Preclinical neuroprotective trials of a PPAR-gamma agonist in HD mouse models

描述（申请人提供）：亨廷顿病（HD）是一种神经退行性疾病，由亨廷顿基因中CAG重复序列的病理性延长引起。没有治疗方法可以延迟人类疾病的发作和/或减缓疾病的进展。转录失调和线粒体功能障碍与HD的发病机制密切相关。过氧化物酶体增殖物激活受体（PPARs）是配体激活的转录因子核激素受体家族的成员. PPAR？激活防止神经元变性，同时线粒体活力增加。最近的研究也提供了证据表明，PPAR？激动剂是神经保护性的，并增加HD细胞模型中的线粒体功能。我们的初步研究表明，突变亨廷顿改变了过氧化物酶体增殖物激活受体？水平的细胞模型和小鼠模型的HD，和PPAR？激动剂罗格列酮在细胞模型中保护细胞免受突变亨廷顿蛋白诱导的细胞死亡，并延长HD小鼠模型的存活期。因此，我们建议确定的可能性，过氧化物酶体增殖反应？活化以改善体内突变亨廷顿蛋白诱导的病理和功能障碍。在目的1中，我们将在片段突变亨廷顿蛋白转基因小鼠模型（N171- 82 Q小鼠）中确定PPAR-γ激动剂罗格列酮对疾病发作和进展的剂量反应和作用。我们将对N171- 82 Q HD小鼠长期给予三种剂量的罗格列酮（10、20、40 mg/kg/天，i.p）。症状前试验在6周龄时开始注射药物，症状试验在12周龄时开始注射药物。将通过加速旋转棒装置评估运动行为表现。在症状前试验中，将在6、12和18周龄时使用结构MRI纵向检查罗格列酮对脑萎缩的影响，在症状试验中，将在16、20周龄时使用结构MRI纵向检查罗格列酮对脑萎缩的影响。将通过首次可检测到的旋转杆缺陷来评价疾病的发作。采用HPLC/MS/MS法测定药物浓度，并通过组织学分析评价罗格列酮对脑病理变化的影响。在目标2中，我们将在全长突变亨廷顿蛋白转基因小鼠模型（BACHD小鼠）中确定罗格列酮对运动功能和脑病理学的影响。我们将在运动缺陷发作前和发作后对BACHD小鼠长期给予最佳剂量的罗格列酮。将通过旋转棒装置评估运动行为表现。在6和12月龄时使用MRI检查脑萎缩，并在12月龄时通过组织学检查神经病理学。这项研究将为进一步的临床试验提供重要的证据。人体内的激动剂。我们的长期目标是为HD患者开发有效的治疗药物。 公共卫生相关性：亨廷顿氏病（HD）是影响人类神经系统的最常见的遗传性疾病，并且与其他神经退行性疾病具有许多共同特征。没有治愈方法，也没有有效的治疗方法来延迟HD的发作或减缓其进展。我们提出的研究将检查临床批准的过氧化物酶体增殖物激活受体的作用？在HD的小鼠模型中，研究了一种激动剂对疾病发作和进展的影响，并导致开发HD治疗剂的策略。

DESCRIPTION (provided by applicant): Huntington disease (HD) is a neurodegenerative disease that is caused by the pathological elongation of the CAG repeats in the huntingtin gene. There is no treatment to delay onset and/or slow down the progression of disease in humans. Transcriptional dysregulation and mitochondrial dysfunction have been strongly implicated in the pathogenesis of HD. Peroxisome proliferator- activated receptors (PPARs) are members of the nuclear hormone receptor family of ligand- activated transcription factors. PPAR? activation prevents neuronal degeneration with a concomitant increase in mitochondrial viability. Recent studies have also provided evidence that PPAR? agonists are neuroprotective and increase mitochondrial function in a cell model of HD. Our preliminary studies indicated that mutant huntingtin altered the PPAR? levels in both cell models and mouse model of HD, and PPAR? agonist rosiglitazone protected cells against mutant huntingtin-induced cell death in cell models and extended survival in a HD mouse model. Therefore, we propose to determine the possibility of PPAR? activation to ameliorate mutant huntingtin-induced pathology and dysfunction in vivo. In Aim 1, we will determine the dose response and effect of PPAR-gamma agonist rosiglitazone on disease onset and progression in a fragment mutant huntingtin transgenic mouse model (N171-82Q mice). We will chronically administer three doses of rosiglitazone (10, 20, 40 mg/kg/day, i.p) to N171-82Q HD mice. Drug injection will be started at 6 weeks of age for presymptomatic trials and at 12 weeks of age for symptomatic trials. Motor behavioral performance will be assessed by accelerating rotarod apparatus. Effect of rosiglitazone on brain atrophy will be examined longitudinally by using structural MRI at 6, 12 and 18 weeks of age for presymptomatic trials and at 16, 20 weeks for symptomatic trials. The onset of disease will be evaluated by first detectable rotarod deficit. Drug concentrations will be measured by HPLC/MS/MS. Effect of rosiglitazone on brain pathological change will be also evaluated by histological analysis. In Aim 2, we will determine the effect of rosiglitazone on motor function and brain pathology in a full-length mutant huntingtin transgenic mouse model (BACHD mice). We will chronically administer optimal dose of rosiglitazone to BACHD mice before onset and after onset of motor deficit. Motor behavioral performance will be assessed by rotarod apparatus. Brain atrophy will be examined by using MRI at 6 and 12 months of age and neuropathology will be examined by histology at 12 months. The proposed study will provide critical evidence for further clinical trials of PPAR? agonists in humans. Our long-term goal is to develop effective therapeutic agents for HD patients. PUBLIC HEALTH RELEVANCE: Huntington's disease (HD) is the most common inherited disorder affecting the nervous system in humans and shares many features with other neurodegenerative diseases. There is no cure, nor are there effective treatments that delay the onset or slow down the progression of HD. Our proposed studies will examine the effect of a clinical approved PPAR? agonist on disease onset and progression in mouse models of HD and result in a strategy to develop therapeutics for HD.