Sominone enhances neurite outgrowth and spatial memory mediated by the neurotrophic factor receptor, RET
Open Access
- 29 July 2009
- journal article
- research article
- Published by Wiley in British Journal of Pharmacology
- Vol. 157 (8), 1427-1440
- https://doi.org/10.1111/j.1476-5381.2009.00313.x
Abstract
Background and purpose: Orally administered withanoside IV (a compound isolated from the roots of Withania somnifera) improved memory deficits in mice with a model of Alzheimer's disease induced by the amyloid peptide Aβ(25-35). Sominone, an aglycone of withanoside IV, was identified as an active metabolite after oral administration of withanoside IV. We aimed to identify receptors or associated molecules of sominone, and to investigate the effects of sominone on memory in normal mice. Experimental approach: Phosphorylation levels of 71 molecules were compared between control and sominone-stimulated cortical cultured cells to search for target molecules of sominone. Object location memory and neurite density in the brain were evaluated in sominone-injected mice. Key results: Phosphorylation of RET (a receptor for the glial cell line-derived neurotrophic factor, GDNF) was increased in neurons by sominone, without affecting the synthesis and secretion of GDNF. Knockdown of RET prevented sominone-induced outgrowths of axons and dendrites. After a single i.p. injection of sominone into normal mice, they could better memorize scenery information than control mice. Sixty minutes after sominone injection, RET phosphorylation was increased, particularly in the hippocampus of mice. After the memory tests, the densities of axons and dendrites were increased in the hippocampus by sominone administration. Conclusions and implications: Sominone could reinforce the morphological plasticity of neurons by activation of the RET pathway and thus enhance memory. Sominone, a compound with low molecular weight, may be a GDNF-independent stimulator of the RET pathway and/or a novel modulator of RET signalling.Keywords
This publication has 42 references indexed in Scilit:
- Hyperactivity, memory deficit and anxiety-related behaviors in mice lacking the p85α subunit of phosphoinositide-3 kinaseBrain & Development, 2009
- Neurturin-Mediated Ret Activation Is Required for Retinal FunctionJournal of Neuroscience, 2008
- Guide to Receptors and Channels (GRAC), 3rd editionBritish Journal of Pharmacology, 2008
- Absence of Ret Signaling in Mice Causes Progressive and Late Degeneration of the Nigrostriatal SystemPLoS Biology, 2007
- RET Is Dispensable for Maintenance of Midbrain Dopaminergic Neurons in Adult MiceJournal of Neuroscience, 2006
- Hippocampal Neuronal Polarity Specified by Spatially Localized mPar3/mPar6 and PI 3-Kinase ActivityCell, 2003
- Characterization of intracellular signals via tyrosine 1062 in RET activated by glial cell line-derived neurotrophic factorOncogene, 2000
- Enhanced Phosphatidylinositol 3-Kinase Activity and High Phosphorylation State of Its Downstream Signalling Molecules Mediated by Ret with the MEN 2B MutationBiochemical and Biophysical Research Communications, 1999
- Glial Cell Line-derived Neurotrophic Factor Signals through the RET Receptor and Activates Mitogen-activated Protein KinasePublished by Elsevier BV ,1996
- Object exploration and reactions to spatial and nonspatial changes in hooded rats following damage to parietal cortex or hippocampal formation.Behavioral Neuroscience, 1992