Mechanistic Assessment of N-Acetylcysteine as an Antioxidant Therapy for Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) Through Dose Response and Treatment Target Engagement

摘要 肌痛性脑脊髓炎/慢性疲劳综合征(ME/CFS)是一种原因不明的多系统/多症状 以严重和衰弱的疲劳为特征的疾病，目前尚无有效的诊断方法 测试也不接受治疗。本提案的重点是探索一种自然发生的和广泛的 可用的膳食补充剂，N-乙酰半胱氨酸(NAC)-一种用于原位合成初级 细胞内抗氧化剂谷胱甘肽(GSH)--作为治疗ME/CFS的一种非常有前途的药物。驾驶这辆车 探索性临床试验是申请者最近令人信服的初步结果，显示4 每日补充1800毫克NAC(A)数周可显著减轻患者体内脑GSH缺陷 用质子磁共振波谱(1HMRS)直接测量ME/CFS(B)的改进 ME/CFS症状和(C)降低ME/CFS患者血浆氧化应激标志物水平 同时在健康对照组中没有引起任何变化。这些新奇发现的意义在于，它们代表了 迄今为止最明确和最直接的证据表明，NAC有能力刺激原位合成和修复 大脑GSH水平，GSH通过“反馈抑制”机制调节自身合成 由此根据组织GSH水平是低还是正常来开启或关闭GSH合成， 分别进行了分析。本提案的主要目的是通过双盲法进一步调查， 安慰剂对照，随机临床试验，原位控制谷胱甘肽合成的机制(S) 1H MRS显示ME/CFS患者只服用不同剂量的NAC或安慰剂 基线时皮质GSH明显缺乏。我们假设，GSH不足的这一狭隘要求是 基线将代表队列选择的改进，将识别最有可能 显示皮质GSH升高对NAC治疗的反应，因为GSH合成不会被反馈- 被禁止了。预期如果成功完成，拟议的研究将推进我们的 了解NaC在体内皮质GSH合成中的作用机制(S)，确认氧化 应激作为饮食NAC的可行治疗靶点，并建立皮质1HMRS测量的变化 GSH和血浆氧化应激标志物作为治疗靶点参与和 治疗反应，重要的是建议最佳的实验条件(队列选择标准，NAC 剂量)，适用于未来NAC治疗ME/CFS的全面疗效临床试验 假设氧化还原不平衡的其他条件。

ABSTRACT Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is an unexplained multisystem/multisymptom disorder characterized by severe and debilitating fatigue for which there are currently no validated diagnostic tests nor accepted therapies. The present proposal focuses on exploring a naturally occurring and widely available dietary supplement, N-acetylcysteine (NAC) – a prodrug for in situ synthesis of the primary intracellular antioxidant, glutathione (GSH) – as a highly promising treatment for ME/CFS. Driving this exploratory clinical trial are recent compelling preliminary findings by the applicants which showed that 4 weeks of daily supplements of 1800mg of NAC (a) alleviated a significant in vivo brain GSH deficit in patients with ME/CFS as measured directly with proton magnetic resonance spectroscopy (1H MRS) (b) ameliorated ME/CFS symptoms and (c) decreased the levels of plasma markers of oxidative stress in ME/CFS patients while eliciting no changes in healthy controls. The significance of these novel findings is that they represent the clearest and most direct evidence to date that NAC has the ability to spur in situ synthesis and restoration of brain GSH levels, and that GSH regulates its own synthesis through a "feedback inhibition" mechanism whereby GSH synthesis is turned on or off depending whether tissue GSH levels are low or normal, respectively. The main objective of the present proposal is to further investigate through a double-blind, placebo-controlled, randomized clinical trial, the mechanism(s) of in situ GSH synthesis control by administering different doses of NAC or placebo only to ME/CFS patients shown by 1H MRS to have a significant cortical GSH deficit at baseline. We postulate that this narrow requirement for a GSH deficit at baseline will represent a cohort selection refinement that would identify patients who would be most likely to show cortical GSH elevations in response to NAC treatment because GSH synthesis would not be feedback- inhibited. The expectation is that if successfully completed, the proposed study would advance our understanding of the mechanism(s) of action of NAC in in vivo cortical GSH synthesis, confirm oxidative stress as a viable treatment target for dietary NAC, and establish changes in 1H MRS measures of cortical GSH and in plasma markers of oxidative stress as biomarkers of treatment target engagement and of therapeutic response and, importantly, suggest optimal experimental conditions (cohort selection criteria, NAC dose) that would be suitable for use in future full-scale efficacy clinical trials of NAC for treatment of ME/CFS or other conditions in which redox imbalance has been postulated.