Qian Xudong, Xu Qianqian, Li Guoyun, Bu Yi, Sun Fan, Zhang Jian
Department of Neurology, Affiliated Hospital of Chengde Medical University, Chengde, 067000, Hebei, People's Republic of China.
Department of Respiratory, Affiliated Hospital of Chengde Medical University, Chengde, 067000, Hebei, People's Republic of China.
Neuropsychiatr Dis Treat. 2021 Feb 17;17:533-543. doi: 10.2147/NDT.S293614. eCollection 2021.
Vascular dementia (VD) is a brain disease featured by cognitive impairment and cerebrovascular pathologies. Idebenone can treat neurodegenerative diseases. This study evaluated the mechanism of Idebenone in VD.
The VD rat model was established by permanent occlusion of bilateral common carotid arteries, followed by intragastrical administration of Idebenone. The learning and spatial memory abilities, and the levels of MDA, SOD, IL-6 and TNF-α were measured. Histological staining was adopted to observe the damage of neurons in the hippocampal cortex and to quantitatively analyze the neuronal damage in CA1 area of hippocampus. Microarray analysis was performed to find out the effect of Idebenone treatment on microRNA (miR) expression in hippocampus of rats. The potential target genes of miR and the pathways regulated by target genes were searched by bioinformatics analysis, and verified by experiments. The mechanism of action behind Idebenone in VD rats was proved by rescue experiment.
Idebenone treatment improved the learning and spatial memory abilities of VD rats, inhibited neuroinflammation and oxidative stress, and prevented neuronal apoptosis. Idebenone treatment elevated miR-216a expression in hippocampus of rats, but the therapeutic effect of Idebenone was averted by lentivirus inhibition of miR-216a. miR-216a targeted RSK2. Overexpression of RSK2 annulled the therapeutic effect of Idebenone on VD rats by activating the IκBα/NF-κB axis.
Idebenone inhibits the activation of RSK2/IκBα/NF-κB axis by increasing miR-216a, thus alleviating oxidative stress and neuroinflammation in VD rats.
血管性痴呆（VD）是一种以认知障碍和脑血管病变为特征的脑部疾病。艾地苯醌可治疗神经退行性疾病。本研究评估了艾地苯醌在VD中的作用机制。
通过永久性结扎双侧颈总动脉建立VD大鼠模型，随后给予艾地苯醌灌胃。测量学习和空间记忆能力以及丙二醛（MDA）、超氧化物歧化酶（SOD）、白细胞介素-6（IL-6）和肿瘤坏死因子-α（TNF-α）水平。采用组织学染色观察海马皮质神经元损伤情况，并对海马CA1区神经元损伤进行定量分析。进行基因芯片分析以了解艾地苯醌治疗对大鼠海马中微小RNA（miR）表达的影响。通过生物信息学分析寻找miR的潜在靶基因以及靶基因调控的通路，并通过实验进行验证。通过拯救实验证实艾地苯醌在VD大鼠中的作用机制。
艾地苯醌治疗改善了VD大鼠的学习和空间记忆能力，抑制了神经炎症和氧化应激，并防止了神经元凋亡。艾地苯醌治疗提高了大鼠海马中miR-216a的表达，但慢病毒抑制miR-216a可消除艾地苯醌的治疗效果。miR-216a靶向核糖体S6激酶2（RSK2）。RSK2的过表达通过激活IκBα/核因子κB（NF-κB）轴消除了艾地苯醌对VD大鼠的治疗效果。
艾地苯醌通过增加miR-216a抑制RSK2/IκBα/NF-κB轴的激活，从而减轻VD大鼠的氧化应激和神经炎症。
