The α2β3γ2 GABAA receptor preferring agonist NS11394 aggravates dystonia in the phenotypic dtsz model.

Abstract

Dystonia is a movement disorder, characterized by involuntary muscle contractions resulting in abnormal movements and/or postures. Antidystonic effects of benzodiazepines in patients with different types of dystonia could be replicated in the dtsz mutant hamster, a phenotypic model of paroxysmal dystonia. Compounds with preferred binding at specific subunits of the gamma aminobutyric acid type A (GABAA) receptor may provide a more beneficial spectrum of effects in comparison with benzodiazepines. We therefore examined the effects of the α1β3γ2 GABAA receptor preferring compound zolpidem (2.0-10.0mg/kg i.p.) and of the α2β3γ2 GABAA receptor preferring compound NS11394 (3.0-30mg/kg i.p.) on the severity of dystonia in the dtsz mutant in comparison with the benzodiazepine clonazepam (0.5-1.0mg/kg i.p.). As expected, clonazepam exerted pronounced antidystonic effects. While zolpidem showed moderate beneficial effects, NS11394 significantly increased the severity of dystonia. The present results indicate for the first time that positive GABAA receptor modulators show contrary effects on dystonia dependent on their preference for alpha-subunits. The potential link between alterations in GABAA receptor subunits and GABAergic disinhibition in dystonia deserves further attention in research on the pathophysiology and therapeutic targets.

• Authors: Christine Spröte, Franziska Richter, Anne Bauer, Julia Gerstenberger, Angelika Richter
• Journal: European journal of pharmacology (Eur J Pharmacol) Vol. 791 Pg. 655-658 (Nov 15 2016) ISSN: 1879-0712 [Electronic] Netherlands
• PMID: 27693801 (Publication Type: Journal Article)
• Copyright: Copyright © 2016 Elsevier B.V. All rights reserved.

Chemical References

• 3'-(5-(1-hydroxy-1-methylethyl)benzoimidazol-1-yl)biphenyl-2-carbonitrile
• Benzimidazoles
• GABA-A Receptor Agonists
• Protein Subunits
• Receptors, GABA-A

Topics

• Animals
• Benzimidazoles (metabolism, pharmacology)
• Cricetinae
• Disease Models, Animal
• Dose-Response Relationship, Drug
• Dystonia (drug therapy, genetics, metabolism)
• Female
• GABA-A Receptor Agonists (pharmacology, therapeutic use)
• Male
• Mutation
• Phenotype
• Protein Subunits (agonists, metabolism)
• Receptors, GABA-A (metabolism)
• Substrate Specificity