Excitotoxic injury stimulates pro-drug-induced 7-chlorokynurenate formation in the rat striatum in vivo.
Peripheral administration of L-4-chlorokynurenine (4-Cl-KYN), which is enzymatically converted in astrocytes to form the glycine(B) receptor antagonist 7-chlorokynurenic acid (7-Cl-KYNA), has been shown to provide neuroprotection against excitotoxic damage. The present study was designed to examine the metabolic fate of 4-Cl-KYN after systemic injection, and to study its brain uptake and subsequent transamination during the acute phase following an excitotoxic insult. To this end, adult rats received intrastriatal injections of vehicle (1 microl) or quinolinic acid (QUIN) (240 nmol/1 microl), and were administered 50 mg/kg 4-Cl-KYN (intraperitoneally) immediately after surgery. After 90 and 180 min, 7-Cl-KYNA concentrations in the vehicle-injected striatum were 54+/-13 and 16+/-2 nM, respectively. The contralateral, QUIN-injected striatum contained 212+/-39 and 97+/-27 nM 7-Cl-KYNA, respectively. This injury-induced increase was accompanied by slightly higher 4-Cl-KYN levels in the QUIN-treated striatum, indicating that better pro-drug availability in part accounts for the enhanced 7-Cl-KYNA formation. These data demonstrate that systemic 4-Cl-KYN application, by targeting reactive glial cells during the early, reversible stage of excitotoxic neurodegeneration, produces disproportionately large amounts of the neuroprotectant 7-Cl-KYNA at the site of the emerging lesion.
Lee
S C
SC
Maryland Psychiatric Research Center, University of Maryland School of Medicine, Baltimore, MD 21228, USA.
Schwarcz
R
R
D000818:Animals; D003342:Corpus Striatum / Q000187:drug effects* / Q000378:metabolism* / Q000473:pathology; D007274:Injections, Intraperitoneal; D007736:Kynurenic Acid / Q000031:analogs & derivatives* / Q000378:metabolism* / Q000493:pharmacokinetics; D007737:Kynurenine / Q000031:analogs & derivatives* / Q000494:pharmacology*; D008297:Male; D009410:Nerve Degeneration / Q000378:metabolism; D018696:Neuroprotective Agents / Q000494:pharmacology*; D009498:Neurotoxins / Q000494:pharmacology*; D009994:Osmolar Concentration; D011355:Prodrugs / Q000494:pharmacology*; D017378:Quinolinic Acid / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley
D018696:Neuroprotective Agents; D009498:Neurotoxins; D011355:Prodrugs; D007737:Kynurenine; C027883:4-chlorokynurenine; D017378:Quinolinic Acid; D007736:Kynurenic Acid; C057013:7-chlorokynurenic acid