Sominone enhances neurite outgrowth and spatial memory mediated by the neurotrophic factor receptor, RET.
OBJECTIVE
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 Abeta(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.


METHODS
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.


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
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.
Tohda
Chihiro
C
Division of Biofunctional Evaluation, Research Center for Ethnomedicine, Institute of Natural Medicine, University of Toyama, Toyama, Japan. chihiro@inm.u-toyama.ac.jp
Joyashiki
Eri
E
D000818:Animals; D000831:Animals, Newborn; D001369:Axons / Q000187:drug effects / Q000502:physiology; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000378:metabolism; D003687:Dehydroepiandrosterone / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology; D003712:Dendrites / Q000187:drug effects / Q000502:physiology; D004875:Ergosterol / Q000031:analogs & derivatives / Q000737:chemistry; D051100:Glial Cell Line-Derived Neurotrophic Factor / Q000378:metabolism; D006624:Hippocampus / Q000378:metabolism; D008297:Male; D008568:Memory / Q000187:drug effects*; D051379:Mice; D008815:Mice, Inbred Strains; D016501:Neurites / Q000187:drug effects* / Q000502:physiology; D010766:Phosphorylation; D051096:Proto-Oncogene Proteins c-ret / Q000502:physiology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013037:Spatial Behavior / Q000187:drug effects*
D051100:Glial Cell Line-Derived Neurotrophic Factor; C543746:sominone; C523922:withanoside IV; D003687:Dehydroepiandrosterone; D051096:Proto-Oncogene Proteins c-ret; C494999:Ret protein, mouse; C495001:Ret protein, rat; D004875:Ergosterol