THE GLYCINE ANTAGONIST AND FREE-RADICAL SCAVENGER 7-CL-THIO-KYNURENATE REDUCES CA1 ISCHEMIC DAMAGE IN THE GERBIL

We examined whether 7-Cl-thio-kynurenate, a potent antagonist at the g lycine site of the N-methyl-D-aspartate receptor which also inhibits l ipid peroxidation, protected CA1 pyramidal cells following transient f orebrain ischemia. Global ischemia was produced in anesthetized gerbil s 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 t o 7 +/- 3%): the protection was associated with a delayed and marked r eduction in the animals' temperature. However, when the gerbils were m aintained normothermic for at least 360 min, 7-Cl-thio-kynurenate stil l provided partial (54 +/- 11%) but significant protection. No protect ion was observed when a reduction in temperature with a time course si milar to that caused by 7-Cl-thio-kynurenate was experimentally induce d in saline-treated ischemic animals. In situ hybridization revealed t hat expression of NMDA-R1, a subunit of the N-methyl-D-aspartate recep tor, was selectively reduced in CA1 seven days following global ischem ia. In ischemic gerbils treated with 7-Cl-thio-kynurenate, protected C A1 cells were still able to express normal amounts of NMDA-R1 messenge r 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 g erbil. Since there is growing evidence that a positive feedback intera ction between activation of glutamate receptors and free radical forma tion may be responsible for the generation of ischemic brain damage, d rugs capable of interfering with both pathogenic mechanisms may be use ful in preventing post-ischemic neuronal death.