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Keywords:

  • aminooxyacetic acid;
  • glutamic acid;
  • kynurenine aminotransferase;
  • neurodegeneration;
  • microdialysis

Abstract

The present study was designed to examine the cellular localization and biosynthetic machinery of the broad-spectrum excitatory amino acid receptor antagonist kynurenic acid in the lesioned rat hippocampus. Seven days after an intrahippocampal injection of 120 nmol quinolinic acid, which causes massive neurodegeneration in the dorsal hippocampus, kynurenic acid tissue levels and the activity of kynurenic acid's anabolic enzyme, kynurenine aminotransferase, were increased by 92% and 67%, respectively, as compared to controls. The steady-state levels of extracellular kynurenic acid, examined by microdialysis in unanaesthetized rats, were also increased in the lesioned tissue (from 93.6 ± 10.2 to 207.6 ± 18.6 fmol/30 μl dialysate). Using microdialysis, three compounds which are known to decrease kynurenic acid production from its bioprecursor l-kynurenine in brain slices and in vivo were tested for their ability to reduce the levels of endogenous kynurenic acid. In unlesioned tissue, aminooxyacetic acid (300 μM), veratridine (50 μM) and glutamate (5 mM), all administered through the dialysis probe, decreased extracellular kynurenic acid concentrations by 30 – 40%, i.e. to a lesser degree than in previous experiments in which kynurenine was used as a bioprecursor. Only the effect of veratridine was abolished in the quinolinate-lesioned hippocampus. These data indicate that kynurenic acid is produced in and liberated from astrocytes, and that aminooxyacetic acid and glutamate (but not veratridine) exert their action by directly affecting glial kynurenic acid biosynthesis. The results also suggest the existence of two distinct intracellular kynurenic acid pools, which are responsible for kynurenic acid storage and rapid kynurenic acid mobilization, respectively. Taken together, these features of kynurenic acid neurobiology may be of relevance in the control of excitatory amino acid receptor function under physiological and pathological conditions.