Hou Xiaowen, Xu Haibin, Chen Wanli, Zhang Nannan, Zhao Ziai, Fang Xin, Zhang Xing, Chen Huisheng, Xu Yuanyuan
School of Public Health, China Medical University, Shenyang 110122, China.
Department of Neurology, General Hospital of Northern Theater Command, Shenyang 110016, China.
Ann Transl Med. 2020 Mar;8(6):375. doi: 10.21037/atm.2020.02.10.
Oxidative damage may contribute to post-stroke cognitive impairment (PSCI), but the underlying mechanisms are not fully elucidated. Dimethyl fumarate (DMF) has been used as an antioxidant in multiple sclerosis and psoriasis patients. We hypothesized that redox state was associated with PSCI, and DMF might exert neuroprotective effect against PSCI via anti-oxidative actions.
To confirm this hypothesis, we first conducted a clinical study (NCT03519828) that enrolled patients diagnosed with acute ischemic stroke within 48 hours. Data were analyzed based on demographic characteristics, disease history, clinical data and redox state. Logistic regression was used to identify the factors associated with PSCI. Next, a middle cerebral artery occlusion (MCAO) rat model was used to explore the antioxidant capacity and neuroprotective effect of DMF. Furthermore, behavioural experiments, histology and immunostaining, and transmission electron microscopy were also performed.
Higher baseline NIHSS score, lower GSH/GSSG and T-AOC levels were found in the PSCI patients. Better performance in Morris water maze and shuttle box testing, more regular arranged neurons and Nissl bodies, less TUNEL-positive cells and autophagosomes, lower expression of 4-HNE, and higher expression of GCLM and NQO1 were found in the (DMF + MCAO) rats compared with the MCAO rats.
These findings suggest that DMF may alleviate PSCI via neuroprotective actions, providing a new therapeutic strategy for PSCI.
氧化损伤可能导致中风后认知障碍（PSCI），但其潜在机制尚未完全阐明。富马酸二甲酯（DMF）已被用于治疗多发性硬化症和银屑病患者。我们假设氧化还原状态与PSCI相关，并且DMF可能通过抗氧化作用对PSCI发挥神经保护作用。
为了证实这一假设，我们首先开展了一项临床研究（NCT03519828），纳入在48小时内被诊断为急性缺血性中风的患者。基于人口统计学特征、病史、临床数据和氧化还原状态对数据进行分析。采用逻辑回归来确定与PSCI相关的因素。接下来，使用大脑中动脉闭塞（MCAO）大鼠模型来探究DMF的抗氧化能力和神经保护作用。此外，还进行了行为实验、组织学和免疫染色以及透射电子显微镜检查。
PSCI患者的基线NIHSS评分较高，谷胱甘肽/氧化型谷胱甘肽（GSH/GSSG）和总抗氧化能力（T-AOC）水平较低。与MCAO大鼠相比，（DMF + MCAO）大鼠在莫里斯水迷宫和穿梭箱测试中表现更好，神经元和尼氏体排列更规则，TUNEL阳性细胞和自噬体更少，4-羟基壬烯醛（4-HNE）表达更低，谷氨酸半胱氨酸连接酶催化亚基（GCLM）和醌氧化还原酶1（NQO1）表达更高。
这些发现表明，DMF可能通过神经保护作用减轻PSCI，为PSCI提供了一种新的治疗策略。
