Discovering the functional diversity of flavonoids derived from Chinese materia medica : drug developments for the prevention of alzheimer's disease and osteoporosis

Flavonoids, a group of natural compounds mainly derived from plants are well known to possess diverse biological effects. In order to search for potential therapeutic agents against Alzheimer’s diseases and post-menopausal osteoporosis, different sub-classes of flavonoids were analyzed to determine the estrogenic activities by activating the estrogen responsive elements (ERE) in cultured human breast cancer MCF-7 cells, the neuroprotective effects including anti-oxidation, anti-β-amyloid (Aβ) aggregation and toxicity in cultured neuronal PC-12 cells and the osteogenic activities by measuring alkaline phosphatase (ALP) activity in cultured osteosarcoma MG-63 cells. After correlation analysis, the neuroprotective and osteogenic activities did not directly correlate with the estrogenic activity of the flavonoids. In addition, the synergistic actions of baicalein and apigenin in estrogenic and neuroprotective effects were evaluated. Among these screened flavonoids, RNFG, baicalein, hibifolin, quercetin-3’-O-glucoside and scutellarin exerted their strong neuroprotection by blocking the apoptosis induced by Aβ, and/or activating Akt survival pathway in neurons. RNFG was obtained from the roots of Panax notoginseng, which possessed a strong activity in preventing Aβ-induced cell death. The pretreatment of RNFG reduced Aβ-induced DNA fragmentation and caspase-3 activation and abolished the increase of Ca2+ mobilization triggered by the aged Aβ. The neuroprotective properties of RNFG required a specific sugar attachment within the main chemical backbone because the flavonol backbone by itself did not show any protective effects. In the memory impairment experiment using passive avoidance task, the administration of RNFG reduced the brain damage in scopolamine-treated rat. These results revealed a novel usage of Radix Notoginseng and some of flavonoids that could be very useful in developing food supplements or potential drugs for prevention or treating Alzheimer’s disease. On the other hand, calycosin, tiliroside, baicalin and hyperin contained the osteogenic effects in bone cells. The mechanisms of flavonoid-induced osteogenesis were revealed, and one of the mechanisms was possibly mediated by a cholinergic enzyme, acetylcholinesterase (AChE). As a well-known hydrolytic enzyme in neurotransmission, AChE was involved in bone differentiation process. In cultured MG-63 cells, PRiMA (p̲roline r̲ich m̲embrane a̲nchor)-linked G4 AChE was the major form of enzyme and might participate in osteogenic differentiation process regardless of its enzymatic activity. The osteogenic role of PRiMA-linked G4 AChE in bone cell was further strengthened by its existence in rat calvarias, and a robust decrease of bone density in ACHE-/- mice. The increasing of PRiMA-linked G4 AChE was one of the mechanisms of flavonoids for osteogenic differentiation and some of the flavonoids might be potential candidates for drug development for osteoporosis