7,8-二羟基黄酮前体药对阿尔茨海默病治疗的可行性及其机制研究

BDNF (brain-derived neurotrophic factor) and its cognate receptor TrkB play a protective role against Alzheimer's Disease (AD) pathogenesis. Using a cell-based screening assay, recently, we report the identification of 7,8-DHF as a bioactive TrkB agonist that passes brain blood barrier and provokes receptor activation. The agonist selectively activates TrkB, but not TrkA or TrkC, in a BDNF-independent manner. Strikingly, 7,8-DHF displays a robust therapeutic effect in a TrkB-dependent way in numerous disease models. This small molecule mimics the physiological actions of BDNF in variety of animal models including stroke, leaning and memory and depression etc. In this proposal, we plan to determine the potential molecular and cellular factors affect the agonistic effect and investigate the therapeutic actions of the prodrug that possesses higher oral bioavailability than parent compound 7,8-DHF. Successful accomplishment of the proposed experiments will provide the molecular mechanisms how the small molecular TrkB agonist exerts the physiological and pharmacological effects. The knowledge from this study will not only provide powerful tool for exploring the biological actions of BDNF/TrkB signaling but also useful pharmacological intervention for clinical treatment of various neurological diseases including AD.

脑源性营养因子及其受体TrkB在阿尔茨海默病的发病机制中起着关键作用。基于细胞筛选试验，发现了一类具有生物活性可通过血脑屏障的TrkB受体激动剂，激动剂只选择性激活TrkB,不作用于TrkA和TrkC。我们前期研究证实7,8-DHF类似于BDNF并以TrkB依赖的方式在中风、学习和记忆、抑郁等多种动物模型中展现出卓越的治疗潜能，近期研究显示激动剂可显著改善5×FAD模型鼠的突触可塑性和记忆障碍问题，而经改良的激动剂前体药口服生物活性升至10%，因此，此项目在明确7,8-DHF对TrkB受体活化机制的前体下，重点评估7,8-DHF前体药对两种AD模型的治疗作用，并通过全基因表达谱及权重基因共表达分析(WGCNA)方法揭示前体药实施其生理功能的主要作用方式和生理机制。本项目的顺利完成不仅为BDNF/TrkB信号通路生物功能研究提供有效手段，还将成为神经退行性疾病药物介入治疗的新里程。

脑源性营养因子及其受体TrkB在阿尔茨海默病的发病机制中起着关键作用。基于细胞筛选试验，发现了一类具有生物活性可通过血脑屏障的TrkB受体激动剂，激动剂只选择性激活TrkB,不作用于TrkA和TrkC。我们前期研究证实7,8-DHF类似于BDNF并以TrkB依赖的方式在中风、学习和记忆、抑郁等多种动物模型中展现出卓越的治疗潜能，近期研究显示激动剂可显著改善5×FAD模型鼠的突触可塑性和记忆障碍问题，而经改良的激动剂前体药口服生物活性升至10%，因此，此项目在明确7,8-DHF对TrkB受体活化机制的前体下，重点评估7,8-DHF前体药对两种AD模型的治疗作用，并通过全基因表达谱及权重基因共表达分析(WGCNA)方法揭示前体药实施其生理功能的主要作用方式和生理机制。本项目研究发现：通过体内药代动力学研究及对AD模型小鼠的干预实验，证明R13是一种能够起到神经保护作用并且可用于治疗阿尔兹海默症的新型医药制剂。