Toda Takahiro, Yamamoto Shinichiro, Yonezawa Ryo, Mori Yasuo, Shimizu Shunichi
Laboratory of Pharmacology, Department of Clinical Pharmacy, Yokohama University of Pharmacy, Yokohama, Japan.
Division of Pharmacology, Faculty of Pharmaceutical Sciences, Teikyo Heisei University, Tokyo, Japan.
Eur J Pharmacol. 2016 Sep 5;786:19-28. doi: 10.1016/j.ejphar.2016.05.033. Epub 2016 May 26.
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.
包括TRPA1、TRPM2和TRPV1在内的一些瞬时受体电位（TRP）蛋白是氧化应激敏感的钙离子通透通道。由氧化应激激活的这些TRP通道介导的钙离子信号传导与多种炎症性疾病的加重和疼痛感觉有关。我们最近报道，酪氨酸磷酸化抑制剂AG490通过清除羟基自由基对过氧化氢诱导的TRPM2激活发挥抑制作用。为了鉴定比AG490更强的氧化应激敏感TRP通道抑制剂，我们检测了酪氨酸磷酸化抑制剂AG相关化合物对在表达TRP通道的人胚肾293细胞中过氧化氢诱导的TRP通道激活的抑制作用。AG555和AG556比AG490更强烈地阻断了过氧化氢对TRPM2的激活。对于TRPV1和TRPA1，所测试的三种化合物均未影响过氧化氢诱导的TRPV1激活；然而，AG555和AG556比AG490更能降低过氧化氢诱导的TRPA1激活。因此，我们在此鉴定出AG555和AG556是对过氧化氢诱导的TRPM2和TRPA1激活具有比AG490更强抑制作用的新化合物。依达拉奉是一种用于治疗脑出血和脑梗死的羟基自由基清除剂，它不影响过氧化氢诱导的TRPM2或TRPA1激活。AG555和AG556可能作为治疗几种与氧化应激相关的TRP疾病的治疗剂的有用先导化合物。
