Shavakandi Seyyedeh-Mahla, Ranjbaran Mina, Nabavizadeh Fatemeh, Vali Reyhaneh, Sehati Fardin, Ashabi Ghorbangol
Department of Physiology, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran.
Nutr Neurosci. 2022 Oct;25(10):2100-2110. doi: 10.1080/1028415X.2021.1940429. Epub 2021 Jun 19.
It has been stated that chronic cerebral hypoperfusion (CCH) markedly prompts neuronal damage and affects cognition. Dimethyl fumarate (DMF), a nuclear erythroid 2-related factor 2 (Nrf2) activator, represents a class of molecules exhibiting neuroprotection. We explored the effect of DMF on CCH using a model of permanent left common carotid occlusion. The left common carotid artery was occluded and then DMF (100mg.kg) was orally administrated three times per week for four consecutive weeks. Behavioral rests, PET imaging and Hematoxylin and Eosin staining, were examined and also, the hippocampal level of inflammatory, Nrf2 antioxidant, neuronal plasticity and apoptotic factors were determined using Western blot analysis and related ELISA kits. The neurological deficit scores were significantly reduced in the treatment group compared with the CCH group (<0.001). DMF decreased the novel object recognition index (NOR) compared with the CCH group, while CCH + DMF increased the NOR compared with the CCH group (<0.001). CCH + DMF reduces the ratio of Bax/Bcl2 and capase-3 activity in comparison to the CCH group (<0.001). Treatment with DMF increased Nrf2, NAD(P)H dehydrogenase-1 and Heme oxygenase-1 and decreased Tumor necrosis factor α and Nuclear factor-κB density compared with the CCH group (<0.001). A significant increase in brain-derived neurotrophic factor and c-fos was found in DMF-treated rats compared with the CCH group (<0.001). Also, retinoic acid inhibits Nrf2 activation via DMF and increases inflammatory factors in hypoperfused rats' hippocampus compared with the CCH group (<0.001). Long-term DMF treatment induces the Nrf2 pathway and has beneficial effects on memory and motility in CCH.
据报道，慢性脑灌注不足（CCH）显著促使神经元损伤并影响认知。富马酸二甲酯（DMF）作为一种核红细胞2相关因子2（Nrf2）激活剂，代表了一类具有神经保护作用的分子。我们使用永久性左颈总动脉闭塞模型探究了DMF对CCH的影响。闭塞左颈总动脉，然后每周口服DMF（100mg/kg）三次，连续四周。检测行为休息、PET成像以及苏木精和伊红染色，并且使用蛋白质免疫印迹分析和相关酶联免疫吸附测定试剂盒测定海马中的炎症、Nrf2抗氧化、神经元可塑性和凋亡因子水平。与CCH组相比，治疗组的神经功能缺损评分显著降低（<0.001）。与CCH组相比，DMF降低了新物体识别指数（NOR），而与CCH组相比，CCH + DMF增加了NOR（<0.001）。与CCH组相比，CCH + DMF降低了Bax/Bcl2比值和caspase-3活性（<0.001）。与CCH组相比，DMF治疗增加了Nrf2、NAD（P）H脱氢酶-1和血红素加氧酶-1，并降低了肿瘤坏死因子α和核因子-κB密度（<0.001）。与CCH组相比，在DMF治疗的大鼠中发现脑源性神经营养因子和c-fos显著增加（<0.001）。此外，与CCH组相比，视黄酸通过DMF抑制Nrf2激活并增加灌注不足大鼠海马中的炎症因子（<0.001）。长期DMF治疗可诱导Nrf2通路，并对CCH的记忆和运动能力产生有益影响。
