title: Glycogen synthase kinase 3 inhibition promotes adult hippocampal neurogenesis in vitro and in vivo.
abstract: Glycogen synthase kinase-3 (GSK-3) is a serine/threonine kinase originally identified as a regulator of glycogen metabolism but it also plays a pivotal role in numerous cellular functions, including differentiation, cell cycle regulation, and proliferation. The dentate gyrus of the hippocampus, together with the subventricular zone of the lateral ventricles, is one of the regions in which neurogenesis takes place in the adult brain. Here, using a chemical genetic approach that involves the use of several diverse inhibitors of GSK-3 as pharmacological tools, we show that inhibition of GSK-3 induces proliferation, migration, and differentiation of neural stem cells toward a neuronal phenotype in in vitro studies. Also, we demonstrate that inhibition of GSK-3 with the small molecule NP03112, called tideglusib, induces neurogenesis in the dentate gyrus of the hippocampus of adult rats. Taken together, our results suggest that GSK-3 should be considered as a new target molecule for modulating the production and integration of new neurons in the hippocampus as a treatment for neurodegenerative diseases or brain injury and, consequently, its inhibitors may represent new potential therapeutic drugs in neuroregenerative medicine.
authors.affiliation: Instituto de Investigaciones Biomédicas, (CSIC-UAM), Arturo Duperier, 4 and Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), 28029-Madrid, Spain.
authors.forename: Jose A
authors.initials: JA
authors.lastname: Morales-Garcia
authors.forename: Rosario
authors.initials: R
authors.lastname: Luna-Medina
authors.forename: Sandra
authors.initials: S
authors.lastname: Alonso-Gil
authors.forename: Marina
authors.initials: M
authors.lastname: Sanz-Sancristobal
authors.forename: Valle
authors.initials: V
authors.lastname: Palomo
authors.forename: Carmen
authors.initials: C
authors.lastname: Gil
authors.forename: Angel
authors.initials: A
authors.lastname: Santos
authors.forename: Ana
authors.initials: A
authors.lastname: Martinez
authors.forename: Ana
authors.initials: A
authors.lastname: Perez-Castillo
mesh_terms: D000818:Animals; D002454:Cell Differentiation / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D018891:Dentate Gyrus / Q000166:cytology / Q000378:metabolism; D038362:Glycogen Synthase Kinase 3 / Q000037:antagonists & inhibitors*; D006571:Heterocyclic Compounds / Q000494:pharmacology*; D008297:Male; D058953:Neural Stem Cells / Q000187:drug effects*; D055495:Neurogenesis / Q000187:drug effects*; D010641:Phenotype; D051381:Rats; D017208:Rats, Wistar; D013830:Thiadiazoles / Q000494:pharmacology*
chemical_list: D006571:Heterocyclic Compounds; C530042:NP00111; D013830:Thiadiazoles; D038362:Glycogen Synthase Kinase 3; C520571:tideglusib