Cerebral synthesis and release of kynurenic acid: An endogenous antagonist of excitatory amino acid receptors

Abstract

Excitatory amino acid (EAA)-mediated synaptic transmission is the most prevalent excitatory system within the mammalian brain. Activation of EAA receptors has been postulated to contribute to neuronal cell death in stroke, epilepsy, hypoglycemia, and Huntington's disease. Kynurenic acid is an endogenous substance that inhibits EAA receptors and may therefore influence important physiologic and pathologic processes. The release of intracerebrally synthesized kynurenic acid into the extracellular fluid (ECF), where it may act at EAA receptors, has not been established in vivo. We studied the synthesis and release of kynurenic acid in the rat striatum using intracerebral microdialysis coupled with high performance liquid chromatography and fluorescence detection. The basal ECF concentration of kynurenic acid in the rat corpus striatum was 17.1 ± 1.1 nM. Peripheral administration of the immediate biosynthetic precursor of kynurenic acid, L-kynurenine, resulted in marked dose-dependent increases in striatal ECF concentrations of kynurenic acid, peaking at 2-2.5 hr. The highest dose of L-kynurenine (100 mg/kg), administered peripherally, resulted in a 108-fold increase in plasma kynurenic acid levels and a 37-fold increase in cerebral ECF levels. Peripheral administration of kynurenic acid, at a dose that caused plasma levels to increase 430-fold, resulted in only 4-fold increases in striatal ECF concentrations. The precursor responsiveness of striatal ECF kynurenic acid to peripherally infused L-kynurenine was blocked by the central application (via the dialysis probe) of aminooxyacetic acid, an inhibitor of the immediate synthetic enzyme for kynurenic acid, kynurenine aminotransferase. Administration of L-tryptophan was less effective than L-kynurenine in increasing ECF kynurenic acid concentrations and did so at a considerably later time interval (6 hr). Infusion of L-kynurenine, but not L-tryptophan, through the dialysis probe dramatically increased striatal ECF concentrations of kynurenic acid. Administration of glutamate, NMDA, quinolinic acid, kainic acid, or quisqualic acid via the dialysis probe for 10 min had no effect on basal ECF levels of kynurenic acid. The conclusions drawn from the present study are that (1) kynurenic acid is present in ECF within the CNS, (2) the CNS can synthesize kynurenic acid and release it into the extracellular space, (3) the majority of CNS kynurenic acid synthesis results from the transport of L-kynurenine across the blood-brain barrier, and (4) extracellular levels of kynurenic acid can be dramatically and selectively increased by pharmacologic manipulation of precursor levels.