LY178002 reduces rat brain damage after transient global forebrain ischemia.
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.
Clemens
J A
JA
Lilly Research Laboratories, Eli Lilly and Co., Indiannapolis, Ind 46285.
Ho
P P
PP
Panetta
J A
JA
D000818:Animals; D001921:Brain / Q000473:pathology*; D002545:Brain Ischemia / Q000473:pathology*; D003342:Corpus Striatum / Q000473:pathology; D005293:Ferritins / Q000494:pharmacology; D006624:Hippocampus / Q000473:pathology; D007501:Iron / Q000494:pharmacology; D008297:Male; D008706:Methemoglobin / Q000494:pharmacology; D010741:Phospholipases A / Q000037:antagonists & inhibitors; D054467:Phospholipases A2; D051381:Rats; D011919:Rats, Inbred Strains; D013844:Thiazoles / Q000737:chemistry / Q000494:pharmacology*; D053778:Thiazolidines; D013858:Thiobarbiturates
D013844:Thiazoles; D053778:Thiazolidines; D013858:Thiobarbiturates; C061319:LY 178002; D005293:Ferritins; D008706:Methemoglobin; D007501:Iron; D010741:Phospholipases A; D054467:Phospholipases A2; C029684:thiobarbituric acid