Angiotensin and Neurodegeneration

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，其特征是黑质纹状体多巴胺（DA）神经元和小胶质细胞激活的严重丧失，病因不明。目前还没有有效的治疗方法来预防或减缓DA神经元的进行性损失。发现可以延缓帕金森病神经退行性变的药物或其他策略需要使用神经元进行性丧失的动物模型。我们最近开发了一种进行性PD模型，使用MPP+慢性连续输送到大鼠脑室。动物表现为纹状体DA和酪氨酸羟化酶（TH）的缺失，黑质DA细胞死亡，小胶质细胞增生和纹状体包涵体。我们将使用该模型来研究脑肾素血管紧张素系统的药理学操作是否提供对DA神经变性和小胶质细胞激活的保护。PD患者脑脊液中脑血管紧张素转换酶（ACE）活性升高，抑制ACE可减少1-甲基-4-苯基-1,2,3,6-四氢吡啶（MPTP）引起的黑质纹状体损伤。虽然卡托普利的神经保护机制仍有待确定，但它被认为与神经退行性变时发生的小胶质细胞活化和活性氧形成的抑制有关。在帕金森病中，小胶质细胞激活可能在症状出现前数年就发生了。目前尚不清楚阻止小胶质细胞激活的药物是否能在启动后逆转这一过程。我们将检验ACE抑制剂卡托普利的假设，卡托普利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。本研究的目的是：1)确定慢性MPP+大鼠PD模型的神经变性和小胶质细胞增生的时间特征；2)确定持续卡托普利治疗是否对慢性PD模型中MPP+诱导的DA神经元退行性变有保护作用，并减轻伴随的神经炎症过程；3)确定在小胶质细胞激活开始后开始卡托普利治疗是否会逆转激活状态并延缓MPP+诱导的神经元损伤的进展。发现一种可以阻止神经退行性疾病进展并可能逆转小胶质细胞激活的药物将是一个重大发现，也是PD预防治疗非常需要的第一步。ACE抑制剂卡托普利是FDA批准的一种广泛用于治疗心血管疾病的药物，如果在实验性PD模型中被证明有利于延缓神经退行性变的进展，将为PD患者的临床研究提供坚实的基础。

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.