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 以严重和使人衰弱的疲劳为特征的疾病，目前尚无有效的诊断方法 测试或接受的治疗。本提案的重点是探索一种自然发生的、广泛存在的 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）-作为一个非常有前途的治疗ME/CFS。推动这一 探索性临床试验是申请人最近令人信服的初步发现， 每天补充1800 mg NAC（a）数周可显著缓解患者体内脑GSH不足 用质子磁共振波谱（1H MRS）直接测量的ME/CFS（B）改善 ME/CFS症状和（c）降低ME/CFS患者中氧化应激的血浆标志物水平 而在健康对照组中没有引起变化。这些新发现的意义在于，它们代表了 迄今为止最清楚和最直接的证据表明，NAC有能力刺激原位合成和恢复， 脑GSH水平，GSH通过“反馈抑制”机制调节自身的合成 由此根据组织GSH水平是低还是正常来开启或关闭GSH合成， 分别本提案的主要目的是通过双盲， 安慰剂对照，随机临床试验，在原位GSH合成控制的机制， 仅对1H MRS显示具有以下特征的ME/CFS患者给予不同剂量的NAC或安慰剂： 基线时皮质GSH明显不足。我们假设，这种对GSH缺乏的狭义要求， 基线将代表队列选择的细化，该细化将确定最有可能 显示皮质GSH对NAC治疗的反应升高，因为GSH合成不会反馈- 压抑我们期望，如果这项拟议的研究顺利完成， 了解NAC在体内皮质GSH合成中的作用机制，证实了氧化 应激作为饮食NAC可行的治疗靶点，并建立皮质1H MRS测量的变化 GSH和氧化应激的血浆标志物作为治疗靶点参与和治疗靶点参与的生物标志物。 治疗反应，重要的是，提示最佳实验条件（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，或 氧化还原不平衡的其他条件已被假定。

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.