Nrf2/ARE调控的乙二醛酶1在糖尿病脑病防治中的作用及芒果苷的效应和机制

Diabetic encephalopathy, characterized by impaired cognitive functions, and electrophysiological, neurochemical, and structural abnormalities, is the most common complication of diabetes mellitus in the central nervous system. Its pathogenesis, however, remains incompletely understood due to multiple factors involved in the process. Our previous research confirmed that methylglyoxal, an important intermediate product of glucose metabolism, functioned during the processes of protein glycation, oxidative stress and inflammation under high glucose conditions, whose presence accelerated the progression of diabetic encephalopathy, due to impaired glyoxalase 1 (Glo-1) which is the main detoxicating enzyme for methylglyoxal in human body. Mangiferin, one of the major compounds from Rhizoma Anemarrhenae, was found to inhibit the changes described above through enhancing Glo-1 activity to improve diabetic encephalopathy, whose regulatory mechanism, however, is still unclear. Nrf2/ARE signaling pathway is one of the most important pathways in transcription control of phase II detoxification enzymes. We assume that the damaged Glo-1 may be caused by the Nrf2/ARE signaling pathway. Therefore, in this study, molecular biological methods and patch clamp will be applied for investigating at cellular, brain tissue section and whole-animal levels the regulation of Glo-1 by the Nrf2/ARE pathway under high glucose conditions, as well as antioxidant system and cognitive function. This study is intended to confirm the important role of Nrf2 signaling activation in prevention and treatment of diabetic encephalopathy. Meanwhile, this study is aimed to further elucidate the molecular mechanism of mangiferin in prevention and treatment of diabetic encephalopathy. This study will provide new evidence for clinical prevention and treatment of diabetic encephalopathy and new targets for drug research and development.

糖尿病脑病是糖尿病在中枢最常见的并发症，受到了极大关注，但发病机制复杂。我们前期研究结果证实葡萄糖代谢的中间产物丙酮醛是糖尿病状态下蛋白糖化、氧化应激和炎症三者间的桥梁，加速了糖尿病脑病的发生，这是由于丙酮醛的解毒酶乙二醛酶1（Glo-1）受损所致；中药知母中的单体成分芒果苷能够增强Glo-1的功能而抑制上述变化，从而改善糖尿病脑病，然而其调节机制仍不清楚。Nrf2/ARE通路是机体调控解毒酶的重要通路之一，我们提出Glo-1受损可能是Nrf2/ARE调控的结果。因此，本项目将从整体动物、离体脑片和细胞水平，采用分子生物学、膜片钳等技术，研究高糖状态下Nrf2/ARE通路对Glo-1的调控作用，及其对抗氧化系统和认知功能的影响，证实该通路激活在糖尿病脑病防治中的重要作用；同时，进一步阐明芒果苷防治糖尿病脑病的分子机制，为糖尿病脑病临床防治提供新思路，为防治药物研发提供新靶标。

糖尿病脑病是糖尿病在中枢最常见的并发症，发病机制复杂。我们前期研究结果证实葡萄糖代谢的中间产物丙酮醛是糖尿病状态下发生蛋白糖化、氧化应激和炎症三者间的桥梁，加速了糖尿病脑病的发生，这是由于丙酮醛的解毒酶乙二醛酶1（Glo-1）受损所致。在本项目中，我们提出并证实糖尿病状态下脑内Glo-1功能的下调与Nrf2/ARE信号通路失活密切相关，且Nrf2的磷酸化水平降低介导了高糖状态下中枢神经元中Nrf2/ARE信号通路的失活，PKC失活和MAPK p38和/或GSK-3β激活参与了Nrf2磷酸化水平的降低。该研究的核心观点为Nrf2/ARE/Glo-1通路失活参与了中枢神经元中的损伤，从而引起糖尿病脑病的发生。同时，在高糖培养的原代大鼠海马和大脑皮质神经元中，我们发现中药知母中的单体成分芒果苷可增强Glo-1的功能，与其激活Nrf2/ARE信号通路有关，从而发挥神经元保护作用，这可能是芒果苷防治糖尿病脑病的分子机制之一。而且，在高糖培养的人源性中枢神经元细胞系SH-SY5Y细胞中，我们发现天然产物槲皮素对PKC、MAPK p38及GSK-3β激酶活性的影响参与了Nrf2的磷酸化水平的调节，从而使Nrf2/ARE信号通路激活，这是槲皮素发挥神经保护作用的重要分子机制。此外，我们还发现来源于芸香科柑橘属幼果的天然产物橙皮素对高糖状态下中枢神经元中Glo-1具有诱导作用，与其激活Nrf2/ARE信号通路有关。该项目阐明了Nrf2/ARE/Glo-1信号通路失活在糖尿病脑病发病机制中具有重要作用，而且发现该通路在糖尿病的常见慢性并发症发病过程中具有普适性，为糖尿病慢性并发症的临床防治提供新思路，为防治药物研发提供新靶标；同时，也为药物研发提供了一些有效的候选化合物。

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