阿部 和穂

The natural flavonoid fisetin (3,3',4',7-tetrahydroxyflavone) is neurotrophic and prevents fibril formation of amyloid beta protein (A beta). It is a promising lead compound for the development of therapeutic drugs for Alzheimer's disease. To find even more effective drugs based on the structure of fisetin, we synthesized a series of fisetin analogues lacking the 7-hydroxyl group and compared their effects on A beta fibril formation determined by the thioflavin T fluorescence assay. 3,3',4'-Trihydroxyflavone and 3',4'-dihydroxyflavone inhibited A beta fibril formation more potently than fisetin or 3',4',7-trihydroxyflavone, suggesting that the 7-hydroxy group is not necessary for anti-amyloidogenic activity. 3,3',4',5'-Tetrahydroxyflavone and 3',4',5'-trihydroxyflavone inhibited A beta fibril formation far more potently than 3,3',4'-trihydroxyflavone and 3',4'-dihydroxyflavone, suggesting that 3',4',5'-trihydroxyl group of the B ring is crucial for the anti-amyloidogenic activity of flavonoids. Based on the structure-activity relationship, we synthesized 3,3',4',5,5'-pentahydroxyflavone, and confirmed that this compound is the most potent inhibitor of A beta fibril formation among fisetin analogues that have been tested. Cytotoxicity assay using rat hippocampal neuron cultures demonstrated that A beta preincubated with 3,3',4',5,5'-pentahydroxyflavone was significantly less toxic than A beta preincubated with vehicle. 3,3',4',5,5'-Pentahydroxyflavone could be a new therapeutic drug candidate for the treatment of Alzheimer's disease. (c) 2012 Elsevier Ireland Ltd. All rights reserved.

Currently, the major drug discovery paradigm for neurodegenerative diseases is based upon high affinity ligands for single disease-specific targets. For Alzheimer's disease (AD), the focus is the amyloid beta peptide (A beta) that mediates familial Alzheimer's disease pathology. However, given that age is the greatest risk factor for AD, we explored an alternative drug discovery scheme that is based upon efficacy in multiple cell culture models of age-associated pathologies rather than exclusively amyloid metabolism. Using this approach, we identified an exceptionally potent, orally active, neurotrophic molecule that facilitates memory in normal rodents, and prevents the loss of synaptic proteins and cognitive decline in a transgenic AD mouse model.

著者らは、以前の研究において南天実エキスがモルモット気管平滑筋を弛緩させることを見出していたが、本研究では南天実に含まれる有効成分のヒゲナミンとナンテニンがどのように関与するかを検討し、ナンテニンがβ受容体刺激作用により素早い弛緩を、ヒゲナミンがCa拮抗作用により緩やかな弛緩を引き起こすことを明らかにした。