毛蕊异黄酮改善高胆固醇饲喂致小鼠神经记忆损伤的机制

High cholesterol-fed mice display many Alzheimer's disease-like pathological features, such as β-amloid deposits and learning and memory deficits. The underlying neurotoxic mechanism may be related to oxidative stress-induced insulin resistance in the mouse brain. Experimental and clinical evidence has been demonstrated that brain insulin resistance can lead to moderate memory deficits and dementia. Mitochondrial is an eukaryotic organelle and involved in energy balance. New evidence shows that oxidative stress can lead to mitochondrial dysfunction and ultimately induce insulin resistance.Peroxisome proliferator-activated receptor-γ coactivator-1α(PGC-1α) is a key regulator of mitochondrial biogenesis. Its activity could be regulated by acetylation. Astragalus is the root of herbaceous legumes or mongolian astragalus and is commonly used to treat diabetes in Asia. But the mechanism of its action is still unclear. Calycosin, a component of astragalus, possesses many biological activities including anti-oxidation and anti-inflammation. Our pilot experimental data showed that calycosin could increase the activity of PGC-1α and activate the NRF1-mediated mitochondrial signaling in the hippocampus of mice that are fed with high-cholesterol diet, a model of metabolic syndrome. It ultimately improved insulin sensitivity and the learning and memory ability in the high cholesterol-fed mice. Subsequently, we aimed to further investigate the neuroprotective mechanism of calycosin.

高胆固醇饲喂诱导小鼠类似老年痴呆(AD)症状，如β-淀粉样蛋白沉积和学习记忆障碍, 其可能的神经毒机制与氧化应激诱导的脑胰岛素抵抗有关。实验和临床证据证实, 脑胰岛素抵抗可以诱发中度记忆损伤甚至痴呆。线粒体是真核细胞的细胞器，参与调节机体的能量平衡。最新证据证明，氧化应激诱导的线粒体功能障碍可以导致胰岛素抵抗。过氧化物酶体增殖物受体γ共激活因子1α(PGC-1α)是调控线粒体增殖的核心分子，其活性受到乙酰化作用调节。黄芪为豆科草本植物蒙古黄芪、膜荚黄芪的根,在亚洲常被用来治疗糖尿病，但治疗机理不清楚。毛蕊异黄酮是黄芪的重要组分,被报道拥有抗氧化和抗炎等多种生物学活性。预实验数据显示, 毛蕊异黄酮增加高胆固醇饲喂致代谢综合症小鼠海马的PGC-1α活性，促进核呼吸因子(NRF1)介导的线粒体信号，最终改善高胆固醇小鼠胰岛素敏感性和学习记忆能力。在此基础上，进一步研究毛蕊异黄酮神经保护作用机制。

高胆固醇饲喂致小鼠认知缺陷，其神经毒机制与脑胰岛素抵抗有关。线粒体是调节能量平衡的细胞器，证据表明，线粒体功能障碍诱导胰岛素抵抗。过氧化物酶体增殖物受体γ共激活因子1α(PGC-1α)是线粒体增殖的主要调节子，它的活性受到乙酰化调控。毛蕊异黄酮具有抗氧化和抗炎活性，我们前期实验证明其可以增加模型小鼠海马的PGC-1α活性改善其认知缺陷。这里，我们旨在探索毛蕊异黄酮神经保护作用机理。在高胆固醇饲喂致认知缺陷的小鼠模型上，从对PGC-1α乙酰化水平调控角度结合核呼吸因子(NRF1)介导的线粒体增殖通路和胰岛素信号通路综合研究毛蕊异黄酮改善高胆固醇饲喂致小鼠记忆缺陷的机理。结果表明，高胆固醇饲喂促进小鼠海马的PGC-1α乙酰化水平增加，导致NRF1介导的线粒体增殖信号下调，从而诱导线粒体障碍，最终导致海马胰岛素抵抗和记忆缺陷;毛蕊异黄酮则通过抑制柠檬酸裂解酶调控(ACL)活性，进而下调乙酰转移酶GCN5表达，导致PGC-1α去乙酰化而增强NRF1介导的线粒体增殖信号，这些药理学作用缓解胰岛素抵抗，被修复的胰岛素信号反过来改善记忆缺陷, 最终修复代谢综合症诱导的神经损伤。该项研究也为代谢综合症诱导神经损伤的预防和治疗提供新思路。该部分研究成果正在整理数据，撰写论文发表。此外，线粒体信号参与II型糖尿病和多莫酸诱导神经兴奋性损伤的认知缺陷病生机制，该部分研究成果分别在Journal of Immunology和Toxicology and Applied Pharmacology杂志上发表，这些结果为II型糖尿病认知缺陷和神经兴奋性认知缺陷治疗提供理论研究基础以及药物筛选靶点；低密度脂蛋白(Lipoprotein)是急性缺血休克的早期缺血发病率的预测因子在Molecular Neurobiology杂志上发表，该部分研究成果为脑缺血中风诊断和治疗提供科学依据；最后线粒体功能障碍诱导的NLRP3的活化和HDAC3/miR-10a/CREB1信号轴等研究为II型糖尿病肾脏损伤的治疗和药物筛选提供科学依据。通过上述研究数据和研究假说以第一作者和通讯作者发表研究论文4篇，资助参与发表论文6篇。培养硕士研究生4名。已经发表的研究成果正在与相关医院和药企探讨应用转化工作。