Therapeutic Neuroprotective Trials of Tiagabine in HD Mouse Models

描述(申请人提供)：替加宾在HD小鼠模型中的治疗性神经保护试验摘要亨廷顿病(HD)是一种进行性和总是致命的遗传性神经退行性疾病。目前尚无有效的治疗方法可以延缓HD的发病或延缓其进展。我们的长期目标是在HD模型中开发有效的化合物，以进一步在人类HD患者身上进行临床试验。我们已经对1040个主要是FDA批准的化合物的NINDS文库进行了筛选，这些化合物在一个可诱导的Huntingtin表达的PC12细胞模型中表达，这种化合物是一种化合物，对HTT的毒性具有剂量依赖的保护作用，减少了包裹体的形成，而不改变HTT的表达。由于硝哌酸不能穿过脑屏障，其亲脂衍生物替加宾在我们的HD细胞模型中也有类似的作用。我们现在建议在两个HD小鼠模型上进行临床前试验。在特定的目标1中，我们将在片段HD小鼠模型N171-82Q(LINE 81)小鼠上测定替加宾对疾病发生和发展的剂量反应。我们将使用运动行为功能、体重、存活率和脑病理作为我们的结果衡量标准。在特定的目的2中，我们将研究替加宾对全长突变的亨廷丁YAC128小鼠运动行为功能和脑病理的影响。替加宾将在小鼠身上长期使用。运动行为表现将使用旋转杆仪进行测试。脑病理检查将采用免疫组织化学和尼氏染色。由于替加宾是FDA批准的药物，因此拟议研究的意义在于，如果该化合物在不同的小鼠模型中具有一致的保护作用，它可能会导致在人类身上进行治疗试验，并可能成为HD的潜在治疗方法。替加宾在HD小鼠模型中的治疗神经保护试验叙述：亨廷顿病(HD)是一种进行性和总是致命的遗传性神经退行性疾病。目前尚无有效的治疗方法可以延缓HD的发病或延缓其进展。我们建议测试一种名为替加宾的化合物，它最初是从我们的化合物筛选HIT in HD细胞模型中开发出来的。拟议研究的意义在于，如果这种化合物在不同的小鼠模型中具有一致的保护作用，它可能会导致在人类身上进行治疗试验，并可能成为HD的潜在治疗方法。

DESCRIPTION (provided by applicant): THERAPEUTIC NEUROPROTECTIVE TRIALS OF TIAGABINE IN HD MOUSE MODELS Abstract Huntington's disease (HD) is a progressive and aways fatal inherited neurodegenerative disorders. There is no currently avaliable treatment which can delay the onset or slow down the progression of HD. Our long term goal is to develop effective compounds in HD models to lead further to clinical trials in human HD patients. We have done screening of NINDS library of 1040 mostly FDA-approved compounds in an inducible huntingtin expressing PC12 cell model, a compound nipecotic acid, dose-dependetly protected cell against htt toxicity and decreased inclusion formation, without changing htt expression. Since nipecotic acid can not cross the brain barrier, its lipophilic derivatives tiagabine has similar effect in our HD cell model. We now propose to conduct preclinical trials in two HD mouse models. In secific Aim 1, we will determine the dose response of tiagabine on onset and progression of disease in the fragment HD mouse model N171-82Q (line 81) mice. We will use motor behavioral function, body weight, survival, and brain pathology as our outcome measures. In Specific Aim 2, we will investigate the effect of tiagabine on motor behavioral function and brain pathology in the full-length mutant huntingtin YAC128 mice. Tiagabine will be chronically administered to mice. Motor behavioral performance will be tested using rotarod apparatus. Brain pathology will be examined using Immunohistochemistry and Nissl staining. Since tiagabine is a FDA approved drug, the significance of proposed study is that if this compound has consistent protection in different mouse models, it might lead to therapeutic trials in human and a potential therapy for HD. THERAPEUTIC NEUROPROTECTIVE TRIALS OF TIAGABINE IN HD MOUSE MODELS Narrative: Huntington's disease (HD) is a progressive and aways fatal inherited neurodegenerative disorders. There is no currently avaliable treatment which can delay the onset or slow down the progression of HD. We propse to test a compound named Tiagabine, which was initially developed from our compound screening hit in HD cell model. The significance of proposed study is that if this compound has consistent protection in different mouse models, it might lead to therapeutic trials in human and a potential therapy for HD.