Lack of efficacy of NMDA receptor-NR2B selective antagonists in the R6/2 model of Huntington disease.
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.
Tallaksen-Greene
Sara J
SJ
Geriatrics Research, Education, and Clinical Center, VAAAHS, Ann Arbor, MI 48105, USA.
Janiszewska
Anita
A
Benton
Kasha
K
Ruprecht
Lech
L
Albin
Roger L
RL
D000818:Animals; D003342:Corpus Striatum / Q000187:drug effects* / Q000473:pathology; D004195:Disease Models, Animal; D005260:Female; D006816:Huntington Disease / Q000188:drug therapy* / Q000473:pathology; D053208:Kaplan-Meier Estimate; D008297:Male; D051379:Mice; D009043:Motor Activity / Q000187:drug effects*; D009929:Organ Size; D010636:Phenols / Q000494:pharmacology / Q000627:therapeutic use; D010880:Piperidines / Q000494:pharmacology / Q000627:therapeutic use; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors*; D012737:Sex Factors; D016896:Treatment Outcome
D010636:Phenols; D010880:Piperidines; D016194:Receptors, N-Methyl-D-Aspartate; C109643:Ro 25-6981; C095106:traxoprodil mesylate; C010739:ifenprodil