title: Inhibitory effects of Tyrphostin AG-related compounds on oxidative stress-sensitive transient receptor potential channel activation.
abstract: Some transient receptor potential (TRP) proteins including TRPA1, TPRM2 and TRPV1 are oxidative stress-sensitive Ca(2+)-permeable channels. Ca(2+) signaling via these TRP channels activated by oxidative stress has been implicated in the aggravation of various inflammatory diseases and pain sensation. We recently reported that Tyrphostin AG490 exerted inhibitory effects on H2O2-induced TRPM2 activation by scavenging the hydroxyl radical. In order to identify stronger inhibitors of oxidative stress-sensitive TRP channels than AG490, we examined the inhibitory effects of Tyrphostin AG-related compounds on H2O2-induced TRP channel activation in human embryonic kidney 293 cells expressing TRP channels. AG555 and AG556 blocked the activation of TRPM2 by H2O2 more strongly than AG490. Regarding TRPV1 and TRPA1, none of the three compounds tested affected H2O2-induced TRPV1 activation; however, AG555 and AG556 reduced H2O2-induced TRPA1 activation more than AG490. Thus, we herein identified AG555 and AG556 as new compounds that exert stronger inhibitory effects on H2O2-induced TRPM2 and TRPA1 activation than AG490. Edaravone, a hydroxyl radical scavenger used in the treatment of cerebral hemorrhage and cerebral infarction, did not affect H2O2-induced TRPM2 or TRPA1 activation. AG555 and AG556 may be useful seed compounds as therapeutic agents for several TRP-related diseases associated with oxidative stress.
authors.affiliation: Laboratory of Pharmacology, Department of Clinical Pharmacy, Yokohama University of Pharmacy, Yokohama, Japan.
authors.forename: Takahiro
authors.initials: T
authors.lastname: Toda
authors.affiliation: Division of Pharmacology, Faculty of Pharmaceutical Sciences, Teikyo Heisei University, Tokyo, Japan.
authors.forename: Shinichiro
authors.initials: S
authors.lastname: Yamamoto
authors.affiliation: Division of Pharmacology, Faculty of Pharmaceutical Sciences, Teikyo Heisei University, Tokyo, Japan; Division of Physiology and Pathology, Department of Pharmacology, Toxicology and Therapeutics, Showa University School of Pharmacy, Tokyo, Japan.
authors.forename: Ryo
authors.initials: R
authors.lastname: Yonezawa
authors.affiliation: Department of Synthetic Chemistry and Biological Chemistry, Graduate School of Engineering, Kyoto University, Kyoto, Japan.
authors.forename: Yasuo
authors.initials: Y
authors.lastname: Mori
authors.affiliation: Division of Pharmacology, Faculty of Pharmaceutical Sciences, Teikyo Heisei University, Tokyo, Japan. Electronic address: s.shimizu@thu.ac.jp.
authors.forename: Shunichi
authors.initials: S
authors.lastname: Shimizu
mesh_terms: D002118:Calcium / Q000378:metabolism; D057809:HEK293 Cells; D006801:Humans; D042541:Intracellular Space / Q000187:drug effects / Q000378:metabolism; D018384:Oxidative Stress / Q000187:drug effects*; D050051:Transient Receptor Potential Channels / Q000378:metabolism*; D020032:Tyrphostins / Q000737:chemistry* / Q000494:pharmacology*
chemical_list: D050051:Transient Receptor Potential Channels; D020032:Tyrphostins; D002118:Calcium
keywords: AG490; AG555; AG556; Oxidative stress; TRPA1; TRPM2