6-demethoxynobiletin, a nobiletin-analog citrus flavonoid, enhances extracellular signal-regulated kinase phosphorylation in PC12D cells.
We previously demonstrated that nobiletin, a polymethoxylated flavone isolated from citrus peels, has the potential to improve cognitive dysfunction in patients with Alzheimer's disease (AD). Recent studies suggest that the generation of intraneuronal amyloid-beta (Aβ) oligomers is an early event in the pathogenesis of AD. Aβ oligomers cause deficits in the regulation of the extracellular signal-regulated kinase (ERK) signaling which is critical for consolidation of the memory. Our previous studies revealed that nobiletin activated ERK signaling and subsequent cyclic AMP response element-dependent transcription. In this study, the effects of five nobiletin analogs, 6-demethoxynobiletin, tangeretin, 5-demethylnobiletin, sinensetin, and 6-demethoxytangeretin, isolated from citrus peels were assessed on ERK phosphorylation in PC12D cells, and the structure-activity relationships were examined. PC12D cells were treated with nobiletin or its analogs, and the cell extracts were analyzed by Western blotting using an antibody specific to phosphorylated ERK. 6-Demethoxynobiletin markedly enhanced ERK phosphorylation in a concentration-dependent manner. These results may be useful in developing drugs and functional foods using citrus peels for the treatment of dementia including AD.
Department of Molecular Toxicology, School of Pharmaceutical Sciences, University of Shizuoka.
Junko
J
Kimura
Kiyomitsu
K
Nemoto
Akihito
A
Yokosuka
Yoshihiro
Y
Mimaki
Masakuni
M
Degawa
Yasushi
Y
Ohizumi
D000544:Alzheimer Disease / Q000188:drug therapy / Q000378:metabolism*; D000818:Animals; D000975:Antioxidants / Q000302:isolation & purification / Q000494:pharmacology* / Q000627:therapeutic use; D015153:Blotting, Western; D002957:Citrus / Q000737:chemistry*; D017362:Cyclic AMP Response Element-Binding Protein / Q000378:metabolism; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism*; D047309:Flavones / Q000302:isolation & purification / Q000494:pharmacology* / Q000627:therapeutic use; D008568:Memory; D016716:PC12 Cells; D010766:Phosphorylation; D008517:Phytotherapy; D010936:Plant Extracts / Q000737:chemistry / Q000494:pharmacology*; D051381:Rats; D015398:Signal Transduction; D013329:Structure-Activity Relationship
D000975:Antioxidants; D017362:Cyclic AMP Response Element-Binding Protein; D047309:Flavones; D010936:Plant Extracts; C008661:nobiletin; D048049:Extracellular Signal-Regulated MAP Kinases