We examined whether 7-Cl-thio-kynurenate, a potent antagonist at the glycine site of the N-methyl-D-aspartate receptor which also inhibits lipid peroxidation, protected CA1 pyramidal cells following transient forebrain ischemia. Global ischemia was produced in anesthetized gerbils by 5 min bilateral carotid artery occlusion; hippocampal injury was assessed seven days later. 7-Cl-thio-kynurenate (100 mg/kg, i.p. x 5) dramatically attenuated ischemia-induced CA1 cell loss (from 95 +/- 1 to 7 +/- 3%): the protection was associated with a delayed and marked reduction in the animals' temperature. However, when the gerbils were maintained normothermic for at least 360 min, 7-Cl-thio-kynurenate still provided partial (54 +/- 11%) but significant protection. No protection was observed when a reduction in temperature with a time course similar to that caused by 7-Cl-thio-kynurenate was experimentally induced in saline-treated ischemic animals. In situ hybridization revealed that expression of NMDA-R1, a subunit of the N-methyl-D-aspartate receptor, was selectively reduced in CA1 seven days following global ischemia. In ischemic gerbils treated with 7-Cl-thio-kynurenate, protected CA1 cells were still able to express normal amounts of NMDA-R1 messenger RNA. Our results demonstrate that 7-Cl-thio-kynurenate, a glutamate receptor blocker possessing radical scavenger properties, is effective in reducing CA1 hippocampal damage following global ischemia in the gerbil. Since there is growing evidence that a positive feedback interaction between activation of glutamate receptors and free radical formation may be responsible for the generation of ischemic brain damage, drugs capable of interfering with both pathogenic mechanisms may be useful in preventing post-ischemic neuronal death.