Abstract
Brain-derived neurotrophic factor (BDNF) and nerve growth factor (NGF) are members of the neurotrophin family that normally play a role in the development and maintenance of the nervous system. However, neurotrophin dysregulation has been implicated in several neurodegenerative diseases and psychiatric disorders including Alzheimer's disease, Parkinson's disease, neuropathic pain, depression, and substance abuse. Despite their central role in the nervous system, neurotrophins have proved to be an elusive pharmacological target. Here, we describe a novel multipotent neurotrophin antagonist, 3-[(5E)-4-oxo-5-[[5-(4-sulfamoylphenyl)-2-furyl]methylene]-2-thioxo-thiazolidin-3-yl]propanoic acid (Y1036). Y1036 binds BDNF (KD = 3.5 ± 0.3 μM) and NGF (KD = 3.0 ± 0.4 μM) preventing either BDNF or NGF from interacting with their obligate receptor(s). Y1036 prevents both BDNF- and NGF-mediated trk activation, downstream activation of the p44/42 mitogen-activated protein kinase pathway, and neurotrophin-mediated differentiation of dorsal-root ganglion sensory neurons. Identification of a BDNF- and NGF-specific antagonist is of considerable interest in the study and treatment of diseases where dysregulation of multiple neurotrophins has been implicated.
Footnotes
This work was supported in part by the Natural Science and Engineering Research Council [Post Graduate Scholarship D] (to J.K.E.).
Article, publication date, and citation information can be found at http://jpet.aspetjournals.org.
doi:10.1124/jpet.109.159079
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ABBREVIATIONS:
- BDNF
- brain-derived neurotrophic factor
- NGF
- nerve growth factor
- EGF
- epidermal growth factor
- PDGF
- platelet-derived growth factor
- FCS
- fetal calf serum
- MAPK
- mitogen-activated protein kinase
- PAGE
- polyacrylamide gel electrophoresis
- vis
- visible
- Y1036
- 3-[(5E)-4-oxo-5-[[5-(4-sulfamoylphenyl)-2-furyl]methylene]-2-thioxo-thiazolidin-3-yl]propanoic acid
- Ro 08-2750
- 2,3,4,10-tetrahydro-7,10-dimethyl-2,4-dioxobenzo[g]pteridine-8-carboxaldehyde
- PD 90780
- 7-(benzolylamino)-4,9-dihydro-4-methyl-9-oxo-pyrazolo[5,1-b]quinazoline-2-carbo xylic acid
- ALE0540
- 2-[(2-hydroxyethyl)amino]-5-nitro-2,3-dihydro-1H-benzo[de]isoquinoline-1,3-dione
- Y1370
- 4-[(4Z)-4-[[5-(2-hydroxyazonoyl-4-methoxy-phenyl)-2-furyl]methylene]-3-methyl-5-oxo-pyrazol-1-yl]benzoic acid.
- Received July 21, 2009.
- Accepted November 11, 2009.
- Copyright © 2010 by The American Society for Pharmacology and Experimental Therapeutics
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