Angiotensin and Neurodegeneration

点击翻译按钮获取中文摘要

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.