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4-Chloro-3-hydroxyanthranilate inhibits quinolinate production in the rat hippocampus in vivo.

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.
AuthorsJ L Walsh, H Q Wu, U Ungerstedt, R Schwarcz
JournalBrain research bulletin (Brain Res Bull) Vol. 33 Issue 5 Pg. 513-6 ( 1994) ISSN: 0361-9230 [Print] United States
PMID8186995 (Publication Type: Journal Article, Research Support, U.S. Gov't, P.H.S.)
Chemical References
  • 3-Hydroxyanthranilic Acid
  • 4-chloro-3-hydroxyanthranilic acid
  • Oxygenases
  • Dioxygenases
  • 3-Hydroxyanthranilate 3,4-Dioxygenase
  • Quinolinic Acid
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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