PRETREATMENT WITH INTRAVENTRICULAR AURINTRICARBOXYLIC ACID DECREASES INFARCT SIZE BY INHIBITING APOPTOSIS FOLLOWING TRANSIENT GLOBAL-ISCHEMIA IN GERBILS

The goal of this study was to determine whether aurintricarboxylic aci d (ATA), an endonuclease inhibitor known to inhibit apoptosis, could a meliorate cell damage in a gerbil model of transient ischemia. Transie nt ischemia was induced in gerbils by bilateral carotid artery occlusi on for a period of 5 minutes. Four micrograms of ATA was administered intraventricularly 1 hour before ischemia, and the brains were assesse d histologically 1 week later to quantitate cell loss in the vulnerabl e CA-1 subsector of the hippocampus. In a separate set of experiments, 4 mu g of ATA was administered intraventricularly 1 hour before ische mia and the brains were assessed for evidence of DNA fragmentation by the TUNEL method. There was only a 16% cell loss compared with nonisch emic controls in animals pretreated with ATA that was significantly le ss (p < 0.05) than the 48% cell loss in animals pretreated with saline alone. TUNEL-positive cells were first evident at 3 days and were sti ll present at 7 days subsequent to ischemia. Maximal staining occurred at 4 days. Pretreatment with ATA virtually eliminated TUNEL staining at 4 days. These results support the hypothesis that the delayed cell death secondary to transient ischemia is, in part, apoptotic. Furtherm ore, ATA afforded significant neuronal protection and prevented DNA fr agmentation.