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）是一种进行性神经退行性疾病，其特征在于黑质纹状体多巴胺能通路的退化。 PD 的主要临床特征包括静止性震颤、强直、启动运动困难和姿势不稳定。目前，还没有理想的疗法可以减缓变性过程的进展，同时缓解与这种疾病相关的症状异常。尽管对帕金森病的发病机制知之甚少，但由于谷胱甘肽损失和游离铁浓度增加而导致的氧化应激和线粒体功能障碍与多巴胺细胞死亡密切相关。越来越明显的是，对于帕金森病这样的复杂疾病，仅针对一个靶点的药物只能部分满足该疾病的治疗需求。该提案的总体目标是开发多功能治疗剂，不仅可用于对症治疗，还可通过促进 DA 神经元的存活来用作疾病缓解剂。多巴胺 D3 优先激动剂除了可以缓解 PD 症状并减少运动并发症外，还被证明可以作为神经保护剂。来自我们的新型混合模板的 D3 偏好化合物 D-264 在两项不同的动物模型研究中被证明具有神经保护作用。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，可能是其神经保护特性的原因。在另一项初步开发中，开发出了具有螯合铁能力的独特多功能多巴胺 D2/D3 激动剂化合物。这些分子不仅有望缓解帕金森病的运动功能障碍，而且有可能通过与铁螯合来减少帕金森病大脑中的氧化应激，而铁与该疾病的发病机制有关。初步研究表明这些化合物具有轻松穿过血脑屏障的能力，并且在细胞培养和体内 MPTP 小鼠模型实验中，其中一种先导分子表明具有神经保护特性。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，从而提高生物利用度，并对多价铁结合 D2/D3 激动剂进行扩大的结构活性关系研究。从这两个系列化合物中选出的分子将在帕金森病动物模型中进行评估，以确定特异性和功效。这些研究的有希望的线索接下来将在神经保护研究中进行评估，其中包括急性神经毒物 MPTP 和慢性阿霉素诱导的多巴胺能谷胱甘肽耗竭转基因小鼠模型。