In situ produced 7-chlorokynurenate provides protection against quinolinate- and malonate-induced neurotoxicity in the rat striatum.
Excitotoxic mechanisms may play a critical role in the pathophysiology of several neurological and psychiatric diseases. Excitatory amino acid receptor antagonists are therefore of great therapeutic interest, but untoward side effects often prevent their clinical use. Targeting the glycine coagonist site of the (NMDA) receptor may bypass these shortcomings. The present study was designed to evaluate the neuroprotective characteristics of l-4-chlorokynurenine (4-Cl-KYN), a synthetic compound which is enzymatically converted to the selective glycine/NMDA receptor antagonist 7-chlorokynurenate (7-Cl-KYNA). Using slow (2 h) intrastriatal infusions of the excitotoxins quinolinate (QUIN; 120 nmol) or malonate (6.8 micromol) as the experimental paradigm, the neuroprotective potency of 4-Cl-KYN was first compared with that of exogenous 7-Cl-KYNA, using glutamate decarboxylase activity as a lesion marker. One hundred and thirty-five nanomoles of the prodrug 4-Cl-KYN or 27 nmol 7-Cl-KYNA, the former used in a pre- and cotreatment regimen, were required to block QUIN or, less efficiently, malonate toxicity. In separate animals, the metabolic fate of this neuroprotective dose of 4-Cl-KYN was examined in vivo. In control striata, the treatment gave rise to 170 +/- 25 pmol 7-Cl-KYNA/mg protein, approximately six times less than an infusion of 27 nmol exogenous 7-Cl-KYNA, indicating greatly superior efficacy of the focally produced antagonist. Notably, the conversion of 4-Cl-KYN to 7-Cl-KYNA increased by 82% in the presence of QUIN. 4-Cl-KYN was also metabolized to 4-chloro-3-hydroxyanthranilate, an established, powerful inhibitor of QUIN synthesis. This unique pharmacological profile and the fact that the prodrug, unlike 7-Cl-KYNA, readily penetrates the blood-brain barrier suggest that 4-Cl-KYN may be exceptionally useful as an anti-excitotoxic agent.
Guidetti
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Maryland Psychiatric Research Center, University of Maryland School of Medicine, Baltimore, Maryland 21228, USA.
Wu
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HQ
Schwarcz
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R
D015095:3-Hydroxyanthranilic Acid / Q000031:analogs & derivatives / Q000378:metabolism; D000818:Animals; D001711:Biotransformation; D003342:Corpus Striatum / Q000187:drug effects* / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D018691:Excitatory Amino Acid Antagonists / Q000378:metabolism / Q000494:pharmacology*; D007263:Infusions, Parenteral; D007736:Kynurenic Acid / Q000031:analogs & derivatives* / Q000378:metabolism / Q000494:pharmacology; D007737:Kynurenine / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000378:metabolism; D008297:Male; D008314:Malonates / Q000008:administration & dosage / Q000633:toxicity*; D009474:Neurons / Q000187:drug effects; D018696:Neuroprotective Agents / Q000008:administration & dosage / Q000378:metabolism*; D011355:Prodrugs / Q000008:administration & dosage / Q000378:metabolism; D017378:Quinolinic Acid / Q000008:administration & dosage / Q000633:toxicity*; D051381:Rats; D017207:Rats, Sprague-Dawley; D018009:Receptors, Glycine / Q000037:antagonists & inhibitors
D018691:Excitatory Amino Acid Antagonists; D008314:Malonates; D018696:Neuroprotective Agents; D011355:Prodrugs; D018009:Receptors, Glycine; D015095:3-Hydroxyanthranilic Acid; C026381:4-chloro-3-hydroxyanthranilic acid; D007737:Kynurenine; C027883:4-chlorokynurenine; D017378:Quinolinic Acid; D007736:Kynurenic Acid; C057013:7-chlorokynurenic acid