Angiotensin and Neurodegeneration

血管紧张素和神经变性

基本信息

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
项目类别：
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

项目摘要

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）：帕金森氏病（PD），一种进行性神经退行性疾病，其特征是骨纹状体多巴胺（DA）神经元和小胶质细胞激活，是未知的病因。目前尚无有效的治疗方法来预防或减慢DA神经元的进行性丧失。在PD中发现药理学剂或其他可能阻碍神经退行性的策略的发现需要使用动物模型，在这种模型中会发生神经元的逐渐丧失。我们最近使用将MPP+慢性连续递送到大鼠的脑室中开发了一种进行性PD模型。这些动物表现出纹状体DA和酪氨酸羟化酶（TH），nigral DA细胞死亡，小胶质细胞增多和纹状体包容体的丧失。我们将使用该模型研究脑肾素血管紧张素系统的药理操作是否提供了针对DA神经变性和小胶质细胞激活的保护。抑制脑血管紧张素转化酶（ACE），其活性在PD患者的脑脊髓液中升高，以减少1-甲基-4-苯基-1,2,3,6-四氢吡啶的1-甲基-4-苯基-4-苯基-4-苯基-4-苯基1,2,6- （MPTP）。虽然卡托普利（Captopril）这种神经保护的机制仍有待确定，但它被认为与抑制小胶质细胞激活和与神经变性发生的活性氧的形成有关。在PD中，小胶质细胞激活可能在症状发作之前多年发生。尚不清楚防止小胶质激活的药物一旦开始运动，是否会扭转该过程。我们将检验以下假设：ACE抑制剂Captopril在美国广泛用于治疗高血压，损害或逆转小胶质细胞激活并保护DA神经元免受MPP+诱导的毒性。研究的目的是：1）确定PD慢性MPP+大鼠模型中神经变性和小胶质细胞增多的时间特征； 2）确定连续的卡托普利处理是否会预防慢性PD模型中DA神经元的MPP诱导的神经变性，并减少随附的神经炎症过程； 3）确定小胶质细胞激活发作后卡托普利治疗的开始是否会扭转激活状态并阻止MPP+诱导的神经元损伤的进展。发现可以阻止神经退行性发展和可能反向小胶质细胞激活的药物的发现将是一个重大发现，并且是预防PD治疗的急需的第一步。 ACE抑制剂卡托普利是一种经FDA认可的药物，广泛用于治疗心血管疾病，如果证明在实验性PD模型中对延迟神经退行性的进展有益，将为PD患者寻求临床研究提供良好的基础。公共卫生相关性：目前尚无有效的疗法来预防或减缓帕金森氏病丢失的黑质性多巴胺能神经元的进行性变性。卡托普利（Capteropril）在美国广泛用于治疗高血压的情况下，在PD模型的急性动物模型中显着减轻了对DA神经元的损害。如果Capteropril也被证明可以有效地减慢进行性PD模型的神经退行性，这将是PD预防治疗的重要第一步。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。