4-Chloro-3-Hydroxyanthranilate Attenuate Quinolinic Acid Accumulation in Brain Following Transient Cerebral Ischemia in the Gerbil

Abstract

The kynurenine pathway is the predominant route of L-tryptophan metabolism in most tissues. Two aspects of L-tryptophan catabolism through this pathway are of particular interest. Firstly, the initial enzyme of the kynurenine pathway in extrahepatic tissues, indoleamine-2,3-dioxygenase (IDO), is induced by interferon-y and other immune stimuli (Saito et al., 1991,1992; Takikawa et al., 1986). Such induction is observed in patients with cancer, infectious disease and following therapeutic interferon administration, and has been implicated in the anti-proliferative and anti-microbial effects of interferon-y (Yasui et al., 1986; Taylor et al., 1991). Secondly, the neuroactive nature of certain metabolites, including quinolinic acid (QUIN), an excitotoxic agonist of N-methyl-D-aspartate receptors, and kynurenic acid (KYNA) an antagonist of excitatory amino acid receptors, has implicated their involvement in a broad spectrum of neurodegenerative disease (Heyes et al., 1992,1993). In a previous study, accumulation of QUIN in gerbil brain was observed 4 and 7 days following transient cerebral ischemia (Saito et al., see Figure 1). Such increases have been demonstrated to be secondary to increases of IDO and other kynurenine pathway enzymes in infiltrated