Zhang Dandan, Xiao Yining, Lv Peiyuan, Teng Zhenjie, Dong Yanhong, Qi Qianqian, Liu Zhijuan
a Hebei Medical University , Shijiazhuang , China.
b Department of Neurology , Hebei General Hospital , Shijiazhuang , China.
Neurol Res. 2018 Jan;40(1):1-10. doi: 10.1080/01616412.2017.1376457. Epub 2017 Nov 10.
Objectives The potential protective effects and mechanisms of edaravone have not been well elucidated in vascular dementia (VaD) induced by chronic cerebral hypoperfusion (CCH). The aim of this study was to investigate whether edaravone could improve cognitive damage in rats induced by CCH, and whether the effects of edaravone were associated with ERK/Nrf2/HO-1 signaling pathway. Methods CCH was induced by bilateral common carotid arteries occlusion (BCCAO). Sprague-Dawley (SD) rats were randomly divided into four groups: sham (sham-operated) group, vehicle (BCCAO + normal saline) group, edaravone3.0 group and edaravone6.0 group. The edaravone3.0 and edaravone6.0 group rats were provided 3.0 mg/kg and 6.0 mg/kg of edaravone, respectively, intraperitoneal (i.p.) injection twice daily following the first day after BCCAO. In this experiment, the spatial learning and memory were assessed using the Morris water maze. The malondialdehyde (MDA) contents and superoxide dismutase (SOD) activities in the hippocampus were measured biochemically. And, the levels of total ERK1/2 (t-ERK1/2), Phospho-ERK1/2 (p-ERK1/2), total Nrf2 (t-Nrf2), nuclear Nrf2 (n-Nrf2), and HO-1 were assessed by western blot. Results The results showed that the treatment with edaravone significantly improved CCH-induced cognitive damage, and boosted endogenous antioxidants SOD activity and HO-1 level, decreased MDA contents in the hippocampus by activating Nrf2 signaling pathway which was related to ERK1/2. We also found that the neuronal morphology of the hippocampal CA1 area significantly improved and the number of Nrf2 positive cells markedly increased in the edaravone treatment groups. Conclusion Our results demonstrated a neuroprotective effect of edaravone on hippocampus against oxidative stress and cognitive deficit induced by CCH. The mechanism may be related to the enhancement of antioxidant defense system by activating ERK/Nrf2/HO-1 signaling pathway.
依达拉奉在慢性脑灌注不足（CCH）诱导的血管性痴呆（VaD）中的潜在保护作用及机制尚未完全阐明。本研究旨在探讨依达拉奉是否能改善CCH诱导的大鼠认知损伤，以及依达拉奉的作用是否与ERK/Nrf2/HO-1信号通路有关。方法：通过双侧颈总动脉闭塞（BCCAO）诱导CCH。将Sprague-Dawley（SD）大鼠随机分为四组：假手术组、溶剂对照组（BCCAO + 生理盐水）、依达拉奉3.0组和依达拉奉6.0组。依达拉奉3.0组和依达拉奉6.0组大鼠在BCCAO后第一天开始，每天腹腔注射（i.p.）依达拉奉，剂量分别为3.0 mg/kg和6.0 mg/kg，每日两次。本实验采用Morris水迷宫评估空间学习和记忆能力。生化检测海马中丙二醛（MDA）含量和超氧化物歧化酶（SOD）活性。并且，通过蛋白质免疫印迹法评估总ERK1/2（t-ERK1/2）、磷酸化ERK1/2（p-ERK1/2）、总Nrf2（t-Nrf2）、核Nrf2（n-Nrf2）和HO-1的水平。结果：结果表明，依达拉奉治疗显著改善了CCH诱导的认知损伤，通过激活与ERK1/2相关的Nrf2信号通路，提高了内源性抗氧化剂SOD活性和HO-1水平，降低了海马中的MDA含量。我们还发现，依达拉奉治疗组海马CA1区的神经元形态显著改善，Nrf2阳性细胞数量明显增加。结论：我们的结果表明依达拉奉对海马具有神经保护作用，可对抗CCH诱导的氧化应激和认知缺陷。其机制可能与通过激活ERK/Nrf2/HO-1信号通路增强抗氧化防御系统有关。
