N-Acetylcysteine for Neuroprotection in Parkinson's Disease

描述（由申请人提供）：帕金森病（PD）是一种神经退行性疾病，其中主要细胞内抗氧化剂谷胱甘肽（GSH）的缺陷被认为在致病级联中介导氧化应激和线粒体功能障碍的增加，导致黑质纹状体多巴胺能神经元的丧失，这是该疾病的标志。因此，目前人们对维持、恢复和/或提高细胞内谷胱甘肽水平的治疗策略非常感兴趣。然而，谷胱甘肽不容易穿过血脑屏障或大多数细胞（包括神经元）的细胞膜，因此，直接从饮食中补充这种抗氧化剂并不能提高其细胞内浓度。另一方面，由于半胱氨酸的生物利用度，它可以穿过血脑屏障和大多数细胞膜，在谷胱甘肽合成途径中是限速的，这种氨基酸及其无毒衍生物，如n-乙酰半胱氨酸（NAC），正在被研究作为潜在的前体，可以通过饮食方式提供，刺激脑谷胱甘肽的原位合成和升高。这项探索性/发展性（R21）研究的总体目标是使用无创质子磁共振波谱（1H MRS）来确定(a) 30名帕金森病（PD）患者的大脑中GSH水平是否比匹配的对照组下降，正如在死后大脑中发现的那样；(b)与基线和安慰剂相比，每天补充2000mg或4000mg NAC 30天后，PD脑内GSH水平是否显著增加，以及(c)脑内GSH的任何这种增加是否与剂量依赖性和参与者氧化应激谱的变化有关。此外，将进行一系列临床评估，包括运动功能的定量测试，以调查NAC干预、脑GSH水平、氧化应激标志物和临床表现之间的潜在关联。如果成功，这项研究将首次客观地证明PD大脑中是否存在GSH缺陷，而膳食NAC补充剂可以减轻这种缺陷，从而为在更大规模的对照临床试验中研究这种神经保护策略提供了令人信服的理由。

DESCRIPTION (provided by applicant): Parkinson's disease (PD) is a neurodegenerative disorder in which deficits of the primary intracellular antioxidant, glutathione (GSH), are postulated to mediate increased oxidative stress and mitochondrial dysfunction in the pathogenic cascade leading up to the loss of nigrostriatal dopaminergic neurons that is the hallmark of the disorder. Therefore, there is currently great interest in treatment strategies that can maintain, restore and/or elevate intracellular GSH levels. However, GSH does not readily cross the blood-brain barrier or the membranes of most cells, including neurons, so that direct dietary supplementation of the antioxidant has not proved viable in increasing its intracellular concentration. On the other hand, since the bioavailability of cysteine, which does cross both the blood-brain barrier and most cell membranes, is rate-limiting in the GSH synthesis pathway, this amino acid and its non-toxic derivatives, such as N-acetylcysteine (NAC), are being investigated as potential precursors that can be supplied through dietary means to spur in situ synthesis and elevation of brain GSH. The overall objective of this Exploratory/Developmental (R21) study is to use noninvasive proton magnetic resonance spectroscopy (1H MRS) to determine (a) whether levels of GSH are decreased in vivo in the brain of 30 patients with Parkinson's disease (PD) compared to matched controls, as has been found in postmortem brain; (b) whether GSH levels in PD brain increase significantly following 30 days of daily supplementation with 2000mg or 4000mg of NAC compared to baseline and placebo, and (c) whether any such increases in brain GSH would be dose-dependent and be associated with a change in the participants' oxidative stress profiles. Additionally, a clinical assessment battery, including quantitative tests of motor function, will be performed to investigate potential associations between the NAC intervention, brain GSH levels, oxidative stress markers, and clinical presentation. If successful, this study will represent the first objective documentation of whether there is a GSH deficit in living PD brain that dietary NAC supplementation can mitigate, thereby providing a compelling justification for investigating such neuroprotective strategies in larger controlled clinical trials. PUBLIC HEALTH RELEVANCE: The overall objective of this study is to use noninvasive proton magnetic resonance spectroscopy (1H MRS) to determine (a) whether levels of the antioxidant glutathione (GSH) are decreased in vivo in the brain of 30 patients with Parkinson's disease (PD) compared to matched controls, as has been found in postmortem brain; (b) whether GSH levels in PD brain increase significantly following 30 days of daily supplementation with 2000mg or 4000mg of N- acetylcysteine (NAC) compared to placebo and baseline, and (c) whether any such increases in brain GSH would be dose-dependent and be associated with a change in the participants' oxidative stress profiles. Additionally, a clinical assessment battery, including quantitative tests of motor function, will be performed to investigate potential associations between the NAC intervention, brain GSH levels, oxidative stress markers, and clinical presentation. If successful, this study will represent the first objective documentation of whether there is a GSH deficit in living PD brain that dietary NAC supplementation can mitigate, thereby providing a compelling justification for investigating such neuroprotective strategies in larger controlled clinical trials.