title: Kuwanon V inhibits proliferation, promotes cell survival and increases neurogenesis of neural stem cells.
abstract: Neural stem cells (NSCs) have the ability to proliferate and differentiate into neurons and glia. Regulation of NSC fate by small molecules is important for the generation of a certain type of cell. The identification of small molecules that can induce new neurons from NSCs could facilitate regenerative medicine and drug development for neurodegenerative diseases. In this study, we screened natural compounds to identify molecules that are effective on NSC cell fate determination. We found that Kuwanon V (KWV), which was isolated from the mulberry tree (Morus bombycis) root, increased neurogenesis in rat NSCs. In addition, during NSC differentiation, KWV increased cell survival and inhibited cell proliferation as shown by 5-bromo-2-deoxyuridine pulse experiments, Ki67 immunostaining and neurosphere forming assays. Interestingly, KWV enhanced neuronal differentiation and decreased NSC proliferation even in the presence of mitogens such as epidermal growth factor and fibroblast growth factor 2. KWV treatment of NSCs reduced the phosphorylation of extracellular signal-regulated kinase 1/2, increased mRNA expression levels of the cyclin-dependent kinase inhibitor p21, down-regulated Notch/Hairy expression levels and up-regulated microRNA miR-9, miR-29a and miR-181a. Taken together, our data suggest that KWV modulates NSC fate to induce neurogenesis, and it may be considered as a new drug candidate that can regenerate or protect neurons in neurodegenerative diseases.
authors.affiliation: Laboratory of Molecular and Stem Cell Pharmacology, College of Pharmacy, Chung-Ang University, Seoul, Republic of Korea.
authors.forename: Sun-Young
authors.initials: SY
authors.lastname: Kong
authors.affiliation: Laboratory of Molecular and Stem Cell Pharmacology, College of Pharmacy, Chung-Ang University, Seoul, Republic of Korea.
authors.forename: Min-Hye
authors.initials: MH
authors.lastname: Park
authors.affiliation: College of Pharmacy and Research Institute of Pharmaceutical Science, Seoul National University, Seoul, Republic of Korea; College of Pharmacy, Sunchon National University, Suncheon, Jeollanam-do, Republic of Korea.
authors.forename: Mina
authors.initials: M
authors.lastname: Lee
authors.affiliation: Laboratory Science Division, International Vaccine Institute, Seoul, Republic of Korea.
authors.forename: Jae-Ouk
authors.initials: JO
authors.lastname: Kim
authors.affiliation: Laboratory of Molecular and Stem Cell Pharmacology, College of Pharmacy, Chung-Ang University, Seoul, Republic of Korea.
authors.forename: Ha-Rim
authors.initials: HR
authors.lastname: Lee
authors.affiliation: College of Pharmacy and Research Institute of Pharmaceutical Science, Seoul National University, Seoul, Republic of Korea.
authors.forename: Byung Woo
authors.initials: BW
authors.lastname: Han
authors.affiliation: Board of Governors Regenerative Medicine Institute, Cedars-Sinai Medical Center, Los Angeles, California, United States.
authors.forename: Clive N
authors.initials: CN
authors.lastname: Svendsen
authors.affiliation: College of Pharmacy and Research Institute of Pharmaceutical Science, Seoul National University, Seoul, Republic of Korea.
authors.forename: Sang Hyun
authors.initials: SH
authors.lastname: Sung
authors.affiliation: Laboratory of Molecular and Stem Cell Pharmacology, College of Pharmacy, Chung-Ang University, Seoul, Republic of Korea.
authors.forename: Hyun-Jung
authors.initials: HJ
authors.lastname: Kim
mesh_terms: D000818:Animals; D001973:Bromodeoxyuridine / Q000494:pharmacology; D002454:Cell Differentiation / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects*; D002470:Cell Survival / Q000187:drug effects*; D002478:Cells, Cultured; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000378:metabolism; D015536:Down-Regulation / Q000187:drug effects; D005419:Flavonoids / Q000494:pharmacology*; D020935:MAP Kinase Signaling System / Q000187:drug effects; D035683:MicroRNAs / Q000235:genetics; D031625:Morus / Q000737:chemistry; D058953:Neural Stem Cells / Q000187:drug effects*; D055495:Neurogenesis / Q000187:drug effects*; D010766:Phosphorylation / Q000187:drug effects; D010936:Plant Extracts / Q000494:pharmacology*; D018517:Plant Roots / Q000737:chemistry; D012333:RNA, Messenger / Q000235:genetics; D051381:Rats; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction / Q000187:drug effects; D015854:Up-Regulation / Q000187:drug effects
chemical_list: D050759:Cyclin-Dependent Kinase Inhibitor p21; D005419:Flavonoids; D035683:MicroRNAs; D010936:Plant Extracts; D012333:RNA, Messenger; D001973:Bromodeoxyuridine