장성욱 (Emory University School of Medicine) | 한빛사논문 > 한빛사

한빛사논문

조회3,154

Emory University School of Medicine

Proc. Natl. Acad. Sci. USA, Published online before print October 2, 2007 Gambogic amide, a selective agonist for TrkA receptor that possesses robust neurotrophic activity, prevents neuronal cell death

Abstract

( neurotrophic effect | nerve growth factor | ligand | receptor dimerization )

Sung-Wuk Jang *, Masashi Okada *, Iqbal Sayeed ${dagger}$ , Ge Xiao ${ddagger}$ , Donald Stein ${dagger}$ , Peng Jin ${sect}$ , and Keqiang Ye *¶

Departments of ^*Pathology and Laboratory Medicine, Emergency Medicine, and Human Genetics, Emory University School of Medicine, Atlanta, GA 30322; and Centers for Disease Control and Prevention, Inorganic Toxicology Laboratory, 4770 Buford Highway, Mail Stop F-18, Atlanta, GA 30341

Edited by Solomon H. Snyder, Johns Hopkins University School of Medicine, Baltimore, MD, and approved August 28, 2007 (received for review July 17, 2007)

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 diseasesand stroke.

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.

The authors declare no conflict of interest.

^¶To whom all correspondence should be addressed.

논문정보

형식Research article
게재일2007년 10월 (BRIC 등록일 )
연구진국외 연구진
분야

댓글 작성 로그인

CV 열람하기

연락처 보기