Flavonoids are regarded as a kind of the most common active components in traditional Chinese medicines. Past studies concerning the flavonoids-­exerted neuroprotection has been focused on the roles of flavonoids in anti-­oxidation, anti-­Ab induced toxicity, regulating neurofilament expression and regulating neurotrophic factor expression (e.g. BDNF, NGF, GDNF). Emerging studies have unveiled that EPO might play an essential role in promoting neuron survival upon stress. However, the role of flavonoids in neuronal EPO regulation remains poorly defined. Given that severe side effects occurred with systematic administration of rhEPP, flavonoids research here centered on its potential function in regulating EPO abundance. Therefore, efforts here were made to screen for promising flavo...[ Read more ]

Flavonoids are regarded as a kind of the most common active components in traditional Chinese medicines. Past studies concerning the flavonoids-­exerted neuroprotection has been focused on the roles of flavonoids in anti-­oxidation, anti-­Ab induced toxicity, regulating neurofilament expression and regulating neurotrophic factor expression (e.g. BDNF, NGF, GDNF). Emerging studies have unveiled that EPO might play an essential role in promoting neuron survival upon stress. However, the role of flavonoids in neuronal EPO regulation remains poorly defined. Given that severe side effects occurred with systematic administration of rhEPP, flavonoids research here centered on its potential function in regulating EPO abundance. Therefore, efforts here were made to screen for promising flavonoids as substitutes for rhEPO in preventing and/or treating neurological disorders.

Plasmid pHRE-­Luc was adopted as a screening tool to select candidates possessing EPO regulatory ability among 59 flavonoids. To further characterize their EPO regulatory abilities, protein level of HIF-­1α and its degraded form, HIF-­1α-­OH were determined. For combination feasibility, flavonoids were paired-­grouped to form EC50 mixtures and the combination effect were compared via pHRE-Luc activity and EPO mRNA expression. The results showed that formononetin, baicalein, apigenin, calycosin, ononin, chrysin and tectorigenin exhibited significant EPO regulatory abilities. Fomononetin, baicalein, ononin and tectorigenin upregulated HRE activation via accumulating HIF-­1α protein but not HIF-­1α-­OH while chrysin, calcosin and apigenin accumulate neither HIF-­1α protein nor HIF-­1α-OH. For combination effect, only calycosin-­tectorigenin and ononin-­tectorigenin possessed synergistic effect at all dosages.

In conclusion, our studies have identified several flavonoids possessing EPO regulatory abilities, while HIF-­1α and HIF-­1α-­OH protein are not enough to account for such regulation. Our data also suggested specific paired-­flavonoids could regulate EPO expression synergistically. This overall could support the feasibility of flavonoids as functional substitutes for rhEPO in neuroprotection. More importantly, these results demonstrate it is promising to develop commercial mixtures of TCM flavonoids as food supplements or drugs for neuroprotection.