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Calpain inhibitors in models of Parkinson's disease

帕金森病模型中的钙蛋白酶抑制剂

基本信息

批准号：
7266985
负责人：
MICHEL BAUDRY
金额：
$ 28.59万
依托单位：
UNIVERSITY OF SOUTHERN CALIFORNIA
依托单位国家：
美国
项目类别：
财政年份：
2004
资助国家：
美国
起止时间：
2004-09-15 至 2009-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7266985
关键词：
1-Methyl-4-phenylpyridinium Accounting Affect Age Amyotrophic Lateral Sclerosis Animal Model Animals Apoptotic Behavioral Binding Biological Assay Brain Calcium Calpain Caspase Cell Death Cessation of life Condition Development Disease Dopamine Dose Endopeptidases Exposure to Goals Hippocampus (Brain)Human Impairment Indium Injection of therapeutic agent Lactate Dehydrogenase Lactate Dehydrogenases Lead Mazindol Mediating Midbrain structure Modeling Mus Nerve Degeneration Neurodegenerative Disorders Neurons Neurotoxins Parkinson Disease Pathogenesis Patients Pattern Peptide Hydrolases Play Process Propidium Diiodide Protocols documentation Quantitative Autoradiography Rattus Recovery Research Personnel Role Rotenone Series Slice Specificity Stream Structure-Activity Relationship Substantia nigra structure Testing Toxic Environmental Substances Toxic effect Toxin Tyrosine 3-Monooxygenase Western Blotting behavior test calpain inhibitor cytochrome c day dopaminergic neuron functional disability granule cell in vivo in vivo Model inhibitor/antagonist insight middle age neurotoxicity novel presynaptic prevent programs response subcutaneous uptake

项目摘要

DESCRIPTION (provided by applicant): Parkinson' s disease is a neurodegenerative disease that specifically affects dopaminergic neurons in the substantia nigra. Although several hypotheses have been proposed to account for the specificity of the neurodegenerative features of the disease, the exact cause of the disease remains to be elucidated. Significant advances in our understanding of the possible causes of the disease were provided by the serendipitous discovery that a neurotoxin, 1-methyl-4-phenyl-1,2,3,6- tetrahydropyridine (MPTP), elicits a pattern of neurodegenerative features in humans and experimental animals identical to that seen in patients with Parkinson' s disease. A potential target to prevent neurodegeneration in Parkinson' s disease is the calcium-dependent protease calpain. Calpain levels are elevated in post-mortem substantia nigra of patients with Parkinson' s disease, MPP+ neurotoxicity in granule cell cultures is associated with calpain activation and blocked by calpain inhibitors, and calpain has been implicated in several neurodegenerative diseases. We have recently obtained a series of novel and potent calpain inhibitors and have demonstrated their potency in preventing NMDA-induced calpain activation in cultured hippocampal slices. The current proposal is aimed at testing the hypothesis that calpain activation plays a critical role in animal models of PD and that calpain inhibitors are neuroprotective in these models. We will first determine the potency and efficacy of calpain inhibitors to prevent MPTP toxicity in cultured slices from rat mesencephalon. We will then use structure activity relationship in conjunction with additional assays to identify the best inhibitors to be tested in in vivo models. Finally, we will test the hypothesis that calpain is activated and that calpain inhibitors are neuroprotective against MPTP-mediated neurotoxicity and behavioral impairments in vivo in C57BI/6 mice, and against rotenone-mediated neurotoxicity in rats. Conversion of the pro-apoptotic factor Bid to its active, truncated form tBid will be tested as part of the mechanisms by which calpain activation induces cell death. These studies will test the hypothesis that calpain inhibitors might prevent neurodegeneration not only in Parkinson' s disease but also in a variety of conditions resulting from exposure to environmental toxins. Finally, because calpain has also been implicated in the mechanisms underlying Amyotrophic Lateral Sclerosis (ALS), our proposal could lead to significant advances in the treatment of this neurodegenerative disease as well.

描述(申请人提供)：帕金森S病是一种神经退行性疾病，专门影响黑质中的多巴胺能神经元。虽然已经提出了几种假说来解释该病神经退行性特征的特殊性，但该病的确切原因仍有待阐明。一项偶然发现，一种名为1-甲基-4-苯基-1，2，3，6-四氢吡啶(MPTP)的神经毒素在人类和实验动物中引起了与帕金森S病患者相同的神经变性特征，这为我们对帕金森病可能病因的理解提供了重大进展。预防帕金森S病神经退行性变的一个潜在靶点是钙依赖的蛋白水解酶Calain。帕金森S病患者死后黑质中钙蛋白水平升高，颗粒细胞培养中MPP+神经毒性与钙蛋白酶激活有关，并被钙蛋白酶抑制剂阻断，钙蛋白酶与多种神经退行性疾病有关。我们最近获得了一系列新的和有效的钙蛋白酶抑制剂，并证明了它们在阻止NMDA诱导的培养海马片钙蛋白酶激活方面的有效性。目前的提议旨在验证这样的假设，即钙蛋白酶激活在帕金森病动物模型中发挥关键作用，以及钙蛋白酶抑制剂在这些模型中具有神经保护作用。我们将首先确定钙蛋白酶抑制剂预防大鼠中脑培养脑片MPTP毒性的效力和有效性。然后，我们将使用结构活性关系结合其他分析来确定要在体内模型中测试的最佳抑制剂。最后，我们将在C57BI/6小鼠体内验证Calain被激活以及Calain抑制剂对MPTP介导的神经毒性和行为损伤具有神经保护作用以及在大鼠中对抗鱼藤酮介导的神经毒性的假设。促凋亡因子BID到其活性的、截短形式的TbID的转换将作为Calain激活诱导细胞死亡机制的一部分进行测试。这些研究将检验这样一种假设，即钙蛋白酶抑制剂不仅可以防止帕金森氏症S病患者的神经退化，而且还可以在暴露于环境毒素的各种情况下防止神经退化。最后，由于Calain也与肌萎缩侧索硬化症(ALS)的发病机制有关，我们的建议也可能导致这种神经退行性疾病的治疗取得重大进展。