Lack of efficacy of NMDA receptor-NR2B selective antagonists in the R6/2 model of Huntington disease.

Abstract

N-methyl-D-aspartate receptor (NMDAR) mediated excitotoxicity is a probable proximate mechanism of neurodegeneration in Huntington disease (HD). Striatal neurons express the NR2B-NMDAR subunit at high levels, and this subunit is thought to be instrumental in causing excitotoxic striatal neuron injury. We evaluated the efficacy of 3 NR2B-selective antagonists in the R6/2 transgenic fragment model of HD. We evaluated ifenprodil (10 mg/kg; 100 mg/kg), RO25,6981 (10 mg/kg), and CP101,606 (30 mg/kg). Doses were chosen on the basis of pilot acute maximally tolerated dose studies. Mice were treated with subcutaneous injections twice daily. Outcomes included survival; motor performance declines assessed with the rotarod, balance beam task, and activity measurements; and post-mortem striatal volumes. No outcome measure demonstrated any benefit of treatments. Lack of efficacy of NR2B antagonists in the R6/2 model has several possible explanations including blockade of beneficial NMDAR mediated effects, inadequacy of the R6/2 model, and the existence of multiple proximate mechanisms of neurodegeneration in HD.

• Authors: Sara J Tallaksen-Greene, Anita Janiszewska, Kasha Benton, Lech Ruprecht, Roger L Albin
• Journal: Experimental neurology (Exp Neurol) Vol. 225 Issue 2 Pg. 402-7 (Oct 2010) ISSN: 1090-2430 [Electronic] United States
• PMID: 20659453 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: Published by Elsevier Inc.

Chemical References

• Phenols
• Piperidines
• Receptors, N-Methyl-D-Aspartate
• Ro 25-6981
• traxoprodil mesylate
• ifenprodil

Topics

• Animals
• Corpus Striatum (drug effects, pathology)
• Disease Models, Animal
• Female
• Huntington Disease (drug therapy, pathology)
• Kaplan-Meier Estimate
• Male
• Mice
• Motor Activity (drug effects)
• Organ Size
• Phenols (pharmacology, therapeutic use)
• Piperidines (pharmacology, therapeutic use)
• Receptors, N-Methyl-D-Aspartate (antagonists & inhibitors)
• Sex Factors
• Treatment Outcome