MODULATION OF STRIATAL QUINOLINATE NEUROTOXICITY BY ELEVATION OF ENDOGENOUS BRAIN KYNURENIC ACID

1 Nicotinylalanine, an inhibitor of kynurenine metabolism, has been sh own to elevate brain levels of endogenous kynurenic acid, an excitator y amino acid receptor antagonist. This study examined the potential of nicotinylalanine to influence excitotoxic damage to striatal NADPH di aphorase (NADPH-d) and gamma-aminobutyric acid (GABA)ergic neurones th at are selectively lost in Huntington's disease. 2 A unilateral inject ion of the N-methyl-D-aspartate (NMDA) receptor agonist, quinolinic ac id, into the rat striatum produced an 88% depletion of NADPH-d neurone s. Intrastriatal infusion of quinolinic acid also produced a dose-depe ndent reduction in striatal GABA content. 3 Nicotinylalanine (2.3, 3.2 , 4.6, 6.4 nmol 5 mu l(-1), i.c.v.) administered with L-kynurenine (45 0 mg kg(-1)), a precursor of kynurenic acid, and probenecid (200 mg kg (-1)), an inhibitor of organic acid transport, 3 h before the injectio n of quinolinic acid (15 nmol) produced a dose-related attenuation of the quinolinic acid-induced loss of NADPH-d neurones. Nicotinylalanine (5.6 nmol 5 mu l(-1)) in combination with L-kynurenine and probenecid also attenuated quinolinic acid-induced reductions in striatal GABA c ontent. 4 Nicotinylalanine (4.6 nmol, i.c.v.), L-kynurenine alone or L -kynurenine administered with probenecid did not attenuate quinolinic acid-induced depletion of striatal NADPH-d neurones. However, combined administration of kynurenine and probenecid did prevent quinolinic ac id-induced reductions in ipsilateral striatal GABA content. 5 Injectio n of nicotinylalanine, at doses (4.6 nmol and 5.6 nmol i.c.v.) which a ttenuated quinolinic acid-induced striatal neurotoxicity, when combine d with L-kynurenine and probenecid produced increases in both whole br ain and striatal kynurenic acid levels. Administration of L-kynurenine and probenecid without nicotinylalanine also elevated kynurenic acid, but to a lesser extent. 6 The results of this study demonstrate that nicotinylalanine has the potential to attenuate quinolinic acid-induce d striatal neurotoxicity. It is suggested that nicotinylalanine exerts its effect by increasing levels of endogenous kynurenic acid in the b rain. The results of this study suggest that agents which influence le vels of endogenous excitatory amino acid antagonists such as kynurenic acid may be useful in preventing excitotoxic damage to neurones in th e CNS.