(R,S)-3,4-dichlorobenzoylalanine (FCE 28833A) causes a large and persistent increase in brain kynurenic acid levels in rats.
Kynurenic acid is an endogenous excitatory amino-acid receptor antagonist with neuroprotective and anticonvulsant properties. We demonstrate here that systemic administration of the new and potent kynurenine 3-hydroxylase inhibitor (R,S)-3,4-dichlorobenzoylalanine (FCE 28833A) causes a dose-dependent elevation in endogenous kynurenine and kynurenic acid levels in rat brain tissue. In hippocampal microdialysates, peak increases of 10- and 80-fold above basal kynurenic acid concentrations, respectively, were obtained after a single oral or intraperitoneal administration of 400 mg/kg FCE 28833A. After intraperitoneal treatment with FCE 28833A, extracellular brain kynurenic acid levels remained significantly elevated for at least 22 h, rendering this compound a far more effective enhancer of kynurenic acid levels than the previously described kynurenine 3-hydroxylase blocker m-nitrobenzoylalanine. FCE 28833A and similar molecules may have therapeutic value in diseases which are linked to a hyperfunction of excitatory amino-acid receptors.
Speciale
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Pharmacia & Upjohn, R & D-CNS, Milano, Italy.
Wu
H Q
HQ
Cini
M
M
Marconi
M
M
Varasi
M
M
Schwarcz
R
R
D000818:Animals; D001921:Brain / Q000187:drug effects* / Q000378:metabolism; D002087:Butyrates / Q000494:pharmacology*; D007736:Kynurenic Acid / Q000378:metabolism*; D008297:Male; D018696:Neuroprotective Agents / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar
D002087:Butyrates; C104254:FCE 28833; D018696:Neuroprotective Agents; D007736:Kynurenic Acid