Systemic DL-kynurenine and probenecid pretreatment attenuates quinolinic acid-induced neurotoxicity in rats

Kynurenine (KYN) is the precursor of kynurenic acid (KYNA), an endogenous antagonist of the glycine site of the NMDA (N-methyl-D-aspartate) receptor. Probenecid (PROB), blocks the excretion of KYNA from the extracellular fluid. KYNA antagonizes the toxic action of quinolinic acid (QUIN), an endogenous NMDA receptor agonist. In this study, we tested the effect of the systemic administration of KYN and PROB, either alone or in combination, on QUIN-induced circling behavior and gamma-aminobutyric acid (GABA) depletion in rats. Circling behavior and GABA depletion induced by QUIN were both partially prevented by PROB (200 and 300 mg/kg) and KYN (300 and 450 mg/kg) treatments. Lower doses of drugs administered separately were nonprotective. However, when administered in combination, doses of 150 or 300 mg/kg KYN plus 100 mg/kg PROB significantly protected animals against QUIN neurotoxicity. These findings suggest a role of KYN and PROB as promoters of KYNA-mediated NMDA receptor antagonism, via an increase of kynurenate in brain extracellular spaces.