced the gene expression of nerve growth factor and, to a lesser extent, brain-derived neurotrophic factor. The induction of GDNF mRNA was transcription-dependent, and the overexpression of dominant-negative Nrf2 attenuated the ability of the (arylthio)cyclopentenone prostaglandins to stimulate GDNF gene expression. These results suggest that (arylthio)cyclopentenone prostaglandins increase GDNF gene expression partly via the Keap1/Nrf2 pathway. A growing number of reports demonstrate the importance of increasing the amounts of neurotrophic factors, especially GDNF, in neuropathological states. Although the precise mechanisms by which the GIF compounds inhibit cell death are under investigation, an increase in neurotrophic factors may contribute to the diverse pharmacological properties of (arylthio)cyclopentenone prostaglandins in vivo and will make them potentially valuable in the treatment of neurodegenerative disorders.
authors.affiliation: Department of Biomolecular Science, Faculty of Engineering, Gifu University, Yanagido, Gifu 501 1193, Japan. yokoh@gifu-u.ac.jp
authors.forename: Yoko
authors.initials: Y
authors.lastname: Hirata
authors.forename: Kyoji
authors.initials: K
authors.lastname: Furuta
authors.forename: Masaaki
authors.initials: M
authors.lastname: Suzuki
authors.forename: Kentaro
authors.initials: K
authors.lastname: Oh-hashi
authors.forename: Yoshihito
authors.initials: Y
authors.lastname: Ueno
authors.forename: Kazutoshi
authors.initials: K
authors.lastname: Kiuchi
mesh_terms: D000818:Animals; D019208:Brain-Derived Neurotrophic Factor / Q000235:genetics / Q000378:metabolism; D045744:Cell Line, Tumor; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D004791:Enzyme Inhibitors / Q000494:pharmacology; D051098:Glial Cell Line-Derived Neurotrophic Factors / Q000235:genetics / Q000378:metabolism; D005910:Glioma / Q000473:pathology; D051379:Mice; D009414:Nerve Growth Factors / Q000235:genetics / Q000378:metabolism*; D018696:Neuroprotective Agents / Q000494:pharmacology*; D011453:Prostaglandins / Q000494:pharmacology*; D012333:RNA, Messenger / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D013997:Time Factors; D015854:Up-Regulation / Q000187:drug effects*
chemical_list: D019208:Brain-Derived Neurotrophic Factor; D004791:Enzyme Inhibitors; D051098:Glial Cell Line-Derived Neurotrophic Factors; D009414:Nerve Growth Factors; D018696:Neuroprotective Agents; D011453:Prostaglandins; D012333:RNA, Messenger