4-Chloro-3-hydroxyanthranilate inhibits quinolinate production in the rat hippocampus in vivo.
Quinolinic acid (QUIN) is a potential pathogen in a variety of excitotoxic 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 awake rats. To this end, QUIN's immediate bioprecursor 3-hydroxyanthranilic acid (30 microM) was applied through a microdialysis probe, and QUIN production was monitored hourly in the perfusate. After 3 h, 4-chloro-3-hydroxyanthranilic acid (3 microM-3 mM) was included in the perfusion medium, and dialysis was continued for another 3 h. The drug caused dose-dependent inhibition of QUIN neosynthesis, with an apparent IC50 value of 32 microM. Discontinuation of drug administration, with continued perfusion of 3-hydroxyanthranilic acid, revealed that the drug effect was reversible. Intravenous application of 4-chloro-3-hydroxyanthranilic acid (14 mg/kg) resulted in a significant decrease in extracellular 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 QUIN production in the rat brain. The results suggest that QUIN synthesis inhibitors such as 4-chloro-3-hydroxyanthranilic acid may become of value in brain diseases that are caused by hyperphysiological quantities of QUIN.
Walsh
J L
JL
Maryland Psychiatric Research Center, University of Maryland School of Medicine, Baltimore 21228.
Wu
H Q
HQ
Ungerstedt
U
U
Schwarcz
R
R
D050561:3-Hydroxyanthranilate 3,4-Dioxygenase; D015095:3-Hydroxyanthranilic Acid / Q000031:analogs & derivatives* / Q000494:pharmacology; D000818:Animals; D049308:Dioxygenases; D004305:Dose-Response Relationship, Drug; D005110:Extracellular Space / Q000378:metabolism; D006624:Hippocampus / Q000187:drug effects / Q000378:metabolism*; D008297:Male; D017551:Microdialysis; D010105:Oxygenases / Q000037:antagonists & inhibitors; D017378:Quinolinic Acid / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley
D015095:3-Hydroxyanthranilic Acid; C026381:4-chloro-3-hydroxyanthranilic acid; D010105:Oxygenases; D049308:Dioxygenases; D050561:3-Hydroxyanthranilate 3,4-Dioxygenase; D017378:Quinolinic Acid