Kynurenic Acid-Enhancing And Anti-Ischemic Effects of the Potent Kynurenine 3-Hydroxylase Inhibitor Fce 28833 in Rodents

Abstract

When injected into the brain of experimental animals, quinolinic acid (QUIN) and kynurenic acid (KYNA) act as a neurotoxin and neuroprotectant, respectively, and these effects are mediated by excitatory amino acid (EAA) receptors (Stone, 1993). Since their identification in the mammalian brain, QUIN and KYNA have therefore been proposed to play roles as endogenous modulators of EAA receptors. Both compounds are metabolites of the kynurenine pathway in the periphery and in the brain, and a large number of studies have been performed to examine their source, metabolism and disposition in the central nervous system in physiological and pathological conditions (see Stone, 1993, for review). In particular, an increased formation of QUIN was observed in several models of nerve cell damage, such as excitotoxin lesions (Speciale et al., 1987), spinal cord trauma (Popovich et al., 1994) and global ischemia (Heyes and Nowak, 1990; Saito et al., 1993), and in humans infected with the HIV virus (Heyes et al., 1991). This enhancement of QUIN production was suggested to contribute to the loss of neurological function. On the other hand, KYNA was found to be likely involved in cerebral self-defence (Schwarcz et al., 1992). This is supported both by occurrence of cell death following the pharmacologically induced decrease in brain KYNA (McMaster et al., 1991) and by the increase in cerebral KYNA production following acute excitotoxic (Schwarcz et al., this volume) or convulsive (Wu and Schwarcz, 1994; Baran et al., 1995) insults.