Characterization of LY231617 protection against hydrogen peroxide toxicity.
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.
Neuroscience Research Division, Eli Lilly and Company, Indianapolis, Indiana, USA.
K S
KS
Fuson
R J
RJ
Mark
J A
JA
Panetta
P C
PC
May
D000818:Animals; D000975:Antioxidants / Q000494:pharmacology*; D019328:Buthionine Sulfoximine / Q000494:pharmacology; D002084:Butylated Hydroxytoluene / Q000031:analogs & derivatives* / Q000494:pharmacology; D002470:Cell Survival / Q000187:drug effects; D046508:Culture Techniques; D015237:Dinoprost / Q000031:analogs & derivatives / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000494:pharmacology; D028441:F2-Isoprostanes; D005978:Glutathione / Q000378:metabolism; D006624:Hippocampus / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D006861:Hydrogen Peroxide / Q000037:antagonists & inhibitors* / Q000378:metabolism / Q000633:toxicity; D007700:Kinetics; D007770:L-Lactate Dehydrogenase / Q000378:metabolism; D009474:Neurons / Q000187:drug effects / Q000378:metabolism; D016877:Oxidants / Q000037:antagonists & inhibitors* / Q000633:toxicity; D051381:Rats; D017207:Rats, Sprague-Dawley
D000975:Antioxidants; D004791:Enzyme Inhibitors; D028441:F2-Isoprostanes; D016877:Oxidants; D002084:Butylated Hydroxytoluene; C075750:8-epi-prostaglandin F2alpha; D019328:Buthionine Sulfoximine; C081064:LY 231617; D015237:Dinoprost; D006861:Hydrogen Peroxide; D007770:L-Lactate Dehydrogenase; D005978:Glutathione