Fustin flavonoid attenuates beta-amyloid (1-42)-induced learning impairment.
Natural flavonoids ameliorate amyloid-beta peptide (Abeta)-induced neurotoxicity. We examined whether the fustin flavonoid affects Abeta-induced learning impairment in mice. Repeated treatment with fustin significantly attenuated Abeta (1-42)-induced conditioned fear and passive avoidance behaviors. This effect was comparable to that of EGb761, a standard extract of ginkgo. Fustin treatment significantly prevented decreases in acetylcholine (ACh) levels, choline acetyltransferase (ChAT) activity, and ChAT gene expression induced by Abeta (1-42). Fustin also consistently suppressed increases in acetyl cholinesterase (AChE) activity and AChE gene expression induced by Abeta (1-42). In addition, fustin significantly attenuated Abeta (1-42)-induced selective decreases in muscarinic M1 receptor gene expression and muscarinic M1 receptor binding activity (as determined by [(3)H]pirenzepine binding) by modulating extracellular signal-regulated kinase 1/2 (ERK 1/2) and cAMP response-element binding protein (CREB) phosphorylation and brain-derived neurotrophic factor (BDNF) expression. These effects of fustin were reversed by treatment with dicyclomine, a muscarinic M1 receptor antagonist, and SL327, a selective ERK inhibitor, but not by chelerythrine, a pan-protein kinase C (PKC) inhibitor. Taken together, our results suggest that fustin attenuates Abeta (1-42)-impaired learning, and that the ERK/CREB/BDNF pathway is important for the M1 receptor-mediated cognition-enhancing effects of fustin.
Jin
Chun-Hui
CH
Neuropsychopharmacology and Toxicology Program, College of Pharmacy, Kangwon National University, Chunchon, South Korea.
Shin
Eun-Joo
EJ
Park
Jae-Bong
JB
Jang
Choon-Gon
CG
Li
Zhengyi
Z
Kim
Min Soo
MS
Koo
Kyo Hwan
KH
Yoon
Hyoung-Jong
HJ
Park
Sang-Jae
SJ
Choi
Won-Cheol
WC
Yamada
Kiyofumi
K
Nabeshima
Toshitaka
T
Kim
Hyoung-Chun
HC
D000109:Acetylcholine / Q000378:metabolism; D000607:Aminoacetonitrile / Q000031:analogs & derivatives / Q000494:pharmacology; D016229:Amyloid beta-Peptides / Q000378:metabolism / Q000494:pharmacology*; D000704:Analysis of Variance; D000818:Animals; D001345:Autoradiography; D001362:Avoidance Learning / Q000187:drug effects; D015153:Blotting, Western; D019208:Brain-Derived Neurotrophic Factor / Q000378:metabolism; D002795:Choline O-Acetyltransferase / Q000235:genetics / Q000378:metabolism; D003071:Cognition / Q000187:drug effects; D003214:Conditioning, Classical / Q000187:drug effects; D017362:Cyclic AMP Response Element-Binding Protein / Q000378:metabolism; D004025:Dicyclomine / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D005239:Fear / Q000187:drug effects; D005419:Flavonoids / Q000494:pharmacology*; D006624:Hippocampus / Q000378:metabolism*; D047468:Immunoprecipitation; D007858:Learning / Q000187:drug effects*; D051379:Mice; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism; D018727:Muscarinic Antagonists / Q000494:pharmacology; D010446:Peptide Fragments / Q000378:metabolism / Q000494:pharmacology*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D043643:Receptor, Muscarinic M1 / Q000235:genetics / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction
D016229:Amyloid beta-Peptides; D019208:Brain-Derived Neurotrophic Factor; D017362:Cyclic AMP Response Element-Binding Protein; D005419:Flavonoids; D018727:Muscarinic Antagonists; D010446:Peptide Fragments; D012333:RNA, Messenger; D043643:Receptor, Muscarinic M1; C424127:SL 327; C075222:amyloid beta-protein (1-42); D000607:Aminoacetonitrile; C522894:fustin; D004025:Dicyclomine; D002795:Choline O-Acetyltransferase; D048052:Mitogen-Activated Protein Kinase 3; D000109:Acetylcholine