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 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.
Jang
Sung-Wuk
SW
Department of Pathology and Laboratory Medicine, Emory University School of Medicine, Atlanta, Georgia, USA.
Liu
Xia
X
Chan
Chi Bun
CB
France
Stefan A
SA
Sayeed
Iqbal
I
Tang
Wenxue
W
Lin
Xi
X
Xiao
Ge
G
Andero
Raul
R
Chang
Qiang
Q
Ressler
Kerry J
KJ
Ye
Keqiang
K
D000818:Animals; D000928:Antidepressive Agents / Q000378:metabolism / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D019208:Brain-Derived Neurotrophic Factor / Q000235:genetics; D002460:Cell Line; D045744:Cell Line, Tumor; D002478:Cells, Cultured; D006624:Hippocampus / Q000166:cytology; D006801:Humans; D007150:Immunohistochemistry; D036701:Limonins / Q000378:metabolism / Q000494:pharmacology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains; D009474:Neurons / Q000187:drug effects* / Q000378:metabolism; D011485:Protein Binding; D055503:Protein Multimerization / Q000187:drug effects; D017434:Protein Structure, Tertiary / Q000502:physiology; D051381:Rats; D020813:Receptor, trkB / Q000819:agonists / Q000378:metabolism
D000928:Antidepressive Agents; D019208:Brain-Derived Neurotrophic Factor; D036701:Limonins; C000610188:deoxygedunin; D020813:Receptor, trkB