Tyrphostins protect neuronal cells from oxidative stress.
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 microm, 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.
Department of Neurosciences, University of California, San Diego, La Jolla, California 92093-0624, USA. ysagara@ucsd.edu
Yutaka
Y
Sagara
Kumiko
K
Ishige
Cindy
C
Tsai
Pamela
P
Maher
D000818:Animals; D000975:Antioxidants / Q000494:pharmacology; D002460:Cell Line; D002462:Cell Membrane / Q000378:metabolism; D002470:Cell Survival; D002839:Chromans / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D018698:Glutamic Acid / Q000378:metabolism; D005978:Glutathione / Q000378:metabolism; D006624:Hippocampus / Q000166:cytology; D015151:Immunoblotting; D020128:Inhibitory Concentration 50; D008564:Membrane Potentials / Q000187:drug effects; D051379:Mice; D008928:Mitochondria / Q000378:metabolism; D008956:Models, Chemical; D009474:Neurons / Q000187:drug effects* / Q000378:metabolism*; D018384:Oxidative Stress; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D051381:Rats; D017382:Reactive Oxygen Species; D013997:Time Factors; D014407:Tumor Cells, Cultured; D020032:Tyrphostins / Q000494:pharmacology*
D000975:Antioxidants; D002839:Chromans; D004791:Enzyme Inhibitors; D017382:Reactive Oxygen Species; D020032:Tyrphostins; D018698:Glutamic Acid; D011505:Protein-Tyrosine Kinases; D005978:Glutathione; C010643:6-hydroxy-2,5,7,8-tetramethylchroman-2-carboxylic acid