益气活血方对糖尿病血糖波动性脑病的干预作用及抗氧化损伤的多靶点机制研究

Closely related to glucose fluctuation, Diabetes mellitus is the most hazard disease threatening human health. Diabetic Encephalopathy (DE) is the major diabetes complication of central nervous system, which is mediated by Oxidation stress through regulating signaling pathways such as Nrf2/ARE. The current treatment strategy for diabetes has many defects, including poor effect of drug control, poor dependency of the patients, etc., which cannot satisfy the clinical needs. According to the TCM theory, diabetes belongs to a combination of "Xiao Ke", "Xuan Yun", "Zhong Feng" and "Pian Ku", with the pathogenesis of yin-yang and qi-blood deficiency, wind-phlegm-blood stasis transresistance, and brain damage. It can be properly treated by qi-yin tonifying strategy. Based on the clinical practice and experience, we developed Yi Qi Huo Xue formula (YQHXf) with effects of qi-yin tonifying, body-fluid promoting, channel dredging, and detoxifying, which is suitable for DE treatment. Our preliminary study showed that YQHXf could decrease the glucose level of DE rats, and significantly protect the organ tissue against damage. Accordingly, this study supposes to clarify the anti-oxidation mechanism from the aspect of modulation of relevant signaling pathways such as Nrf2/ARE and further evaluate the therapeutic effect of YQHXf against the glucose fluctuation-induced DE. This study can lay the experimental foundation for development of anti-DE compound prescription of TCM，and thereby provide new ideas for clinical treatment of DE.treatment. Our preliminary study showed that YQHXf could decrease the glucose level of DE rats, and significantly protect the organ tissue against damage. Accordingly, this study supposes to clarify the anti-oxidation mechanism from the aspect of modulation of relevant signaling pathways such as Nrf2/ARE and further evaluate the therapeutic effect of YQHXf against the glucose fluctuation-induced DE. This study can lay the experimental foundation for development of anti-DE compound prescription of TCM，and thereby provide new ideas for clinical treatment of DE.

糖尿病是危害人类健康的三大疾病之一，与血糖波动密切相关。氧化应激通过对Nrf2/ARE等信号通路调控介导血糖波动和并发症的发生发展，糖尿病脑病是其中主要的中枢神经系统并发症。现今的糖尿病防治策略存在药物控制不佳、患者治疗依存性差等缺陷，无法满足临床需求。糖尿病脑病属中医学的“消渴”合并“眩晕”、“中风”、“偏枯”等范畴，病机主要为阴阳气血亏虚，风痰瘀互阻，上损脑络，治宜益气养阴法等法。本项目根据临床实践经验拟定益气活血方，以其益气生津、通络降糖、解毒养阴的功效治疗糖尿病脑病。前期实验表明，该方能降低糖尿病血糖波动大鼠的血糖水平，明显保护相关脏器损伤。在此基础上，本项目将从抗氧化损伤的角度研究该方对氧化应激介导的Nrf2/ARE等相关信号通路的调控机制，评价其对糖尿病血糖波动性脑病的整体治疗作用。通过该研究，将为抗糖尿病脑病中药复方新药的开发奠定实验基础，为糖尿病脑病的临床治疗提供新的思路。

糖尿病是危害人类健康的三大疾病之一，能引起心血管和神经系统并发症，有较高的致残率和致死率，近20年来发病率显著增长。糖尿病的并发症及预后不仅受整体血糖水平影响，还与血糖波动密切相关。血糖波动越大，并发症发生率越高、预后越差。因此有效降血糖并减小血糖波动危害对糖尿病的临床防治具有重要意义。糖尿病脑病是最主要的一种糖尿病中枢神经系统并发症，表现为认知功能障碍和大脑病生理改变。经典的“糖尿病共同机制学说”指出，高血糖和血糖波动引起的氧化应激反应，能促进糖尿病并发症的发展，是糖尿病并发症核心的共同机制。有研究表明，氧化应激能破坏血脑屏障、增加糖基化终产物形成、促进中枢神经细胞凋亡、引起神经发生障碍，可能与糖尿病脑病有关。目前，除磺酰脲类、α-糖苷酶抑制剂等传统药物外，非磺酰脲类胰岛素促泌剂、超短效胰岛素类似物等均可用于降低餐后高血糖。糖尿病患者往往采用在家自我治疗的方法，存在饮食、药物控制不佳、治疗依存性差等缺陷，因此迫切需要研发可用于糖尿病血糖波动治疗的新型药物或方法。而中医药在治疗糖尿病脑病方面，显现出独特的优势。中医将糖尿病归属“消渴病”范畴，糖尿病脑病是消渴病日久而发的脑系并发症，称为消渴病脑病，归类“消瘅”。其病位在脑，属上盛下虚、本虚标实之证，基本病机为阴阳气血俱虚，痰湿郁瘀或风痰瘀血而致气血逆乱，上犯于脑，脑脉痹阻，神机失用，临床常以益气养阴法等分别从虚、痰、瘀、风、毒论治。本项目组结合自身临床经验，提出在益气养阴的基础上，加入活血通络之法，用于糖尿病脑病的治疗。以生黄芪、川芎、葛根、生地、天花粉组成的益气活血方，本项目将在前期基础上建立2 型糖尿病血糖波动大鼠模型，以评价益气活血方降血糖、控制血糖波动作用；同时围绕海马组织探究该方对血糖波动致中枢神经系统损伤的保护作用。进而从抗氧化损伤的角度出发，应用实时定量PCR芯片技术对氧化应激介导的Nrf2/ARE、NF-κB、MAPKs 等相关信号通路进行“高通量”分析，以阐明益气活血方抗氧化损伤的多靶点作用机制。通过本项目研究，能进一步验证“糖尿病血糖波动—脑并发症—氧化应激”三者的关系，明确益气活血方降血糖、控制血糖波动和保护中枢神经系统的作用，揭示作用机制，将为糖尿病脑病的临床治疗提供新的治法和思路，为抗糖尿病中药复方新药的开发奠定基础，并为临床糖尿病脑病的中医药治疗提供新的依据。