NET-PD LS-1 Nicotine and Neuroprotection in Parkinson's Disease

NET-PD LS-1 尼古丁和帕金森病的神经保护

• 批准号: 8460309
• 负责人: Frank Oser
• 金额: $ 4.82万
• 依托单位: OCHSNER CLINIC FOUNDATION
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-09-30 至 2015-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8460309
• 关键词: Activities of Daily Living; Adult; Affect; Animal Model; Antidiabetic Drugs; Antioxidants; Apoptosis; Biogenesis; Calcium; Caring; Cell Death; Cellular Phone; Chronic; Clinical; Clinical Trials; Communities; Complex; Creatine; Diagnosis; Digit structure; Disease; Distress; Dose; Double-Blind Method; Electron Transport; England; Enrollment; Etiology; European Union; Family; Free Radicals; Funding; Futility; Future; Gene Proteins; Genes; Goals; Health; Health Care Costs; Health Services; Homeostasis; Human; Individual; Inherited; Lead; Levodopa; Maintenance; Measures; Mediating; Membrane; Mental Depression; Midbrain structure; Mitochondria; Modality; Molecular Abnormality; Mutation; National Institute of Neurological Disorders and Stroke; Nerve Degeneration; Neurodegenerative Disorders; Neurons; Neurosciences; Neurotoxins; Nicotine; North America; Outcome Measure; Outcome Study; Oxidative Stress; Parkinson Disease; Participant; Patient Participation; Patients; Phase; Phase III Clinical Trials; Pioglitazone; Placebos; Play; Proteins; Quality of life; Recruitment Activity; Role; Rotenone; Safety; Seminal; Stress; Testing; Therapeutic Equivalency; Travel; Visit; alpha synuclein; apoptosis inducing factor; cognitive function; disability; dopaminergic neuron; follow-up; improved; mitochondrial dysfunction; neuroprotection; operation; parkin gene/protein; primary outcome; theories; treatment strategy

DESCRIPTION (provided by applicant): About 1.2 million patients suffer from Parkinson's Disease (PD) and > 100,000 patients are diagnosed with PD every year. The occurrence of PD may only increase in the future adding to the personal suffering of numerous families as well as an increase in the health care cost for the family and the nation. The etiology of PD is not known. Progressive degeneration of the midbrain dopaminergic neurons is the main pathological finding in human PD. Factors that cause of progressive nigral degeneration are not known. Experimental evidence suggests that mitochondrial dysfunction may be the seminal factor inducing apoptosis of nigral neurons. Mitochondria play a major role in energy synthesis and calcium homeostasis. Damage to mitochondria will lead to decreased energy synthesis, altered calcium homeostasis, and increased oxidative stress and these factors will trigger cell death through mitochondrial-mediated cascades of apoptosis. The factors inducing mitochondrial distress in human PD are unknown. Exogenous (MPTP and rotenone) and endogenous neurotoxins (increased free radicals) induce severe damage to Complex I of the electron transfer chain of the mitochondria, contributing to mitochondrial stress and cell death. Mutations of several genes do cause inherited forms of PD. The proteins derived from many of the PD related genes are localized in the matrix, the inner and outer membranes of the mitochondria and contribute to the structural and functional integrity of mitochondria. Some mutations cause an accumulation of protein (alpha-synuclein) and result in cell death. Mutations of other genes may induce loss of neuro- and mitochondrial protection and decrease mitochondrial biogenesis, (e.g.. Parkin) Mutations of genes of proteins localized to membranes and matrix induce loss of mitochondrial structural and functional integrity and lead to cell death. The long-term objective of the NET-PD consortium is to identify agents that are mitochondrial protectants. LS1 is a multi-center. Phase 3, double-blind clinical trial that tests the hypothesis that daily administration of creatine (10gm/day) is more effective than placebo in slowing clinical decline in PD between baseline and the 5 year follow-up visit against the background of dopaminergic therapy and best PD care.

描述（由申请人提供）：大约120万患者患有帕金森病（PD），每年有> 10万患者被诊断患有PD。未来PD的发生率可能只会增加，增加许多家庭的个人痛苦以及家庭和国家的医疗保健费用的增加。 PD的病因尚不清楚。中脑多巴胺能神经元的进行性变性是人类PD的主要病理学发现。导致进行性黑质变性的因素尚不清楚。线粒体功能障碍可能是导致黑质神经元凋亡的重要因素。线粒体在能量合成和钙稳态中起主要作用。线粒体损伤将导致能量合成减少、钙稳态改变和氧化应激增加，这些因素将通过线粒体介导的凋亡级联触发细胞死亡。在人类PD中诱导线粒体窘迫的因素尚不清楚。外源性（MPTP和鱼藤酮）和内源性神经毒素（增加的自由基）诱导线粒体电子传递链复合体I的严重损伤，导致线粒体应激和细胞死亡。几个基因的突变确实会导致遗传性PD。来源于许多PD相关基因的蛋白质定位于线粒体的基质、内膜和外膜中，并有助于线粒体的结构和功能完整性。一些突变导致蛋白质（α-突触核蛋白）的积累并导致细胞死亡。其他基因的突变可能会导致神经和线粒体保护的丧失，并减少线粒体的生物合成，（例如。定位于膜和基质的蛋白质的基因突变诱导线粒体结构和功能完整性的丧失并导致细胞死亡。NET-PD联盟的长期目标是鉴定作为线粒体保护剂的药物。 LS 1是一个多中心。检验假设的III期、双盲临床试验 每天服用肌酸（10克/天）比安慰剂更有效地减缓临床 在多巴胺能治疗和最佳PD护理的背景下，基线和5年随访访视之间的PD下降。