sl-327 and fustin

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.

Topics: Acetylcholine; Aminoacetonitrile; Amyloid beta-Peptides; Analysis of Variance; Animals; Autoradiography; Avoidance Learning; Blotting, Western; Brain-Derived Neurotrophic Factor; Choline O-Acetyltransferase; Cognition; Conditioning, Classical; Cyclic AMP Response Element-Binding Protein; Dicyclomine; Dose-Response Relationship, Drug; Fear; Flavonoids; Hippocampus; Immunoprecipitation; Learning; Mice; Mitogen-Activated Protein Kinase 3; Muscarinic Antagonists; Peptide Fragments; Receptor, Muscarinic M1; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger