Novel Neuroprotective Treatment for Parkinson's Disease

帕金森病的新型神经保护治疗

基本信息

批准号：
8687751
负责人：
Aloke K Dutta
金额：
$ 44.28万
依托单位：
WAYNE STATE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2005
资助国家：
美国
起止时间：
2005-05-01 至 2016-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8687751
关键词：
1-Methyl-4-phenylpyridinium Acute Address Affect Affinity Age Agonist Animal Model Animals Antioxidants Attenuated Binding Biological Assay Biological Availability Blood - brain barrier anatomy Brain Brain-Derived Neurotrophic Factor Cell Culture Techniques Cell Death Cells Chinese Hamster Ovary Cell Chronic Clinical Complex Corpus striatum structure Development Disease Disease Progression Disease model Dopamine Dopaminergic Cell Dose Drug Kinetics Drug Targeting Dyskinetic syndrome Evaluation Exhibits Functional disorder Funding GDNF gene Glutathione Goals Human Cloning Hybrids In Vitro Inflammation Iron Iron Chelating Agents Lead Lesion Levodopa Mediating Midbrain structure Modeling Motor Movement Mus Nerve Degeneration Neurodegenerative Disorders Neurons Neuroprotective Agents Neurotoxins Oral Oxidative Stress Parkinson Disease Pathogenesis Performance Permeability Process Property Rattus Rest Tremor Rotation Series Site Specificity Structure-Activity Relationship Substantia nigra structure Symptoms Testing Therapeutic Therapeutic Agents Time Toxic effect Toxicity Tests Transgenic Mice Up-Regulation analog base behavior test design dopaminergic neuron drug development follow-up human old age (65+)immortalized cell improved in vivo lactacystin mitochondrial dysfunction mouse model neuroprotection nigrostriatal dopaminergic pathway novel potency testing receptor research study response restoration small molecule

项目摘要

DESCRIPTION (provided by applicant): Parkinson's Disease (PD) is a progressive neurodegenerative disorder characterized by degeneration of the nigrostriatal dopaminergic pathway. The cardinal clinical features of PD include resting tremor, rigidity, difficulty initiating movement, and postural instability. Currently, no ideal therapies are available for slowing the progression of the degeneration process and at the same time relieving symptomatic abnormalities associated with this disease. Although the pathogenesis of PD is poorly understood both oxidative stress and mitochondrial dysfunction resulting from loss of glutathione with increased concentration of free iron have been strongly implicated in dopamine cell death. It is increasingly evident that for a complex disease such as PD, a drug targeting only one target site will only partially address the therapeutic need of the disease. The overall goal in this proposal is to develop multifunctional therapeutic agents which will be useful not only in symptomatic treatment but also could be used as disease-modifying agents by promoting survival of DA neurons. Dopamine D3 preferring agonists besides providing symptomatic relief in PD with less motor complications, have also been shown to act as neuroprotective agents. A D3 preferring compound D-264 derived from our novel hybrid template was shown to be neuroprotective in two different animal models studies. Our studies demonstrated that interaction of D-264 with the D3 receptor along with its other properties e.g. antioxidant, might be responsible for its neuroprotection property. In another preliminary development, unique multifunctional dopamine D2/D3 agonist compounds with a capacity to chelate iron have been developed. Such molecules are not only expected to relieve motor dysfunction in PD but also will have the potential to reduce oxidative stress in the PD brain by chelating with iron which has been implicated in the pathogenesis of the disease. Initial studies indicate facile blood-brain-barrier crossing ability of these compounds, and in cell culture and in vivo MPTP mouse model experiments one of the lead molecules indicated neuroprotection property. We now propose to expand drug development studies based on hybrid D-264 related analogues to improve pharmacokinetic properties to increase bioavailability and to carry out expanded structure activity relationship studies on multivalent iron binding D2/D3 agonists. Selected molecules from these two series of compounds will be evaluated in PD animal models to determine specificity and efficacy. Promising leads from these studies will next be evaluated in neuroprotection studies which include both acute neurotoxicant MPTP and chronic dox-inducible dopaminergic glutathione depletion transgenic mouse models.

描述（由申请人提供）：帕金森氏病（PD）是一种进行性神经退行性疾病，其特征是黑质纹状体多巴胺能途径的变性。 PD的基本临床特征包括静止震颤，僵化，难以发挥运动和姿势不稳定。当前，尚无理想的疗法可用于减慢退化过程的进展，同时缓解与这种疾病相关的有症状异常。尽管PD的发病机理众所周知，由于谷胱甘肽丧失而导致的氧化应激和线粒体功能障碍，自由铁的浓度升高与多巴胺细胞死亡有关。越来越明显的是，对于一种复杂的疾病（例如PD），仅针对一个目标部位的药物只会部分解决该疾病的治疗需求。该提案的总体目标是开发多功能治疗剂，这些治疗剂不仅在有症状的治疗中很有用，而且可以通过促进DA神经元的存活来用作改良疾病的药物。多巴胺D3除了提供较少运动并发症的PD症状缓解外，还偏爱激动剂，还显示出充当神经保护剂。在两种不同的动物模型研究中，D3更喜欢从我们的新型杂种模板中得出的化合物D-264。我们的研究表明，D-264与D3受体的相互作用及其其他特性，例如抗氧化剂可能是其神经保护性能的原因。在另一个初步的发展中，已经开发了具有螯合铁能力的独特多功能多巴胺D2/D3激动剂。这种分子不仅被期望缓解PD的运动功能障碍，而且还有可能通过用铁螯合涉及疾病的发病机理，从而减少PD脑中的氧化应激。初步研究表明，这些化合物的血脑屏障交叉能力容易，在细胞培养和体内MPTP小鼠模型实验中，铅分子之一表明神经保护特性。现在，我们建议扩大基于混合D-264相关类似物的药物开发研究，以改善药代动力学特性，以提高生物利用度并在多价铁结合D2/D3激动剂上进行扩展的结构活动关系研究。将在PD动物模型中评估这两个系列化合物的选定分子，以确定特异性和功效。接下来将评估这些研究的有希望的潜在客户，包括神经保护研究，包括急性神经毒性MPTP和慢性DOX诱导的多巴胺能谷胱甘肽消耗性转基因小鼠模型。