血管性痴呆（VD）是世界范围内第二常见类型痴呆，发病机制不十分明确。大脑神经元PI3K /Akt/Nrf2信号通路是VD发病机制中有关氧化应激和凋亡研究的活跃前沿。甲酯化脂氧素A4（LXA4 ME）具有抗氧化应激和抗凋亡作用。我们预实验结果提示：PI3K、Akt、Nrf2与学习记忆相关。因此提出假说：PI3K/Akt/ Nrf2信号通路可能参与VD发生, 而LXA4 ME可能通过激活该通路发挥抗氧化应激和抗凋亡作用，进而改善大鼠学习记忆能力。综上，我们建立VD动物模型和海马神经元缺氧缺糖细胞模型，采用免疫组化、TUNEL、RT-qPCR、Western-Blot、激光共聚焦显微镜等技术，从基因、分子、细胞、组织和动物整体等层面探讨该通路在VD中的作用，并应用LXA4 ME和PI3K抑制剂-LY294002干预。本研究将从LXA4 ME抗氧化应激和抗凋亡作用这个新视角为VD的防治提供新思路。

Vascular dementia (VD) is an acquired syndrome of cognitive impairment which is induced by various kinds of cerebral vascular diseases. It is incontrovertible that VD is the second most common cause of dementia after Alzheimer’s disease in the world. Up to now, the pathogenesis of VD is not yet entirely clear and there are no especially effective drugs. The active frontline of illustrating the characters of oxidative stress and apoptosis in the etiology of VD still focuses on the PI3K/Akt//Nrf2 signaling pathway of hippocampal circuit. Studies have shown that LipoxinA4 methyl ester (LXA4 ME) has significant anti-oxidation and anti-apoptosis effects. Our pre-study showed that phosphatidylinositol-3-kinase (PI3K), protein kinase B (Akt), nuclear factor erythroid 2- related factor 2 (Nrf2) are strictly associated with learning and memory after chronic cerebral hypoperfusion, but the exact mechanism is still unknown. So we suggest that the PI3K/Akt/Nrf2 signaling pathway may be involved in the occurrence of VD, and LXA4 ME probably play its anti-oxidation and anti-apoptosis effects through activating this signaling pathway, and then improve the learning and memory abilities of VD rats. To explore the hypothesis, we will establish the VD rat model and perform the cellular model derived from hippocampi of rats as well. The cells will be cultured in oxygen/glucose deprivation environment. In this study, the techniques of immunohistochemistry, electron microscopy, real-time quantitative PCR, Western-Blot, confocal laser scanning microscope will be used to investigate the changes of the PI3K/Akt/Nrf2 signaling pathway in animal and hippocampal neuron from different levels of gene, molecule, cell, tissue and VD rats. Meanwhile, LXA4 ME and the inhibitor of PI3K –LY294002 will be used as interventions. Our research will put new insight into the therapy of VD through exploring the anti-oxidation and anti-apoptosis effects of LXA4 ME.