N-Acetylcysteine for Neuroprotection in Parkinson's Disease

描述(申请人提供)：帕金森病(PD)是一种神经退行性疾病，在这种疾病中，主要细胞内抗氧化剂谷胱甘肽(GSH)的缺乏被认为是介导氧化应激增加和线粒体功能障碍的致病级联反应，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GSH水平的治疗策略非常感兴趣。然而，谷胱甘肽不容易通过血脑屏障或包括神经元在内的大多数细胞的膜，因此直接补充抗氧化剂在增加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在GSH合成途径中是限速的，它确实跨越了血脑屏障和大多数细胞膜，因此这种氨基酸及其无毒的衍生物，如N-乙酰半胱氨酸(NAC)，正在被研究为潜在的前体，可以通过饮食手段提供，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波谱(1HMRS)来确定(A)与死后大脑中发现的匹配对照组相比，体内帕金森氏病(PD)患者大脑中的GSH水平是否降低；(B)与基线和安慰剂相比，每天补充2000 mg或4000 mg NAC 30天后，PD大脑中的GSH水平是否显著上升；以及(C)大脑GSH水平的任何这种增加是否会呈剂量依赖关系，并与参与者的氧化应激特征的变化有关。此外，还将进行一组临床评估，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联系。如果成功，这项研究将是第一个客观的文献，证明在活体PD脑中是否存在GSH缺陷，饮食中补充NAC可以缓解这种缺陷，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。 与公共卫生相关：本研究的总体目标是使用非侵入性质子磁共振波谱(1HMRS)来确定(A)与死后大脑中发现的匹配对照组相比，体内抗氧化剂谷胱甘肽(GSH)的水平是否降低；(B)与安慰剂和基线相比，每天补充2000 mg或4000 mg的N-乙酰半胱氨酸(NAC)30天后，PD脑中的GSH水平是否显著升高；以及(C)脑中GSH的任何这种增加是否会呈剂量依赖关系，并与参与者的氧化应激特征的变化有关。此外，还将进行一组临床评估，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联系。如果成功，这项研究将是第一个客观的文献，证明在活体PD脑中是否存在GSH缺陷，饮食中补充NAC可以缓解这种缺陷，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.