Deoxygedunin, a natural product with potent neurotrophic activity in mice

Gedunin, a family of natural products from the Indian neem tree, possess a variety of biological activities. Here we report the discovery of deoxygedunin, which activates the mouse TrkB receptor and its downstream signaling cascades. Deoxygedunin is orally available and activates TrkB in mouse brain...

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Bibliographic Details
Published in:PloS one 2010-07, Vol.5 (7), p.e11528-e11528
Main Authors: Jang, Sung-Wuk, Liu, Xia, Chan, Chi Bun, France, Stefan A, Sayeed, Iqbal, Tang, Wenxue, Lin, Xi, Xiao, Ge, Andero, Raul, Chang, Qiang, Ressler, Kerry J, Ye, Keqiang
Format: Article
Language:English
Subjects:
Alzheimer's disease
Animals
Antidepressants
Antidepressive Agents - metabolism
Antidepressive Agents - pharmacology
Apoptosis
Apoptosis - drug effects
Brain
Brain-derived neurotrophic factor
Brain-Derived Neurotrophic Factor - genetics
Cancer
Cascades
Cell death
Cell Line
Cell Line, Tumor
Cells, Cultured
Degeneration
Growth factors
Hippocampus - cytology
Humans
Immunohistochemistry
Kinases
Laboratories
Ligands
Limonins - metabolism
Limonins - pharmacology
Male
Medical treatment
Medicine
Mice
Mice, Inbred C57BL
Mice, Mutant Strains
Mutation
Natural products
Neem
Nervous system
Nervous system diseases
Neurodegeneration
Neurological diseases
Neurons
Neurons - drug effects
Neurons - metabolism
Neuroprotection
Neuroscience
Neuroscience/Neuronal Signaling Mechanisms
Otolaryngology
Pathology
Pharmacology
Protein Binding
Protein Multimerization - drug effects
Protein Structure, Tertiary - physiology
Proteins
Rats
Receptor, trkB - agonists
Receptor, trkB - metabolism
Rodents
Signaling
TrkB receptors
Vestibular ganglion
Vestibular system
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Summary:Gedunin, a family of natural products from the Indian neem tree, possess a variety of biological activities. Here we report the discovery of deoxygedunin, which activates the mouse TrkB receptor and its downstream signaling cascades. Deoxygedunin is orally available and activates TrkB in mouse brain in a BDNF-independent way. Strikingly, it prevents the degeneration of vestibular ganglion in BDNF -/- pups. Moreover, deoxygedunin robustly protects rat neurons from cell death in a TrkB-dependent manner. Further, administration of deoxygedunin into mice displays potent neuroprotective, anti-depressant and learning enhancement effects, all of which are mediated by the TrkB receptor. Hence, deoxygedunin imitates BDNF's biological activities through activating TrkB, providing a powerful therapeutic tool for treatment of various neurological diseases.
ISSN:1932-6203
1932-6203
DOI:10.1371/journal.pone.0011528