COMPARISON OF THE NEUROCHEMICAL AND BEHAVIORAL-EFFECTS RESULTING FROMTHE 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 ai m of identifying new compounds able to inhibit the synthesis of quinol inic acid (an endogenous excitotoxin) and to increase that of kynureni c acid, an endogenous antagonist of ionotropic glutamate receptors. Am ong these analogues, we selected m-nitrobenzoylalanine (mNBA) as an in hibitor of kynurenine hydroxylase and o-methoxybenzoylalanine (oMBA) a s an inhibitor of kynureninase. When administered to rats, mNBA was mo re potent than oMBA in increasing the content of kynurenine and of kyn urenic 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 kynurenat e in hippocampal extracellular spaces (as measured with a microdialysi s technique) and, when simultaneously injected, their effects were add itive, This biochemical effect was associated with a decrease in locom otor activity in rats and with a protection of audiogenic convulsions in DBA/2 mice. In conclusion, the results of the present experiments i ndicate the possibility of increasing the neosynthesis of kynurenic ac id by inhibiting the enzymes that metabolize kynurenine to 3-hydroxyky nurenine 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 excitato ry amino acid receptors.