title: Quercetin-3-O-glucuronide promotes the proliferation and migration of neural stem cells.
abstract: 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.
authors.affiliation: Institute of Pharmaceutical Research and Development, College of Pharmacy, Wonkwang University, Iksan, Korea; Hanbang Body-Fluid Research Center, Wonkwang University, Iksan, Korea.
authors.forename: Samrat
authors.initials: S
authors.lastname: Baral
authors.affiliation: Institute of Pharmaceutical Research and Development, College of Pharmacy, Wonkwang University, Iksan, Korea; Hanbang Body-Fluid Research Center, Wonkwang University, Iksan, Korea.
authors.forename: Ramesh
authors.initials: R
authors.lastname: Pariyar
authors.affiliation: Hanbang Body-Fluid Research Center, Wonkwang University, Iksan, Korea; College of Korean Medicine, Wonkwang University, Iksan, Korea.
authors.forename: Jaehyo
authors.initials: J
authors.lastname: Kim
authors.affiliation: Hanbang Body-Fluid Research Center, Wonkwang University, Iksan, Korea; College of Korean Medicine, Wonkwang University, Iksan, Korea.
authors.forename: Ho-Sub
authors.initials: HS
authors.lastname: Lee
authors.affiliation: Institute of Pharmaceutical Research and Development, College of Pharmacy, Wonkwang University, Iksan, Korea; Hanbang Body-Fluid Research Center, Wonkwang University, Iksan, Korea. Electronic address: jwseo@wku.ac.kr.
authors.forename: Jungwon
authors.initials: J
authors.lastname: Seo
mesh_terms: D000284:Administration, Oral; D000818:Animals; D019208:Brain-Derived Neurotrophic Factor / Q000378:metabolism; D002465:Cell Movement / Q000187:drug effects*; D049109:Cell Proliferation / Q000187:drug effects*; D002478:Cells, Cultured; D000089662:Doublecortin Protein; D005419:Flavonoids / Q000008:administration & dosage / Q000494:pharmacology*; D005960:Glucosides; D006801:Humans; D008297:Male; D008813:Mice, Inbred ICR; D058953:Neural Stem Cells / Q000166:cytology*; D019636:Neurodegenerative Diseases / Q000188:drug therapy / Q000235:genetics; D055495:Neurogenesis / Q000187:drug effects; D018696:Neuroprotective Agents; D051058:Oncogene Protein v-akt / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D011794:Quercetin / Q000008:administration & dosage / Q000494:pharmacology / Q000031:analogs & derivatives; D015398:Signal Transduction / Q000187:drug effects
chemical_list: D019208:Brain-Derived Neurotrophic Factor; C000714847:Dcx protein, mouse; D000089662:Doublecortin Protein; D005419:Flavonoids; D005960:Glucosides; D018696:Neuroprotective Agents; C532085:quercetin 3'-O-glucoside; D011794:Quercetin; D051058:Oncogene Protein v-akt
keywords: Akt; Apoptosis; Migration; Neural stem cell; Proliferation; Quercetin; Quercetin-3-O-Glucuronide