Systemic administration of 4-chlorokynurenine prevents quinolinate neurotoxicity in the rat hippocampus.
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.
Wu
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HQ
Maryland Psychiatric Research Center, University of Maryland School of Medicine, P.O. Box 21247, Baltimore, MD 21228, USA. hwu@umaryland.edu
Lee
S C
SC
Schwarcz
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R
D000818:Animals; D001927:Brain Diseases / Q000473:pathology / Q000517:prevention & control; D015314:Dialysis Solutions / Q000737:chemistry; D006624:Hippocampus / Q000187:drug effects* / Q000473:pathology; D007274:Injections, Intraperitoneal; D007736:Kynurenic Acid / Q000031:analogs & derivatives / Q000097:blood; D007737:Kynurenine / Q000031:analogs & derivatives* / Q000097:blood / Q000494:pharmacology; D008297:Male; D017551:Microdialysis; D018696:Neuroprotective Agents / Q000494:pharmacology; D011355:Prodrugs / Q000494:pharmacology*; D017378:Quinolinic Acid / Q000633:toxicity*; D051381:Rats; D017207:Rats, Sprague-Dawley
D015314:Dialysis Solutions; D018696:Neuroprotective Agents; D011355:Prodrugs; D007737:Kynurenine; C027883:4-chlorokynurenine; D017378:Quinolinic Acid; D007736:Kynurenic Acid; C057013:7-chlorokynurenic acid