Comparison of the neurochemical and behavioral effects resulting from the inhibition of kynurenine hydroxylase and/or kynureninase.
Several kynurenine analogues were synthesized and tested as inhibitors of the enzymes kynurenine hydroxylase and/or kynureninase with the aim of identifying new compounds able to inhibit the synthesis of quinolinic acid (an endogenous excitotoxin) and to increase that of kynurenic acid, an endogenous antagonist of ionotropic glutamate receptors. Among these analogues, we selected m-nitrobenzoylalanine (mNBA) as an inhibitor of kynurenine hydroxylase and o-methoxybenzoylalanine (oMBA) as an inhibitor of kynureninase. When administered to rats, mNBA was more potent than oMBA in increasing the content of kynurenine and of kynurenic acid in the brain, blood, liver, and kidney. This confirms that hydroxylation is the main pathway of kynurenine metabolism. Both mNBA and oMBA (50-400 mg/kg i.p.) increased the concentration of kynurenate in hippocampal extracellular spaces (as measured with a microdialysis technique) and, when simultaneously injected, their effects were additive. This biochemical effect was associated with a decrease in locomotor activity in rats and with a protection of audiogenic convulsions in DBA/2 mice. In conclusion, the results of the present experiments indicate the possibility of increasing the neosynthesis of kynurenic acid by inhibiting the enzymes that metabolize kynurenine to 3-hydroxykynurenine or to anthranilic acid. The increased synthesis of kynurenate is associated with behavioral effects such as sedation and protection from seizures, which suggests a functional antagonism of the excitatory amino acid receptors.
Chiarugi
A
A
Department of Preclinical and Clinical Pharmacology, University of Florence, Italy.
Carpenedo
R
R
Molina
M T
MT
Mattoli
L
L
Pellicciari
R
R
Moroni
F
F
D000409:Alanine / Q000031:analogs & derivatives / Q000494:pharmacology; D000818:Animals; D000927:Anticonvulsants / Q000494:pharmacology; D001522:Behavior, Animal / Q000502:physiology*; D004347:Drug Interactions; D005110:Extracellular Space / Q000378:metabolism; D006867:Hydrolases / Q000037:antagonists & inhibitors*; D006993:Hypnotics and Sedatives / Q000494:pharmacology; D007700:Kinetics; D007736:Kynurenic Acid / Q000378:metabolism*; D007737:Kynurenine / Q000378:metabolism; D050601:Kynurenine 3-Monooxygenase; D008297:Male; D006899:Mixed Function Oxygenases / Q000037:antagonists & inhibitors*; D017378:Quinolinic Acid / Q000378:metabolism*; D051381:Rats; D017208:Rats, Wistar
C095159:2-methoxybenzoylalanine; D000927:Anticonvulsants; D006993:Hypnotics and Sedatives; C086214:(3-nitrobenzoyl)alanine; D007737:Kynurenine; D006899:Mixed Function Oxygenases; D050601:Kynurenine 3-Monooxygenase; D006867:Hydrolases; C021480:kynureninase; D017378:Quinolinic Acid; D007736:Kynurenic Acid; D000409:Alanine