Nobiletin and its related flavonoids with CRE-dependent transcription-stimulating and neuritegenic activities.
cAMP response element (CRE) transcription is dysregulated in neurodegenerative disorders in the central nervous system (CNS), including polyglutamine diseases. As the first step to find natural compounds with protective action against neurodegeneration in the CNS, we here examined whether six citrus flavonoids, namely nobiletin, 5-demethylnobiletin, tangeretin, sinensetin, 6-demethoxytangeretin, and 6-demethoxynobiletin, stimulated CRE-dependent transcription and induced neurite outgrowth in PC12D cells. Among the compounds, nobiletin most potently enhanced CRE-dependent transcription and neurite outgrowth by activating ERK/MAP kinase-dependent signalling to increase CREB phosphorylation. The transcription and neurite outgrowth were stimulated by nobiletin in a concentration-dependent manner, with a strong correlation between them. Furthermore, a 11-day oral administration of nobiletin rescued impaired memory in olfactory-bulbectomized mice documented to be accompanied by a cholinergic neurodegeneration. These results suggest that nobiletin with the activity to improve impaired memory may become a potential leading compound for drug development for neurodegenerative disorders exhibiting the dysregulated CRE-dependent transcription.
Nagase
Hiroyuki
H
Department of Pharmaceutical Molecular Biology, Graduate School of Pharmaceutical Sciences, Tohoku University, Aoba, Aramaki, Aoba-ku, Sendai 980-8578, Japan.
Omae
Naoki
N
Omori
Akiko
A
Nakagawasai
Osamu
O
Tadano
Takeshi
T
Yokosuka
Akihito
A
Sashida
Yutaka
Y
Mimaki
Yoshihiro
Y
Yamakuni
Tohru
T
Ohizumi
Yasushi
Y
D000818:Animals; D000242:Cyclic AMP / Q000378:metabolism*; D047309:Flavones / Q000737:chemistry* / Q000494:pharmacology*; D051379:Mice; D015394:Molecular Structure; D016501:Neurites / Q000187:drug effects* / Q000378:metabolism*; D009830:Olfactory Bulb / Q000187:drug effects / Q000378:metabolism / Q000601:surgery; D016716:PC12 Cells; D051381:Rats; D020218:Response Elements / Q000235:genetics*; D013329:Structure-Activity Relationship; D018808:Transcription Factor AP-1 / Q000235:genetics; D014158:Transcription, Genetic / Q000187:drug effects* / Q000235:genetics
D047309:Flavones; D018808:Transcription Factor AP-1; C008661:nobiletin; D000242:Cyclic AMP