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

描述(申请人提供)：每年约有120万帕金森氏症患者被诊断为帕金森氏病。今后帕金森病的发生可能只会增加，增加无数家庭的个人痛苦，并增加家庭和国家的保健费用。帕金森病的病因尚不清楚。中脑多巴胺能神经元进行性变性是人类帕金森病的主要病理改变。引起进行性黑质变性的因素尚不清楚。实验证据表明，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着重要作用。线粒体的损伤将导致能量合成减少，钙稳态改变，氧化应激增加，这些因素将通过线粒体介导的级联凋亡来触发细胞死亡。导致人类帕金森病患者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)导致线粒体电子转移链复合体I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帕金森病。来自许多PD相关基因的蛋白质定位于线粒体的基质、内膜和外膜中，有助于线粒体结构和功能的完整性。一些突变会导致蛋白质(α-突触核蛋白)的积累，导致细胞死亡。其他基因的突变可能会导致神经元和线粒体保护的丧失，并降低线粒体的生物发生(例如。Parkin)定位于膜和基质的蛋白质基因突变会导致线粒体结构和功能完整性的丧失，并导致细胞死亡。Net-PD联盟的长期目标是确定哪些药物是线粒体保护剂。LS1是一个多中心。阶段3，检验假设的双盲临床试验 每天服用肌酸(10克/天)在减缓临床症状方面比安慰剂更有效。 在多巴胺能治疗和最佳帕金森病护理的背景下，基线和5年随访期间帕金森病患者的帕金森病发生率下降。

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.