Nortriptyline推迟Huntington病小鼠的发病(英文)  

NORTRIPTYLINE DELAYS DISEASE ONSET IN HUNTINGTON’S DISEASE MICE

作　　者：管英俊[1] 于丽[1] 高海玲[1] 岳炳德[1] 马丽[1] 陈燕春[1] 赵春艳[1] 王红雁[2] Robert M.Friedlander 

机构地区：[1]潍坊医学院组织学与胚胎学教研室,潍坊261042 [2]哈佛医学院布里盖姆妇女医院神经凋亡实验室,波士顿马萨诸塞州02115

出　　处：《神经解剖学杂志》2006年第4期379-383,共5页Chinese Journal of Neuroanatomy

摘　　要：Huntington病(HD)是一种常染色体显性遗传性神经退行性疾病,主要组织病理学特征是纹状体运动神经元进行性死亡,目前尚无有效治疗方法,本实验探讨了nortriptyline(去甲替林)的潜在疗效。采用N548mu[1955-128]huntingtin ST14A细胞系进行体外培养,观察不同浓度nortriptyline对细胞存活的影响。选用R6/2转基因鼠,从第5周开始每天腹腔注射nortriptyline,直至21周,对照组腹腔注射与nortriptyline组等剂量的生理盐水。结果发现,nortriptyline对移入不同温度环境的ST14A细胞具有保护作用。nortriptyline可推迟R6/2转基因鼠的发病,由102d推迟到127d,与对照组比较具有显著性差异。nortriptyline对R6/2转基因鼠死亡率的影响,与对照组比较无显著性差异。作为检测nortriptyline毒性的指标,nortriptyline对R6/2转基因鼠体重的影响,与对照组比较无显著性差异。结果表明,nortriptyline可推迟Huntington转基因鼠的发病,是目前毒性低、能够延长Huntington转基因鼠存活的有效药物。Huntington＇s disease （HD） is an autosomal dominant neurodegenerative disease. A cardinal histopathologic feature of HD is the progressive loss of striatal medium spiny neurons. As there is no effective treatment for this fatal disease so far, we explore the therapeutic potential of nortriptyline to identify drugs that might be effective treatments for HD. N548mu [ 1955-128] huntingtin stable ST14A cell line was cultured and incubated in the presence or absence of serial concentrations of nortriptyline. Then R6/2 transgenic HD mice were treated with nortriptyline from five to twenty-one weeks of age. Nortriptyline protected striatal cells expressing mutant huntingtin when shifted to a nonpermissive temperature. Nortriptyline delay the disease onset to 127 d in R6/2 mice as compared with 102 d in saline-treated controls, but nortriptyline did not significantly delay mortality. As a gross marker of lack of systemic toxicity, there was no significant difference in the weight of the treated and control R6/2 mice. The results demonstrate that clinically reasonable doses of one of the identified drugs, nortriptyline, delays disease onset in a mouse model of the disease more than any previously identified compound. The most desirable features of a drug for HD are minimal toxicity and the ability to extend symptom-free living. Nortriptyline appears to be one such good candidate.

关 键 词：Huntington病nortriptyline R6/2转基因鼠ST14A细胞系 

分 类 号：R742.2[医药卫生—神经病学与精神病学]