This Article Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Clemens, J. A. Articles by Panetta, J. A. Search for Related Content PubMed PubMed Citation Articles by Clemens, J. A. Articles by Panetta, J. A. Pubmed/NCBI databases Compound via MeSH Substance via MeSH Hazardous Substances DB IRON

Stroke, Vol 22, 1048-1052, Copyright © 1991 by American Heart Association

ARTICLES

LY178002 reduces rat brain damage after transient global forebrain ischemia

JA Clemens, PP Ho and JA Panetta
Lilly Research Laboratories, Eli Lilly and Co., Indiannapolis, Ind 46285.

Several feasible mechanisms have been proposed as sources of neuronal damage from ischemia and subsequent reperfusion. Included among these are oxidative damage caused by free radical production and lipid peroxidation and products derived from phospholipid breakdown. A series of 4-thiazolidinone compounds represented by LY178002 (5-[3,5-bis(1,1- dimethylethyl)-4-hydroxyphenyl]methylene-4-thiazolidinon e) have been described as inhibitors of multiple enzymes in the arachidonic acid cascade, including fatty acid cyclooxygenase, 5-lipoxygenase, and phospholipase A2. Accordingly, we evaluated LY178002 in a four-vessel occlusion model of global forebrain ischemia with reperfusion. A 2-hour pretreatment of 11 male Wistar rats with 150 mg/kg LY178002 significantly protected against striatal (p = 0.0007) and hippocampal CA1 (p = 0.006) damage after 30 minutes of global ischemia. Similar protection was observed for the striatum (p = 0.005) and hippocampal CA1 layer (p = 0.025) after pretreatment of 13 rats with 50 mg/kg LY178002. We further evaluated LY178002 as a possible inhibitor of lipid peroxidation because part of its chemical structure incorporates the aromatic backbone of the known antioxidant butylated hydroxytoluene. We found LY178002 to be a potent inhibitor of iron- dependent lipid peroxidation. Few substances possessing a single pharmacological activity have been found to be of significant therapeutic benefit in global ischemia of 30 minutes' duration because the mechanisms that lead to cell death in response to ischemia are likely to be multifactorial. Thus, the efficacy of LY178002 in this model may be due to its ability to inhibit multiple sources of damage.

This article has been cited by other articles:

				J. Koistinaho, S. Koponen, P. H. Chan, and C. Y. Hsu Expression of Cyclooxygenase-2 mRNA After Global Ischemia Is Regulated by AMPA Receptors and Glucocorticoids • Editorial Comment Stroke, September 1, 1999; 30(9): 1900 - 1906. [Abstract] [Full Text] [PDF]

				S. Miettinen, F. R. Fusco, J. Yrjanheikki, R. Keinanen, T. Hirvonen, R. Roivainen, M. Narhi, T. Hokfelt, and J. Koistinaho Spreading depression and focal brain ischemia induce cyclooxygenase-2 in cortical neurons through N-methyl-D-aspartic acid-receptors and phospholipase A2 PNAS, June 10, 1997; 94(12): 6500 - 6505. [Abstract] [Full Text] [PDF]

				E. D. Hall, P. K. Andrus, S. L. Smith, T. J. Fleck, H. M. Scherch, B. S. Lutzke, G. A. Sawada, J. S. Althaus, P. F. Vonvoigtlander, G. E. Padbury, et al. Pyrrolopyrimidines: Novel Brain-Penetrating Antioxidants with Neuroprotective Activity in Brain Injury and Ischemia Models J. Pharmacol. Exp. Ther., May 1, 1997; 281(2): 895 - 904. [Abstract] [Full Text]