Wang Xue-Rui, Shi Guang-Xia, Yang Jing-Wen, Yan Chao-Qun, Lin Li-Ting, Du Si-Qi, Zhu Wen, He Tian, Zeng Xiang-Hong, Xu Qian, Liu Cun-Zhi
Acupuncture and Moxibustion Department, Beijing Hospital of Traditional Chinese Medicine affiliated to Capital Medical University, 23 Meishuguanhou Street, Dongcheng District, Beijing 100010, China.
Acupuncture and Moxibustion Department, Beijing Hospital of Traditional Chinese Medicine affiliated to Capital Medical University, 23 Meishuguanhou Street, Dongcheng District, Beijing 100010, China.
Free Radic Biol Med. 2015 Dec;89:1077-84. doi: 10.1016/j.freeradbiomed.2015.10.426. Epub 2015 Nov 9.
Emerging evidence suggests acupuncture could exert neuroprotection in the vascular dementia via anti-oxidative effects. However, the involvement of Nrf2, a master regulator of antioxidant defense, in acupuncture-induced neuroprotection in vascular dementia remains undetermined. The goal of our study was to investigate the contribution of Nrf2 in acupuncture and its effects on vascular dementia. Morris water maze and Nissl staining were used to assess the effect of acupuncture on cognitive function and hippocampal neurodegeneration in experimental vascular dementia. The distribution of Nrf2 in neurons in hippocampus, the protein expression of Nrf2 in both cytosol and nucleus, and the protein and mRNA levels of its downstream target genes NQO1 and HO-1 were detected by double immunofluorescent staining, Western blotting and realtime PCR analysis respectively. Cognitive function and microglia activation were measured in both wild-type and Nrf2 gene knockout mice after acupuncture treatment. We found that acupuncture could remarkably reverse the cognitive deficits, neuron cell loss, reactive oxygen species production, and decreased cerebral blood flow. It was notable that acupuncture enhanced nuclear translocation of Nrf2 in neurons and up-regulate the protein and mRNA levels of Nrf2 and its target genes HO-1 and NQO1. Moreover, acupuncture could significantly down-regulated the over-activation of microglia after common carotid artery occlusion surgery. However, the reversed cognitive deficits, neuron cell loss and microglia activation by acupuncture were abolished in Nrf2 gene knockout mice. In conclusion, these findings provide evidence that the neuroprotection of acupuncture in models of vascular dementia was via the Nrf2 activation and Nrf2-dependent microglia activation.
新出现的证据表明，针灸可能通过抗氧化作用对血管性痴呆发挥神经保护作用。然而，抗氧化防御的主要调节因子Nrf2在针灸诱导的血管性痴呆神经保护中的作用仍未确定。我们研究的目的是探讨Nrf2在针灸中的作用及其对血管性痴呆的影响。采用Morris水迷宫和尼氏染色法评估针灸对实验性血管性痴呆认知功能和海马神经退行性变的影响。分别通过双重免疫荧光染色、蛋白质印迹法和实时PCR分析检测海马神经元中Nrf2的分布、细胞质和细胞核中Nrf2的蛋白质表达及其下游靶基因NQO1和HO-1的蛋白质和mRNA水平。在野生型和Nrf2基因敲除小鼠中测量针灸治疗后的认知功能和小胶质细胞激活情况。我们发现，针灸可以显著逆转认知缺陷、神经元细胞丢失、活性氧产生和脑血流量减少。值得注意的是，针灸增强了神经元中Nrf2的核转位，并上调了Nrf2及其靶基因HO-1和NQO1的蛋白质和mRNA水平。此外，针灸可以显著下调颈总动脉闭塞手术后小胶质细胞的过度激活。然而，在Nrf2基因敲除小鼠中，针灸逆转的认知缺陷、神经元细胞丢失和小胶质细胞激活被消除。总之，这些发现提供了证据，表明针灸在血管性痴呆模型中的神经保护作用是通过Nrf2激活和Nrf2依赖性小胶质细胞激活实现的。
