4-CHLORO-3-HYDROXYANTHRANILATE INHIBITS QUINOLINATE PRODUCTION IN THERAT HIPPOCAMPUS IN-VIVO

Quinolinic acid (QUIN) is a potential pathogen in a variety of excitot oxic and neuroviral brain diseases. In the present study, the ability of the QUIN synthesis inhibitor 4-chloro-3-hydroxyanthranilic acid to attenuate the production of QUIN was assessed in the hippocampus of aw ake rats. To this end, QUIN's immediate bioprecursor 3-hydroxyanthrani lic acid (30 mu M) was applied through a microdialysis probe, and QUIN production was monitored hourly in the perfusate. After 3 h, 4-chloro -3-hydroxyanthranilic acid (3 mu M-3 mM) was included in the perfusion medium, and dialysis was continued for another 3 h. The drug caused d ose-dependent inhibition of QUIN neosynthesis, with an apparent IC50 v alue of 32 mu M. Discontinuation of drug administration, with continue d perfusion of 3-hydroxyanthranilic acid, revealed that the drug effec t was reversible. Intravenous application of 4-chloro-3-hydroxyanthran ilic acid (14 mg/kg) resulted in a significant decrease in extracellul ar QUIN, reaching a nadir of 67% of saline-treated controls after 3 h. The data indicate that both intracerebral and systemic administration of 4-chloro-3-hydroxyanthranilic acid effectively interferes with QUI N production in the rat brain. The results suggest that QUIN synthesis inhibitors such as 4-chloro-3-hydroxyanthranilic acid may become of v alue in brain diseases that are caused by hyperphysiological quantitie s of QUIN.