Novel Neuroprotective Treatment for Parkinson's Disease

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，其特征为黑质纹状体多巴胺能通路的变性。帕金森病的主要临床特征包括静止性震颤、僵硬、开始运动困难和姿势不稳定。目前，没有理想的疗法可用于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。虽然PD的发病机制知之甚少，氧化应激和线粒体功能障碍导致的谷胱甘肽浓度增加的游离铁的损失已强烈牵连多巴胺细胞死亡。越来越明显的是，对于PD等复杂疾病，仅靶向一个靶点的药物只能部分满足疾病的治疗需求。本提案的总体目标是开发多功能治疗剂，其不仅可用于对症治疗，而且可通过促进DA神经元的存活而用作疾病修饰剂。多巴胺D3优选激动剂除了在PD中提供症状缓解和较少的运动并发症之外，还显示出作为神经保护剂。在两种不同的动物模型研究中，来自我们的新型杂交模板的D3偏好化合物D-264显示出神经保护作用。我们的研究表明，D-264与D3受体的相互作用沿着其其他特性，如抗氧化剂，可能是其神经保护特性的原因。在另一个初步开发中，已经开发了具有螯合铁能力的独特的多功能多巴胺D2/D3激动剂化合物。这些分子不仅有望缓解PD中的运动功能障碍，而且还具有通过与铁螯合来降低PD脑中的氧化应激的潜力，铁与疾病的发病机制有关。初步研究表明，这些化合物的血脑屏障穿越能力，并在细胞培养和体内MPTP小鼠模型实验的铅分子之一，表明神经保护性能。我们现在建议扩展基于混合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，并对多价铁结合D2/D3激动剂进行扩展的构效关系研究。将在PD动物模型中评价来自这两个系列化合物的选定分子，以确定特异性和功效。这些研究中有前途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dox诱导的多巴胺能谷胱甘肽耗竭转基因小鼠模型。 公共卫生相关性：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变性。据估计，PD影响大约1- 2%的65岁以上的人。PD的主要治疗剂是L-DOPA，其通过在多巴胺耗尽的神经元中产生多巴胺来改善疾病的症状。然而，长期使用L-多巴引起运动波动和运动障碍，并减少对给定L-多巴剂量的反应持续时间。长期使用左旋多巴也会引起“开”和“关”发作，并可能导致DA神经元毒性，从而加速DA神经变性过程。越来越明显的是，对于PD等复杂疾病，仅靶向一个靶点的药物只能部分满足疾病的治疗需求。本提案的总体目标是开发多功能治疗剂，其不仅可用于对症治疗，而且可通过促进DA神经元存活用作疾病修饰剂。

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. PUBLIC HEALTH RELEVANCE: Parkinson's Disease (PD) is a progressive neurodegenerative disorder characterized by degeneration of the nigrostriatal dopaminergic pathway. It is estimated that PD affects approximately 1-2 % of people older than 65 years of age. The primary therapeutic agent for PD is L-DOPA which improves the symptoms of the disease by producing dopamine in dopamine depleted neurons. However, long term use of L-dopa gives rise to motor fluctuations with dyskinesias and a decrease in duration of response to a given L-dopa dose. Prolonged use of L-dopa also gives rise to "on" and "off" episodes and may lead to toxicity to DA neurons and hence, accelerating the DA neurodegeneration process. 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 DA neuron survival.