Quercetin is a bioactive compound exerting therapeutic effects on in vivo animal models of neurodegeneration or neurotoxicity. However, the narrow therapeutic dose-range of quercetin has been a point of concern since previous studies have demonstrated that quercetin induces cytotoxicity in vitro. Quercetin is metabolized to quercetin glucuronates such as quercetin-3-O-glucuronide (Q3GA), primarily detected in the plasma and the brain. Here, we examined whether and how quercetin or Q3GA regulates neural stem cells (NSCs) in vivo and in vitro. Immunohistochemistry showed that oral administration of quercetin increased nestin-, DCX-, BrdU/DCX-, and BrdU/NeuN-positive cells in the dentate gyrus of mice. However, quercetin decreased the viability of human embryonic NSCs in culture, accompanied by decreased Akt phosphorylation and increased cleavage of caspase-3 and PARP. In contrast, Q3GA increased BrdU-positive cell proliferation, Akt phosphorylation, and cyclin D1 expression. PI3K/Akt inhibitor LY294002 reversed Q3GA-induced Akt phosphorylation and cyclin D1 expression, thereby reducing Q3GA-induced proliferation. Furthermore, Q3GA increased the protein secretion of BDNF and its blockade using anti-BDNF antibody reversed Q3GA-induced proliferation. Under differentiation state, Q3GA promotes NSC migration, along with increased mRNA expression of CXCR4. Moreover, Q3GA significantly reversed scopolamine-induced reduction of Akt phosphorylation in the mouse hippocampus and ameliorated scopolamine-induced memory impairments. Our results demonstrate that quercetin and its metabolite Q3GA control NSC viability in a converse manner through contrary regulation of Akt, accounting for the conflicting effects of quercetin in vivo and in vitro. This study provides a novel mechanism for the positive effects of Q3GA on neurogenesis and suggests its therapeutic potential in neurodegenerative diseases.

Objective:To investigate the effects of Gastrodiae rhizoma,a dried root of Gastrodia elata Blume,on proliferation and differentiation of human NSCs derived from embryonic stem cells.Methods:A 70%ethanol extract of Gastrodiae rhizoma（EEGR） was estimated with4-hydroxybenzyl alcohol as a representative constituent by HPLC.Results:MTT assay showed that the treatment with EEGR increased the viability of NSCs in growth media.Compared to contro1,EEGR increased the number of dendrites and denritic spines extended from a differentiated NSC.Whereas EEGR decreased the mRNA expression of Nestin,it increased that of Tuj1 and MAP2 in NSCs grown in differentiation media.Immunocytochemical analysis using confocal microscopy also revealed the increased expression of MAP2 in dendrites of EEGR-treated NSCs.Furthermore,EEGR decreased mRNA expression of Sox2 in NSCs grown even in growth media.Conclusions:In conclusion,our study demonstrates for the first time that EEGR induced proliferation and neuronal differentiation of NSCs,suggesting its potential benefits on NSC-based therapies and neuroregeneration in various neurodegenerative diseases and brain Injuries.