Angiotensin and Neurodegeneration

血管紧张素和神经变性

• 批准号: 7586312
• 负责人: Patricia K Sonsalla
• 金额: $ 20.48万
• 依托单位: UNIV OF MED/DENT NJ-R W JOHNSON MED SCH
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-09-01 至 2010-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7586312
• 关键词: 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; 1-Methyl-4-phenylpyridinium; Acute; Angiotensin II; Angiotensin-Converting Enzyme Inhibitors; Angiotensins; Animal Model; Animals; Anti-Inflammatory Agents; Anti-inflammatory; Attenuated; Brain; Brain region; CCL2 gene; Captopril; Cardiovascular Diseases; Cell Count; Cell Death; Cerebral Ventricles; Cerebrospinal Fluid; Cerebrum; Characteristics; Chronic; Clinical; Clinical Management; Clinical Research; Condition; Corpus striatum structure; Disease; Disease Progression; Disease model; Dopamine; Enzyme Gene; Enzyme Inhibition; Enzymes; Etiology; Exhibits; Experimental Models; Genetic Variation; Goals; Human; ITGAM gene; Inclusion Bodies; Infusion procedures; Interleukin-10; Interleukin-6; Knowledge; Measurement; Microglia; Modeling; Motion; Nerve Degeneration; Neurodegenerative Disorders; Neuroglia; Neurons; Neuroprotective Agents; Neurotoxins; Oxidative Stress; Parkinson Disease; Pathogenesis; Patients; Peptidyl-Dipeptidase A; Personal Satisfaction; Pharmaceutical Preparations; Pharmacotherapy; Play; Polymerase Chain Reaction; Prevention therapy; Process; Public Health; Rattus; Reactive Oxygen Species; Renin-Angiotensin System; Reporting; Research Project Grants; Role; Solid; Staining method; Stains; Symptoms; Testing; Thinking; Time; Tissue Stains; Toxic effect; Tyrosine 3-Monooxygenase; United States Food and Drug Administration; Week; base; chemokine; cytokine; disorder prevention; dopaminergic neuron; enzyme activity; hypertension treatment; mRNA Expression; nervous system disorder; neurochemistry; neuron loss; neuroprotection; preclinical study; prevent; progressive neurodegeneration; receptor; research study; response; toxicant

DESCRIPTION (provided by applicant): Parkinson's disease (PD), a progressive neurodegenerative disorder characterized by a profound loss of nigrostriatal dopamine (DA) neurons and microglial activation, is of unknown etiology. There is at present no effective treatment available for preventing or slowing the progressive loss of the DA neurons. The discovery of pharmacological agents or other strategies that could retard neurodegeneration in PD requires the use of an animal model in which a progressive loss of neurons occurs. We recently developed a progressive PD model using chronic continuous delivery of MPP+ into the cerebral ventricle of the rat. The animals exhibit loss of striatal DA and tyrosine hydroxylase (TH), nigral DA cell death, microgliosis and striatal inclusion bodies. We will use this model to investigate if pharmacological manipulation of the brain renin angiotensin system provides protection against DA neurodegeneration and microglial activation. Inhibition of the brain angiotensin converting enzyme (ACE), the activity of which is elevated in the cerebrospinal fluid of PD patients, is documented to reduce nigrostriatal damage induced by 1-methyl-4-phenyl-1,2,3,6- tetrahydropyridine (MPTP). While the mechanism of this neuroprotection by captopril remains to be determined, it is thought to be related to the suppression of microglial activation and formation of reactive oxygen species that occurs with neurodegeneration. In PD, microglial activation likely occurs for years prior to symptom onset. It is not known if drugs which prevent microglial activation can reverse the process once it is set in motion. We will test the hypothesis that the ACE inhibitor, captopril, which is widely used in the US for the treatment of hypertension, impairs or reverses microglial activation and protects DA neurons from MPP+-induced toxicity. The aims of the studies are: 1) to determine the temporal characteristics of neurodegeneration and microgliosis in the chronic MPP+ rat model of PD; 2) to determine if continuous captopril treatment will protect against MPP+-induced neurodegeneration of DA neurons in the chronic PD model and reduce the accompanying neuroinflammatory process; and 3) determine if initiation of captopril therapy after the onset of microglial activation will reverse the activation state and retard the progression of MPP+-induced neuronal damage. The discovery of a drug which can stop the progression of neurodegeneration and possibly reverse microglial activation would be a momentous finding and a much needed first step for PD prevention therapy. The ACE inhibitor captopril is an FDA approved drug that is widely used to treat cardiovascular disorders and if shown to be beneficial in retarding progression of neurodegeneration in experimental PD models would provide a solid basis for pursuing clinical studies in PD patients. PUBLIC HEALTH RELEVANCE: Currently there is no effective therapy for preventing or slowing the progressive degeneration of the nigrostriatal dopaminergic neurons that are lost in Parkinson's disease. Captopril, widely used in the U.S. for the treatment of hypertension, markedly attenuates damage to DA neurons in an acute animal model of PD model. If captopril is also shown to be effective in slowing neurodegeneration in a progressive PD model, this would be a significant and much needed first step towards prevention therapy for PD. Because captopril is an FDA approved drug, it would not require years of testing before being used in the clinical management of PD and related disorders.

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（DA）神经元的严重缺失和小胶质细胞活化，病因不明。目前没有有效的治疗方法可用于预防或减缓DA神经元的进行性损失。发现可以延缓PD神经变性的药理学试剂或其他策略需要使用其中发生神经元进行性损失的动物模型。我们最近开发了一个渐进的PD模型，使用慢性连续输送MPP+到大鼠的脑室。动物表现出纹状体DA和酪氨酸羟化酶（TH）的损失，黑质DA细胞死亡，小胶质细胞增生和纹状体包涵体。我们将使用这个模型来调查，如果药理学操作的大脑肾素血管紧张素系统提供保护，对DA神经变性和小胶质细胞激活。脑血管紧张素转换酶（ACE）的抑制，其活性在PD患者的脑脊液中升高，被证明可以减少1-甲基-4-苯基-1，2，3，6-四氢吡啶（MPTP）诱导的黑质纹状体损伤。虽然卡托普利的神经保护机制仍有待确定，但认为其与抑制小胶质细胞活化和神经退行性病变中活性氧的形成有关。在PD中，小胶质细胞活化可能在症状发作前数年发生。目前尚不清楚阻止小胶质细胞激活的药物是否可以逆转这一过程。我们将测试的假设，即ACE抑制剂，卡托普利，这是广泛用于在美国治疗高血压，损害或逆转小胶质细胞活化和保护DA神经元MPP+诱导的毒性。本研究的目的是：1）确定慢性MPP+大鼠PD模型中神经变性和小胶质细胞增生的时间特征; 2）确定持续的卡托普利治疗是否会保护慢性PD模型中MPP+诱导的DA神经元的神经变性并减少伴随的神经炎症过程;和3）确定在小胶质细胞活化开始后开始卡托普利治疗是否会逆转活化状态并延缓MPP+诱导的神经元损伤的进展。发现一种可以阻止神经变性进展并可能逆转小胶质细胞活化的药物将是一个重大发现，也是PD预防治疗急需的第一步。ACE抑制剂卡托普利是FDA批准的药物，广泛用于治疗心血管疾病，如果在实验性PD模型中显示出对延缓神经变性进展有益，将为在PD患者中进行临床研究提供坚实的基础。 公共卫生相关性：目前还没有有效的治疗方法来预防或减缓帕金森病中丢失的黑质纹状体多巴胺能神经元的进行性变性。在美国广泛用于治疗高血压的卡托普利在PD模型的急性动物模型中显著减轻对DA神经元的损伤。如果在进行性PD模型中也显示出卡托普利在减缓神经变性方面有效，这将是PD预防治疗的重要且急需的第一步。由于卡托普利是FDA批准的药物，因此在用于PD和相关疾病的临床管理之前不需要多年的测试。