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）的缺乏被认为介导致病级联中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损失，这是该疾病的标志。因此，目前对可以维持、恢复和/或提高细胞内GSH水平的治疗策略有很大兴趣。然而，GSH不容易穿过血脑屏障或大多数细胞（包括神经元）的膜，因此直接膳食补充抗氧化剂在增加其细胞内浓度方面并不可行。另一方面，由于半胱氨酸的生物利用度（其确实穿过血脑屏障和大多数细胞膜）在GSH合成途径中是限速的，因此正在研究这种氨基酸及其无毒衍生物（如N-乙酰半胱氨酸（NAC））作为潜在的前体，其可以通过饮食方式提供以刺激脑GSH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非侵入性质子磁共振光谱（1H MRS）来确定（a）与匹配的对照组相比，30名帕金森病（PD）患者的大脑中体内GSH水平是否降低，正如在死后大脑中发现的那样;（B）与基线和安慰剂相比，在每天补充2000 mg或4000 mg NAC 30天后，PD脑中的GSH水平是否显著增加，以及（c）脑GSH的任何此类增加是否具有剂量依赖性，并与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，以研究NAC干预、脑GSH水平、氧化应激标志物和临床表现之间的潜在相关性。如果成功，这项研究将代表第一个客观的文件，是否有一个GSH赤字在生活PD脑，饮食NAC补充可以减轻，从而提供了一个令人信服的理由，调查这种神经保护策略在较大的对照临床试验。

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.