TY - JOUR
T1 - Nobiletin and its related flavonoids with CRE-dependent transcription-stimulating and neuritegenic activities
AU - Nagase, Hiroyuki
AU - Omae, Naoki
AU - Omori, Akiko
AU - Nakagawasai, Osamu
AU - Tadano, Takeshi
AU - Yokosuka, Akihito
AU - Sashida, Yutaka
AU - Mimaki, Yoshihiro
AU - Yamakuni, Tohru
AU - Ohizumi, Yasushi
N1 - Funding Information:
This work was supported in part by Grant-in-Aid for Scientific Research from the Ministry of Education, Culture, Sports, Science and Technology of Japan (Y.O.; T.Y.) and Brain Science Foundation (T.Y.).
PY - 2005/12/2
Y1 - 2005/12/2
N2 - 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.
AB - 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.
KW - Bulbectomy
KW - CRE-dependent transcription
KW - Flavonoids
KW - Memory impairment
KW - Neurite outgrowth
KW - Neurodegeneration
KW - Nobiletin
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U2 - 10.1016/j.bbrc.2005.10.001
DO - 10.1016/j.bbrc.2005.10.001
M3 - Article
C2 - 16253614
AN - SCOPUS:27144554955
VL - 337
SP - 1330
EP - 1336
JO - Biochemical and Biophysical Research Communications
JF - Biochemical and Biophysical Research Communications
SN - 0006-291X
IS - 4
ER -