Riluzole prolongs survival time and alters nuclear inclusion formation in a transgenic mouse model of Huntington's disease
Riluzole prolongs survival time and alters nuclear inclusion formation in a transgenic mouse model of Huntington's disease
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DOI：
10.1002/mds.10229
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发表时间：
2002-07-01
影响因子：
8.6
通讯作者：
Kosinski, CM
中科院分区：
文献类型：
--
作者：
Schiefer, J;Landwehrmeyer, GB;Kosinski, CM
谷氨酸兴奋毒性被认为与亨廷顿病（HD）的发病机制有关。利鲁唑是一种具有谷氨酸拮抗剂特性的物质，用于肌萎缩侧索硬化症的神经保护治疗，目前正在临床试验中用于治疗HD。R6/2转基因小鼠表达人类HD基因外显子1并扩增CAG三联体重复序列，可作为具有进展性神经异常和有限存活的HD小鼠模型。我们从症状前阶段开始口服利鲁唑治疗R6/2 HD转基因小鼠，直到死亡，以研究其在该小鼠模型中的潜在神经保护作用，发现利鲁唑组的生存时间比安慰剂处理的转基因对照组显著增加。此外，利鲁唑治疗延迟了进行性体重减轻，并显著减少了体重减轻；然而，运动协调和自发运动活动的行为测试没有显示统计学上的显著差异。我们还检查了HD特征性神经元核内包涵体（NII）的免疫组织学形成。在疾病晚期，利鲁唑处理的转基因小鼠纹状体NII的泛素化发生了深刻的变化，即NII泛素化程度降低，并被泛素化微聚集体所包围。针对突变亨廷顿蛋白的抗体染色显示，NIL的这一成分没有显著差异。总之，这些数据表明利鲁唑是人类HD神经保护治疗的有希望的候选药物。(C) 2002运动障碍学会。
Glutamate excitotoxicity has been suggested to contribute to the pathogenesis of Huntington's disease (HD). Riluzole is a substance with glutamate antagonistic properties that is used for neuroprotective treatment in amyotrophic lateral sclerosis and which is currently tested in clinical trials for treatment of HD. R6/2 transgenic mice, which express exon 1 of the human HD gene with an expanded CAG triplet repeat, serve as a well-characterized mouse model for HD with progressing neurological abnormalities and limited survival. We treated R6/2 HD transgenic mice with riluzole orally beginning at a presymptomatic stage until death to investigate its potential neuroprotective effects in this mouse model and found that survival time in the riluzole group was significantly increased in comparison to placebo-treated transgenic controls. Additionally, the progressive weight loss was delayed and significantly reduced by riluzole treatment; behavioral testing of motor coordination and spontaneous locomotor activity, however, showed no statistically significant differences. We also examined the formation of the HD characteristic neuronal intranuclear inclusions (NII) immunohistologically. At a late disease stage, striatal NII from riluzole-treated transgenic mice showed profound changes in ubiquitination, i.e., NII were less ubiquitinated and surrounded by ubiquitinated micro-aggregates. Staining with antibodies directed against the mutated huntingtin revealed no significant difference in this component of NIL Taken together, these data suggest that riluzole is a promising candidate for neuroprotective treatment in human HD. (C) 2002 Movement Disorder Society.