Serotonin Therapy for Parkinson's Disease and Neurodegenerative Disorders

血清素疗法治疗帕金森病和神经退行性疾病

• 批准号: 8597339
• 负责人: WILLIAM A. WOLF
• 金额: --
• 依托单位: EDWARD HINES JR VA HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-10-01 至 2014-09-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8597339
• 关键词: Adverse effects; Affect; Age; Agonist; Alzheimer' s Disease; Amyotrophic Lateral Sclerosis; Animal Model; Animals; Award; Basal Ganglia; Biochemical; Brain; Cell Death; Cells; Chronic; Clinical Data; Data; Development; Disease; Dopamine; Elderly; Epidemiology; Etiology; Funding; Genetic; Glutamates; Goals; Healthcare Systems; Immunohistochemistry; Investigation; Label; Lead; Legal patent; Lewy Bodies; Measures; Mediating; Medical center; Microinjections; Modeling; Modification; Motor; Nerve Degeneration; Neurodegenerative Disorders; Neuronal Dysfunction; Neurons; Neuroprotective Agents; Neurotransmitters; Nitric Oxide; Nitric Oxide Synthase; Nitric Oxide Synthase Type I; Nitrosation; Oxidopamine; Parkinson Disease; Parkinsonian Disorders; Pathogenesis; Pathway interactions; Patients; Peroxonitrite; Pharmaceutical Preparations; Phenotype; Play; Population; Positioning Attribute; Pre-Clinical Model; Prevalence; Primates; Process; Production; Property; Proteins; Publishing; Quality of life; Rattus; Recombinants; Relative Risks; Research; Rodent Model; Role; Serotonin; Serotonin Receptor 5-HT1A; Substantia nigra structure; Surveys; Testing; Toxin; Translating; Up-Regulation; Veterans; Work; adeno-associated viral vector; alpha synuclein; alpha synuclein gene; base; brain tissue; burden of illness; cost; design; dopaminergic neuron; extracellular; improved; in vivo; in vivo Model; indexing; inhibitor/antagonist; neurochemistry; neuroprotection; novel; oxidation; pars compacta; pre-clinical; programs; public health relevance; success; time interval; treatment strategy

DESCRIPTION (provided by applicant): Parkinson's Disease (PD) is a slowly progressive neurodegenerative disease involving the loss of dopamine (DA) neurons in the brain. The prevalence rate of PD is estimated at 0.3% of the population, making it the second most common neurodegenerative disorder following Alzheimer's disease. VA medical centers annually treat 20,000 - 40,000 patients per year at high cost and numbers are predicted to climb as the population ages. In contrast to the modest advances made in symptomatic treatment for PD there is presently no treatment proven to slow or halt the progressive degeneration of DA neurons. In recognition of this need the VA has issued an RFA entitled "BLR&D Merit Review Award for Research on Amyotrophic Lateral Sclerosis, Parkinson's Disease and Alzheimer's Disease" to study the etiology and pathogenesis of these diseases. Our primary objective in this competing renewal is to identify promising pharmacotherapeutic approaches that can rapidly translate into neuroprotection in PD by building upon our previous success in developing a novel symptomatic treatment for PD. In the previous funding cycle we demonstrated that a serotonin 5-HT1A receptor agonist reduced glutamatergic activity in the basal ganglia. Pre-clinical evidence supports a role for glutamate in exacerbating DA neuron degeneration. It is unclear how glutamate contributes to the development of PD, but one possibility is through nitric oxide production. Another prominent factor in the pathogenesis of PD is the protein, alpha synuclein (ASyn), but again its precise involvement is unclear. We propose that DA neuronal degeneration is caused by an interaction in which excessive glutamatergic or "excitotoxic" tone modifies ASyn properties and function through nitric oxide. We will test the hypothesis that reducing "excitotoxic" drive to DA neurons will be neuroprotective by reducing nitric oxide and we will demonstrate that administration of 5-HT1A agonists is one means of achieving this goal. To accomplish this, our lab has developed an in vivo rat model of slowly progressive (occurring over many weeks) DA neuronal degeneration involving targeted upregulation of ASyn. In this model, ASyn upregulation in the substantia nigra pars compacta (SNc) is caused by intranigral microinjection of a recombinant adeno-associated viral vector containing the ASyn gene. This model was initially developed several years ago, but it has not been widely used to study neuroprotective strategies. In Aim I, we will establish that 5-HT1A receptors within basal ganglia circuitry are situated to reduce excitatory drive to the SNc. To accomplish this we will carry out double label immunohistochemistry and retrograde tracing studies. In Aim II we will use our in vivo model to test the neuroprotective efficacy of treatment strategies, including 5-HT1A agonists, aimed at reducing glutamate-mediated activity and glutamate-related mechanisms in the SNc. Animals will be assessed for motor function throughout 18 weeks of observation. At varying time intervals, immunohistochemical and biochemical studies will measure indices of DA neuronal dysfunction, DA cell loss and biochemical modifications of ASyn across treatment groups. In Aim III we will use the in vivo model to demonstrate the importance of nitric oxide in mediating neurodegeneration. Specifically, we will determine how the approaches used in Aim II affect nitric oxide synthase activity and nitrosation of ASyn. For comparison, we will assess the neuroprotective and biochemical effects of two nitric oxide synthase inhibitors as well. These studies will fill a gap in our understanding of the interaction between ASyn and glutamate- related mechanisms that lead to DA neuronal degeneration. This information will also further our understanding of the mechanisms underlying the motor and potential neuroprotective actions of 5-HT1A drugs. Together, the results of these studies will guide us to developing rational strategies for slowing the progressive degeneration of DA neurons in patients suffering from Parkinson's Disease. PUBLIC HEALTH RELEVANCE: Parkinson's Disease (PD) is a slowly progressive neurodegenerative disease caused by degeneration of dopamine (DA) neurons in the brain. The prevalence rate of PD is estimated at 0.3% of the population or 1% of the population over age 65, making it the second most common neurodegenerative disorder following Alzheimer's disease. VA medical centers annually treat 20,000 - 40,000 patients per year at high cost, with numbers expected to climb as the population ages. A 2003 quality of life survey for veterans with PD in the VA health care system has demonstrated that the illness burden for these patients remains extremely high. There is a pressing need to develop neuroprotective strategies for slowing or halting the disease process as none curently exist. In this proposal we wil build upon our previous work to understand the mechanisms underlying DA neuronal degeneration and to identify and develop neuroprotective therapy for PD. Such therapy will improve the quality of life for PD patients.

描述（由申请人提供）： 帕金森氏病（PD）是一种缓慢进行性神经退行性疾病，涉及大脑中多巴胺（DA）神经元的丧失。 PD的患病率估计为占人群的0.3％，使其成为高阿尔茨海默氏病后第二常见的神经退行性疾病。 VA医疗中心每年每年以高成本治疗20,000至40,000名患者，预计随着人口年龄的增长，数量将攀升。与对PD的有症状治疗方面的适度进展相反，目前尚无治疗证明可以减慢或停止DA神经元的进行性变性。为了认识到这一需求，VA发布了RFA，标题为“ Blr＆d优异审查奖，授予肌萎缩性侧面硬化症，帕金森氏病和阿尔茨海默氏病的研究”，以研究这些疾病的病因和发病机理。我们在这种竞争更新中的主要目标是确定有希望的药物治疗方法，这些方法可以通过我们以前在开发新型PD症状治疗方面的成功来迅速转化为PD的神经保护作用。在上一个资金周期中，我们证明了5-羟色胺5-HT1A受体激动剂减少了基底神经节的谷氨酸能活性。临床前证据支持谷氨酸在加剧DA神经元变性中的作用。目前尚不清楚谷氨酸如何有助于PD的发展，但一种可能性是通过一氧化氮的产生。 PD发病机理的另一个突出因素是蛋白质α突触核蛋白（ASYN），但它的精确参与尚不清楚。我们建议DA神经元变性是由一种相互作用引起的，在这种相互作用中，过度的谷氨酸能或“兴奋性”音调通过一氧化氮修饰ASYN的性质和功能。我们将通过减少一氧化氮来检验以下假设：将“兴奋毒性”驱动到DA神经元将受到神经保护性的影响，我们将证明给药5-HT1A激动剂是实现这一目标的一种手段。为此，我们的实验室开发了一种涉及ASYN的靶向上调的DA神经元变性的缓慢进行的体内大鼠模型。在该模型中，底虫pars compacta（SNC）中的Asyn上调是由含有Asyn基因的重组腺相关病毒载体的in液内显微注射引起的。该模型最初是几年前开发的，但并未被广泛用于研究神经保护策略。在AIM I中，我们将确定基底神经节电路中的5-HT1A受体的位置以减少向SNC的兴奋性驱动。为此，我们将进行双重标签免疫组织化学和逆行跟踪研究。在AIM II中，我们将使用我们的体内模型来测试包括5-HT1A激动剂在内的治疗策略的神经保护功效，旨在减少SNC中谷氨酸介导的活性和与谷氨酸相关的机制。在观察18周的过程中，将评估动物的运动功能。在不同的时间间隔内，免疫组织化学和生化研究将测量治疗组的DA神经元功能障碍，DA细胞损失和生化修饰的指标。在AIM III中，我们将使用体内模型来证明一氧化氮在介导神经变性中的重要性。具体而言，我们将确定AIM II中使用的方法如何影响一氧化氮合酶活性和ASYN的硝化作用。为了进行比较，我们还将评估两种一氧化氮合酶抑制剂的神经保护作用和生化作用。这些研究将填补我们对导致DA神经元变性的ASYN和与谷氨酸与谷氨酸与谷氨酸相关机制之间相互作用的理解的空白。这些信息还将进一步了解5-HT1A药物的运动和潜在神经保护作用的机制。总之，这些研究的结果将指导我们制定理性策略，以减慢患有帕金森氏病的患者的DA神经元的进行性变性。 公共卫生相关性： 帕金森氏病（PD）是由大脑中多巴胺（DA）神经元变性引起的一种缓慢进行性神经退行性疾病。 PD的患病率估计为65岁以上人口的0.3％或1％的人口，使其成为阿尔茨海默氏病后第二个最常见的神经退行性疾病。 VA医疗中心每年每年以高成本治疗20,000至40,000名患者，预计人口年龄将攀升。在VA医疗保健系统中对PD退伍军人的2003年生活质量调查表明，这些患者的疾病负担仍然很高。由于不存在，因此需要制定神经保护策略来减缓或停止疾病过程。在这项建议中，我们将基于我们以前的工作，以了解神经元变性的机制，并识别和开发PD神经保护疗法。这种疗法将改善PD患者的生活质量。