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J. Biol. Chem., Vol. 277, Issue 39, 36204-36215, September 27, 2002
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From the Tyrphostins are a family of tyrosine
kinase inhibitors originally synthesized as potential anticarcinogenic
compounds. Because tyrphostins have chemical structures similar to
those of the phenolic antioxidants, we decided to test the protective
efficacy of tyrphostins against oxidative stress-induced nerve cell
death (oxytosis). Many commercially available tyrphostins, at
concentrations ranging from 0.5 to 200 µM, protect
both HT-22 hippocampal cells and rat primary neurons from oxytosis
brought about by treatment with glutamate, as well as by treatment with
homocysteic acid and buthionine sulfoximine. The tyrphostins protect
nerve cells by three distinct mechanisms. Some tyrphostins, such as
A25, act as antioxidants and eliminate the reactive oxygen species that
accumulate as a result of glutamate treatment. These tyrphostins also
protect cells from hydrogen peroxide and act as antioxidants in an
in vitro assay. In contrast, tyrphostins A9 and AG126 act
as mitochondrial uncouplers, collapsing the mitochondrial membrane
potential and thereby reducing the generation of reactive oxygen
species from mitochondria during glutamate toxicity. Finally, the third
group of tyrphostins does not appear to be effective as antioxidants but rather protects cells by increasing the basal level of cellular glutathione. Therefore, the effects of tyrphostins on cells are not limited to their ability to inhibit tyrosine kinases.
Tyrphostins Protect Neuronal Cells from Oxidative Stress*
§,, and
Department of Neurosciences, University of
California, San Diego, La Jolla, California 92093-0624, ¶ Department of Pharmacology, College of Pharmacy, Nihon
University, 7-7-1 Narashinodai, Funabashi-shi, Chiba-ken 274-8555, Japan, and Department of Cell Biology, The Scripps Research
Institute, La Jolla, California 92037-1000
*
This work was supported by a grant from Nihon University,
Japan (to K. I.) and National Institutes of Health Grants NS28212 (to
P. M.) and AG01029 (to Y. S.).The costs of publication of this
article were defrayed in part by the
payment of page charges. The article
must therefore be hereby marked
"advertisement" in accordance with 18 U.S.C. Section
1734 solely to indicate this fact.
Copyright © 2002 by The American Society for Biochemistry and Molecular Biology, Inc.
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