Therapeutic Neuroprotective Trials of Tiagabine in HD Mouse Models

描述（由申请人提供）：噻加宾在HD小鼠模型中的治疗性神经退行性试验摘要亨廷顿病（HD）是一种进行性和致死性遗传性神经退行性疾病。目前尚无可延迟HD发作或减缓HD进展的治疗方法。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患者中进行临床试验。我们已经在可诱导的表达亨廷顿蛋白的PC 12细胞模型中筛选了1040种主要是FDA批准的化合物的NINDS文库，化合物哌啶甲酸剂量依赖性地保护细胞免受htt毒性和减少包涵体形成，而不改变htt表达。由于哌啶甲酸不能穿过脑屏障，其亲脂性衍生物噻加宾在我们的HD细胞模型中具有类似的作用。我们现在建议在两种HD小鼠模型中进行临床前试验。在特定目的1中，我们将确定噻加滨对片段HD小鼠模型N171- 82 Q（系81）小鼠中疾病发作和进展的剂量反应。我们将使用运动行为功能、体重、存活率和脑病理学作为我们的结局指标。在具体目标2中，我们将研究噻加宾对全长突变亨廷顿蛋白YAC 128小鼠的运动行为功能和脑病理学的影响。将对小鼠长期给予噻加滨。将使用旋转棒装置测试运动行为表现。将使用免疫组织化学和尼氏染色检查脑病理学。由于噻加宾是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小鼠模型中具有一致的保护作用，则可能导致人体治疗试验和HD的潜在治疗。在HD小鼠模型中进行的噻加宾的治疗性神经退行性试验叙述：亨廷顿氏病（HD）是一种进行性的、总是致命的遗传性神经退行性疾病。目前尚无可延迟HD发作或减缓HD进展的治疗方法。我们建议测试一种名为Tiagabine的化合物，该化合物最初是从我们在HD细胞模型中的化合物筛选中开发的。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，则可能导致人类的治疗试验和HD的潜在治疗。

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.