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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.

SUBMITTER: Tallaksen-Greene SJ

PROVIDER: S-EPMC2939157 | biostudies-literature | 2010 Oct

REPOSITORIES: biostudies-literature

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

Tallaksen-Greene Sara J SJ Janiszewska Anita A Benton Kasha K Ruprecht Lech L Albin Roger L RL

Experimental neurology 20100724 2

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). ...[more]

PMID: 20659453

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Project description:BackgroundPostherpetic neuralgia is spontaneous pain and allodynia that persist long after the disappearance of the cutaneous lesions caused by herpes zoster. Inoculation of mice with herpes simplex virus-1 causes herpes zoster-like skin lesions and herpetic and postherpetic pain. Although NMDA receptors have been suggested to be involved in postherpetic pain as in other types of neuropathic pain, the neural mechanism remains unclear. NMDA receptor NR2B subunit is the most tyrosine-phosphorylated protein in the brain, and Tyr1472 is the major phosphorylation site of this subunit.ResultsTo elucidate the role of Tyr1472 phosphorylation of the NR2B subunit in herpetic and postherpetic allodynia, we inoculated herpes simplex virus-1 into the unilateral hind paw of knock-in mice with a mutation of Tyr1472 of the NR2B subunit to Phe (Y1472F-KI). On day 7 post-inoculation, acute herpetic allodynia was observed in more than 80% of the inoculated wild-type and Y1472F-KI mice. Y1472F-KI mice showed significantly reduced intensity and incidence of postherpetic allodynia on days 45-50 post-inoculation as compared with wild-type mice. The innervation in the skin at the postherpetic neuralgia phase was retained to a greater extent in the Y1472F-KI mice. The level of activating transcription factor-3 mRNA, a marker of axonal damage, increased much less in the dorsal root ganglia (DRGs) of Y1472F-KI mice than in those of wild-type mice; and the level of nerve growth factor mRNA significantly increased in wild-type mice, but not at all in Y1472F-KI mice on day 7 post-inoculation. Production of nerve growth factor was at the basal level in the skin of both groups of mice on day 50 post-inoculation. Nerve growth factor and glial cell-derived neurotrophic factor stimulated neurite outgrowth of cultured DRG neurons from Y1472F-KI mice, similarly or less so as they did the outgrowth of those from wild-type mice. Wild-type DRG neurons were more susceptible to glutamate neurotoxicity than Y1472F-KI ones.ConclusionsTaken together, the present data suggest that phosphorylation of the NR2B subunit at its Tyr1472 is involved in the development of postherpetic allodynia due to nerve damage and that the nerve damage at the acute herpetic phase is correlated with the incidence of postherpetic pain.

Dataset Information

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

Publications

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

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