title: Andrographolide Stimulates Neurogenesis in the Adult Hippocampus.
abstract: Andrographolide (ANDRO) is a labdane diterpenoid component of Andrographis paniculata widely used for its anti-inflammatory properties. We have recently determined that ANDRO is a competitive inhibitor of glycogen synthase kinase-3β (GSK-3β), a key enzyme of the Wnt/β-catenin signaling cascade. Since this signaling pathway regulates neurogenesis in the adult hippocampus, we evaluated whether ANDRO stimulates this process. Treatment with ANDRO increased neural progenitor cell proliferation and the number of immature neurons in the hippocampus of 2- and 10-month-old mice compared to age-matched control mice. Moreover, ANDRO stimulated neurogenesis increasing the number of newborn dentate granule neurons. Also, the effect of ANDRO was evaluated in the APPswe/PS1ΔE9 transgenic mouse model of Alzheimer's disease. In these mice, ANDRO increased cell proliferation and the density of immature neurons in the dentate gyrus. Concomitantly with the increase in neurogenesis, ANDRO induced the activation of the Wnt signaling pathway in the hippocampus of wild-type and APPswe/PS1ΔE9 mice determined by increased levels of β-catenin, the inactive form of GSK-3β, and NeuroD1, a Wnt target gene involved in neurogenesis. Our findings indicate that ANDRO stimulates neurogenesis in the adult hippocampus suggesting that this drug could be used as a therapy in diseases in which neurogenesis is affected.
authors.affiliation: Centro de Investigaciones Biomédicas (CIB), Facultad de Ciencias Biológicas y Facultad de Medicina, Universidad Andrés Bello, Santiago, Chile.
authors.forename: Lorena
authors.initials: L
authors.lastname: Varela-Nallar
authors.affiliation: Centro de Investigaciones Biomédicas (CIB), Facultad de Ciencias Biológicas y Facultad de Medicina, Universidad Andrés Bello, Santiago, Chile.
authors.forename: Sebastian B
authors.initials: SB
authors.lastname: Arredondo
authors.affiliation: Centro de Envejecimiento y Regeneración (CARE), Departamento de Biología Celular y Molecular, Facultad de Ciencias Biológicas, Pontificia Universidad Católica de Chile, Santiago, Chile.
authors.forename: Cheril
authors.initials: C
authors.lastname: Tapia-Rojas
authors.affiliation: Instituto de Farmacología y Morfofisiología, Universidad Austral de Chile, Valdivia, Chile.
authors.forename: Juan
authors.initials: J
authors.lastname: Hancke
authors.affiliation: Centro de Envejecimiento y Regeneración (CARE), Departamento de Biología Celular y Molecular, Facultad de Ciencias Biológicas, Pontificia Universidad Católica de Chile, Santiago, Chile; Center for Healthy Brain Ageing, School of Psychiatry, Faculty of Medicine, University of New South Wales, Sydney, Australia; Centro de Excelencia en Biomedicina de Magallanes (CEBIMA), Universidad de Magallanes, Punta Arenas, Chile.
authors.forename: Nibaldo C
authors.initials: NC
authors.lastname: Inestrosa
mesh_terms: D000544:Alzheimer Disease / Q000378:metabolism; D000818:Animals; D049109:Cell Proliferation / Q000187:drug effects; D018891:Dentate Gyrus / Q000187:drug effects* / Q000502:physiology*; D004195:Disease Models, Animal; D004224:Diterpenes / Q000008:administration & dosage*; D038362:Glycogen Synthase Kinase 3 / Q000037:antagonists & inhibitors / Q000378:metabolism; D000071679:Glycogen Synthase Kinase 3 beta; D051379:Mice; D008810:Mice, Inbred C57BL; D058953:Neural Stem Cells / Q000187:drug effects* / Q000502:physiology*; D055495:Neurogenesis / Q000187:drug effects*; D060449:Wnt Signaling Pathway / Q000187:drug effects
chemical_list: D004224:Diterpenes; C030419:andrographolide; D000071679:Glycogen Synthase Kinase 3 beta; C000605507:Gsk3b protein, mouse; D038362:Glycogen Synthase Kinase 3