Abstract |
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.
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Authors | J L Walsh, H Q Wu, U Ungerstedt, R Schwarcz |
Journal | Brain research bulletin
(Brain Res Bull)
Vol. 33
Issue 5
Pg. 513-6
( 1994)
ISSN: 0361-9230 [Print] United States |
PMID | 8186995
(Publication Type: Journal Article, Research Support, U.S. Gov't, P.H.S.)
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Chemical References |
- 3-Hydroxyanthranilic Acid
- 4-chloro-3-hydroxyanthranilic acid
- Oxygenases
- Dioxygenases
- 3-Hydroxyanthranilate 3,4-Dioxygenase
- Quinolinic Acid
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Topics |
- 3-Hydroxyanthranilate 3,4-Dioxygenase
- 3-Hydroxyanthranilic Acid
(analogs & derivatives, pharmacology)
- Animals
- Dioxygenases
- Dose-Response Relationship, Drug
- Extracellular Space
(metabolism)
- Hippocampus
(drug effects, metabolism)
- Male
- Microdialysis
- Oxygenases
(antagonists & inhibitors)
- Quinolinic Acid
(metabolism)
- Rats
- Rats, Sprague-Dawley
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