Theranostic Metabolic Imaging of Oxidative Stress in Multiple Sclerosis.

摘要 氧化应激在多发性硬化症(MS)中起着至关重要的作用。重要的是，氧化应激更为突出 原发和继发进展性多发性硬化症(PP/SPMS)比复发缓解(RRMS)形式更好，以及 针对氧化应激的替代治疗策略正在测试PP/SPMS。不幸的是，在那里 目前在体内测量氧化应激的方法有限。超极化~(13)C磁共振 光谱成像(HP 13C MRSI)是一种安全的检测注射后体内代谢反应的方法 惠普探头。HP[1-13C]-脱羟基抗坏血酸(DHA)已显示出潜在的体内氧化应激成像 在体内，但会引起一过性呼吸骤停和胰腺毒性，限制其翻译潜力。的确有 因此，需要一种新的成像策略来评估体内大脑中的氧化应激。 N-乙酰半胱氨酸(NAC)是天然氨基酸L-半胱氨酸的N-乙酰基衍生物，具有 几十年来一直被用作临床上的抗氧化剂。最近的一项研究报告称，在患有多发性硬化症的人中 NAC显著增加了大脑的葡萄糖代谢和认知功能，确认NAC是一种 潜在的治疗方法。根据所有这些研究结果，我们建议： 目的1：优化和验证HP[1，4-13C]NAC作为无创脑探头的可行性 临床场强下MS小鼠的氧化还原状态：[1，4-13C]NAC浓度和MRSI获取 将优化方案以检测[1，4-13C]NAC在MS小鼠脑内的代谢，以提供 最好的数据质量。体外氧化应激标志物与体内Hp Ac/Cys-to-Nac的相关性将是 从生物学上验证了我们的成像方法。完成这一目标将提供一个优化的工具 量化MS小鼠脑内的体内氧化还原状态。 目的2.应用氧化应激的声学代谢成像来监测治疗的反应：我们 将应用结合HP[1，4-13C]NAC和HP[1-13C]DHA的多模式代谢成像方法 策略，以及互补的生物分析，以调查临床相关治疗的效果 富马酸二甲酯(DMF)，一种潜在的影响氧化应激的新治疗分子(Acivicin)以及 NAC本身作为治疗作用，在临床前MS模型中体外氧化之间的相关性 压力标记物和体内Hp比率将被用于生物学验证我们的成像方法，以及 比较HP[1，4-13C]NAC和HP[1-13C]DHA策略。这一目标的完成将验证一种新的代谢 监测治疗反应的成像工具，与体内多发性硬化症的氧化应激变化有关。 总体影响：预期的总体影响是，通过验证一种新的放射学磁共振成像 允许评估氧化应激的方法，并在临床转换后，该项目的结果将 可能会改善多发性硬化症患者的临床管理-特别是对高需求的SPMS/PPMS人群 改善护理，帮助改进治疗方案，并最终带来更好的结果和患者的生活质量。

ABSTRACT Oxidative stress plays a crucial role in Multiple Sclerosis (MS). Importantly, oxidative stress is more prominent in primary and secondary progressive MS (PP/SPMS) than in the relapsing remitting (RRMS) form, and alternative treatment strategies targeting oxidative stress are being tested for PP/SPMS. Unfortunately, there are presently limited in vivo methods for measuring oxidative stress. Hyperpolarized 13C Magnetic Resonance Spectroscopic Imaging (HP 13C MRSI) is a safe method that detects metabolic reactions in vivo post injection of HP probes. HP [1-13C]-dehydroxyascorbate (DHA) has shown potential for in vivo imaging of oxidative stress in vivo, but causes transient respiratory arrest and pancreatic toxicity, limiting its translational potential. There is thus a need for a new imaging strategy to assess oxidative stress in the brain in vivo. N-acetylcysteine (NAC) is the N-acetyl derivative of the naturally occurring amino acid, L-cysteine, and has been used as an antioxidant in clinical practice for decades. In people living with MS, a recent study reported that NAC significantly increased cerebral glucose metabolism and cognitive function, identifying NAC as a potential therapy. Based on all these findings, we propose to: Aim 1: Optimize and validate HP [1,4-13C]NAC as a theranostic probe to non-invasively detect cerebral redox status in MS mice at clinical field strength: The concentration of [1,4-13C]NAC and the MRSI acquisition scheme will be optimized for detection of the metabolism of [1,4-13C]NAC in the brain of MS mice, to provide the best data quality. Correlations between ex vivo oxidative stress markers and in vivo HP Ac/Cys-to-NAC will be performed to biologically validate our imaging method. Completion of this aim will provide an optimized tool for quantifying in vivo redox state in the MS mouse brain. Aim 2. Apply theranostic metabolic imaging of oxidative stress to monitor response to therapies: We will apply a multimodal metabolic imaging approach combining both HP [1,4-13C]NAC and HP [1-13C]DHA strategies, as well as complementary biological assays, to investigate the effects of a clinically-relevant therapy dimethylfumarate (DMF), a novel potential therapeutic molecule affecting oxidative stress (Acivicin) as well as the effect of NAC itself used as treatment, in a preclinical model of MS. Correlations between ex vivo oxidative stress markers and in vivo HP ratios will be performed to biologically validate our imaging approaches, and compare HP [1,4-13C]NAC and HP [1-13C]DHA strategies. Completion of this aim will validate a new metabolic imaging tool for monitoring therapeutic response linked to changes in oxidative stress in MS in vivo. Overall Impact: The expected overall impact is that, through validation of a new theranostic MR imaging approach allowing for assessment of oxidative stress, and upon clinical translation, results from this project will likely improve the clinical management for MS patients – especially for the SPMS/PPMS population in high need of improved care -, help refine therapy regimens and, ultimately lead to better outcome and patient quality of life.