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Author Notes:

To whom all correspondence should be addressed. E-mail: kye@emory.edu

Edited by Solomon H. Snyder, Johns Hopkins University School of Medicine, Baltimore, MD, and approved August 28, 2007

Author contributions: S.-W.J., I.S., and K.Y. designed research; S.-W.J., M.O., and I.S. performed research; G.X., D.S., and P.J. contributed new reagents/analytic tools; S.-W.J. and K.Y. analyzed data; and K.Y. wrote the paper.

We thank Dr. P. Perez (Universidad de Salamanca, Salamanca, Spain) and Dr. Y. Barde (Max Planck Institute of Neurobiology, Munich, Germany) for various Trk constructs.

This article contains supporting information online at www.pnas.org/cgi/content/full/0706662104/DC1.

This article is a PNAS Direct Submission.

The authors declare no conflict of interest.

Subjects:

Research Funding:

This work was supported by National Institutes of Health Grants R01 NS045627 (to K.Y.) and R01 NS04851 (to D.S.).

Keywords:

  • neurotrophic effect
  • nerve growth factor
  • ligand
  • receptor dimerization

Gambogic amide, a selective agonist for TrkA receptor that possesses robust neurotrophic activity, prevents neuronal cell death

Tools:

Journal Title:

Proceedings of the National Academy of Sciences

Volume:

Volume 104, Number 41

Publisher:

, Pages 16329-16334

Type of Work:

Article | Post-print: After Peer Review

Abstract:

Nerve growth factor (NGF) binds to TrkA receptor and triggers activation of numerous signaling cascades, which play critical roles in neuronal plasticity, survival, and neurite outgrowth. To mimic NGF functions pharmacologically, we developed a high-throughput screening assay to identify small-molecule agonists for TrkA receptor. The most potent compound, gambogic amide, selectively binds to TrkA, but not TrkB or TrkC, and robustly induces its tyrosine phosphorylation and downstream signaling activation, including Akt and MAPKs. Further, it strongly prevents glutamate-induced neuronal cell death and provokes prominent neurite outgrowth in PC12 cells. Gambogic amide specifically interacts with the cytoplasmic juxtamembrane domain of TrkA receptor and triggers its dimerization. Administration of this molecule in mice substantially diminishes kainic acid-triggered neuronal cell death and decreases infarct volume in the transient middle cerebral artery occlusion model of stroke. Thus, gambogic amide might not only establish a powerful platform for dissection of the physiological roles of NGF and TrkA receptor but also provide effective treatments for neurodegenerative diseases and stroke.

Copyright information:

© 2007 by The National Academy of Sciences of the USA

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