Novel Neuroprotective Treatment for Parkinson's Disease

帕金森病的新型神经保护治疗

• 批准号: 8328605
• 负责人: Aloke K Dutta
• 金额: $ 45.15万
• 依托单位: WAYNE STATE UNIVERSITY
• 依托单位国家: 美国
• 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/8328605
• 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 Delivery Systems; Drug Kinetics; 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

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）：帕金森病（PD）是一种以黑质纹状体多巴胺能通路变性为特征的进行性神经退行性疾病。PD的主要临床特征包括静息性震颤、僵直、初始运动困难和体位不稳定。目前，还没有理想的治疗方法可以减缓变性过程的进展，同时缓解与该疾病相关的症状异常。虽然帕金森病的发病机制尚不清楚，但氧化应激和线粒体功能障碍引起的谷胱甘肽丧失和游离铁浓度增加与多巴胺细胞死亡密切相关。越来越明显的是，对于像帕金森病这样的复杂疾病，仅靶向一个靶点的药物只能部分地解决该疾病的治疗需求。本研究的总体目标是开发多功能治疗药物，不仅可用于对症治疗，还可通过促进DA神经元的存活作为疾病调节剂。多巴胺D3优先激动剂除了提供症状缓解PD运动并发症较少，也被证明是神经保护剂。从我们的新杂交模板中得到的D3偏好化合物D-264在两种不同的动物模型研究中显示出神经保护作用。我们的研究表明，D-264与D3受体的相互作用以及它的其他特性，如抗氧化，可能是其神经保护特性的原因。在另一个初步发展中，独特的多功能多巴胺D2/D3激动剂化合物具有螯合铁的能力已经开发出来。这些分子不仅有望缓解PD的运动功能障碍，而且还可能通过与铁的螯合来减少PD脑中的氧化应激，这与疾病的发病机制有关。初步研究表明，这些化合物具有易穿越血脑屏障的能力，在细胞培养和体内MPTP小鼠模型实验中，其中一个先导分子显示出神经保护作用。我们现在建议扩大基于混合D-264相关类似物的药物开发研究，以改善药代动力学特性，提高生物利用度，并开展多价铁结合D2/D3激动剂的扩展结构活性关系研究。从这两个系列化合物中选择的分子将在PD动物模型中进行评估，以确定特异性和有效性。从这些研究中获得的有希望的线索将在神经保护研究中进行评估，包括急性神经毒性MPTP和慢性多巴胺能谷胱甘肽消耗转基因小鼠模型。