http://scholar.google.com/scholar_url?url=http://downloads.hindawi.com/journals/np/aip/935403.pdf&hl=en&sa=X&scisig=AAGBfm3ZwPw89YwMS9BnvOh-BMJyfx92HA&nossl=1&oi=scholaralrt
Lorena Varela-Nallar, PhD 1*, Sebastian B. Arredondo,
MSc1, Cheril Tapia-Rojas, MSc 2,
Juan Hancke, DVM 3, and Nibaldo C. Inestrosa,
PhD 2,4,5,*.
1Centro de Investigaciones
Biomédicas (CIB), Facultad de Ciencias Biológicas y Facultad
de Medicina, Universidad Andrés Bello, Santiago, Chile
2Centro de Envejecimiento y
Regeneración (CARE), Departamento de Biología Celular y
Molecular, Facultad de Ciencias Biológicas, Pontificia Universidad
Católica de Chile,
Santiago, Chile.
4Instituto de Farmacología y
Morfofisiología, Universidad Austral de Chile, Valdivia,
Chile.
5Center for Healthy Brain
Ageing, School of Psychiatry, Faculty of Medicine, University of
New South Wales, Sydney, Australia
6Centro de Excelencia en
Biomedicina de Magallanes (CEBIMA), Universidad de
Magallanes, Punta Arenas, Chile.
Running title: Andrographolide stimulates adult neurogenesis
*Correspondence: Dr. Lorena Varela-Nallar, Center for Biomedical
Research, Universidad
Andrés Bello, República 239, 8370146, Santiago, Chile. E-mail: lorena.varela@unab.cl;
Dr. Nibaldo C. Inestrosa, CARE Biomedical Center, Pontificia
Universidad Católica de
Chile, Alameda 340, P. O. Box 114-D, Santiago, Chile. E-mail: ninestrosa@bio.puc.cl.
2
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-3â (GSK-3â), a key
enzyme of the Wnt/â-catenin signaling cascade. Since this signaling pathway regulates
neurogenesis in the adult hippocampal dentate gyrus, we evaluated
whether ANDRO is
able to stimulate this process. Treatment with ANDRO increased
neural progenitor cell
proliferation and the number of immature neurons in the
hippocampus of 2- and 10-monthold
mice compared to age-matched control mice. Moreover, ANDRO
stimulated a net
increase in neurogenesis increasing the number of newborn dentate
granule neurons. Also,
the effect of ANDRO was evaluated in the double transgenic
APPswe/PS1ÄE9 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/PS1ÄE9 mice determined by
increased levels of â-
catenin, the inactive form of GSK-3â, 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.
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