The kynurenine 3-hydroxylase inhibitor Ro 61-8048 improves dystonia in a genetic model of paroxysmal dyskinesia.

Abstract

The effects of the novel kynurenine 3-hydroxylase inhibitor 3,4-dimethoxy-N-[4-(3-nitrophenyl)thiazol-2-yl]benzenesulfonamide (Ro 61-8048) on severity of dystonia were examined in dt(sz) mutant hamsters, an animal model of paroxysmal dystonia, in which stress precipitates dystonic episodes. Ro 61-8048 (50, 100 and 150 mg/kg i.p.) significantly reduced the severity of dystonia in dt(sz) hamsters without leading to marked central side effects. Determinations of kynurenic acid concentrations in brain homogenates demonstrated that Ro 61-8048 (100 mg/kg i.p.) provoked a two- to threefold increase of the endogeneous broad spectrum glutamate receptor antagonist kynurenic acid in the striatum, cerebellum and brainstem of mutant hamsters. The antidystonic efficacy of Ro 61-8048 at well-tolerated doses suggests that kynurenine 3-hydroxylase inhibitors should be considered as new therapeutic candidates for the treatment of dyskinesias.

• Authors: Angelika Richter, Melanie Hamann
• Journal: European journal of pharmacology (Eur J Pharmacol) Vol. 478 Issue 1 Pg. 47-52 (Sep 30 2003) ISSN: 0014-2999 [Print] Netherlands
• PMID: 14555184 (Publication Type: Comparative Study, Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Enzyme Inhibitors
• Ro 61-8048
• Sulfonamides
• Thiazoles
• Mixed Function Oxygenases
• Kynurenine 3-Monooxygenase

Topics

• Animals
• Chorea (drug therapy, enzymology, genetics)
• Cricetinae
• Disease Models, Animal
• Dose-Response Relationship, Drug
• Dystonia (drug therapy, enzymology, genetics)
• Enzyme Inhibitors (pharmacology, therapeutic use)
• Female
• Kynurenine 3-Monooxygenase
• Male
• Mesocricetus
• Mixed Function Oxygenases (antagonists & inhibitors, genetics, metabolism)
• Sulfonamides (pharmacology, therapeutic use)
• Thiazoles (pharmacology, therapeutic use)