Systemic administration of 4-chlorokynurenine prevents quinolinate neurotoxicity in the rat hippocampus

Abstract

The synthetic compound 4-chlorokynurenine has been shown to be enzymatically transaminated to the selective glycine(B) receptor antagonist 7-chlorokynurenate. Since 4-chlorokynurenine, in contrast to 7-chlorokynurenate, readily penetrates the blood-brain barrier, the present study evaluated its neuroprotective properties after systemic administration in rats. Intrahippocampal injection of the NMDA receptor agonist quinolinate (15 nmol/l microl) was used as the neurotoxic paradigm. Serum and hippocampal tissue measurements confirmed that 4-chlorokynurenine serves as an effective pro-drug of 7-chlorokynurenate both in the periphery and in the brain. These studies and complementary hippocampal microdialysis experiments compared the effects of single and repeated injections of 4-chlorokynurenine (50 or 200 mg/kg, intraperitoneal (i.p.), 10 min prior to an intrahippocampal quinolinate injection; or 50 mg/kg, i.p., 10 min before and 30, 120 and 360 min after quinolinate). With the multiple-dosing regimen, extracellular 7-chlorokynurenate levels in the hippocampus reached a maximum of approximately 750 nM 7 h after quinolinate and gradually decreased with a half-life of about 3 h. In contrast, a single injection of 200 mg/kg 4-chlorokynurenine resulted in a considerably shorter rise in extracellular 7-chlorokynurenate without yielding higher peak levels. In separate animals, repeated treatment with 50 mg/kg 4-chlorokynurenine, but not a single injection of 200 mg/kg of the pro-drug, provided total protection against quinolinate-induced excitotoxicity. These data suggest that a prolonged and functionally relevant blockade of hippocampal glycine(B) receptors can be achieved after the systemic administration of 4-chlorokynurenine.