Fuson K S, Mark R J, Panetta J A, May P C
Neuroscience Research Division, Eli Lilly and Company, Indianapolis, Indiana, USA.
J Neurochem. 1999 Mar;72(3):1154-60. doi: 10.1046/j.1471-4159.1999.0721154.x.
The compound LY231617 [2,6-bis(1,1-dimethylethyl)-4-[[(1-ethyl)amino]methyl]phenol hydrochloride] has been reported to afford significant neuroprotection against hydrogen peroxide (H2O2)-induced toxicity in vitro and global ischemia in vivo. We now report on further mechanistic studies of H2O2 toxicity and protection by LY231617. Brief exposure to H2O2 (15 min) elicited an oxidative insult comparable with that generated by overnight treatment. H2O2-mediated cellular degeneration was characterized using lactate dehydrogenase (LDH) release, changes in total glutathione, and a new marker of oxidative stress, 8-epiprostaglandin F2alpha (8-isoprostane). LY231617 attenuated H2O2-mediated degeneration under a variety of exposure conditions, including a more clinically relevant posttreatment paradigm. Levels of 8-isoprostane paralleled LDH release under various treatment paradigms of 100 microM H2O2 +/- 5 microM drug. In contrast, despite affording significant protection, LY231617 had modest to no effects on cellular levels of glutathione. Taken together, these results are consistent with a membrane site of action for LY231617 and suggest that the compound affords cytoprotection via its antioxidant properties.
化合物LY231617 [2,6 - 双(1,1 - 二甲基乙基)-4 - [[(1 - 乙基)氨基]甲基]苯酚盐酸盐]已被报道在体外对过氧化氢(H2O2)诱导的毒性以及在体内对全脑缺血具有显著的神经保护作用。我们现在报告关于H2O2毒性以及LY231617的保护作用的进一步机制研究。短暂暴露于H2O2(15分钟)所引发的氧化损伤与过夜处理所产生的损伤相当。使用乳酸脱氢酶(LDH)释放、总谷胱甘肽的变化以及氧化应激的一个新标志物8 - 表前列腺素F2α(8 - 异前列腺素)来表征H2O2介导的细胞变性。在各种暴露条件下，包括更具临床相关性的治疗后模式下，LY231617都能减轻H2O2介导的变性。在100 microM H2O2 ± 5 microM药物的各种治疗模式下，8 - 异前列腺素的水平与LDH释放平行。相比之下，尽管提供了显著的保护作用，但LY231617对细胞内谷胱甘肽水平的影响不大或没有影响。综上所述，这些结果与LY231617的膜作用位点一致，并表明该化合物通过其抗氧化特性提供细胞保护作用。
