胍丁胺及I1咪唑啉受体在抑郁症发生发展及药物治疗中的作用

Depression is a common mental disorder that threatens human health seriously. Agmatine is considered as a candidate for novel neurotransmitter or transmodulator, as well as an endogenous ligand of immidazoline receptor. Our previouse studies showed that exogenous agmatine had antidepressant-like effect; however, whether endogenouse agmatine plays a role in the occurrence, development and drug treatment of depression remains unknown. Using a series of transgene and gene knockout mice targeting agmatine and I1-imidazoline recptor system we have established, including the transgene mice of agmatine synthetase and catabolic enzyme, as well as I1-imidazoline receptor transgene and knockout mice, this project focuses on the role of agmatine and I1-imidazoline receptor in the occurrence, development and drug treatment of depression. Furthermore, not only the receptor mechanism of exogenous agmatine's antidepressant-like effect but also the neurobiological mechanisms of endogenous agmatine participating in the depression are investigated. This project is based on a lot of our previous works, and has solid foundations. Through this study, we expect to find a new pathway or mechanism that participates in the occurrence and development of depression, which may provide a novel approach to treating depression via modulating agmatine and I1-imidazoline receptor functions.

抑郁症是一种严重威胁人类健康的精神疾病。胍丁胺被认为一种新的候选神经递质/调质，是咪唑啉受体的内源性配体。我们前期研究显示外源性胍丁胺具有抗抑郁作用，但是内源性胍丁胺在抑郁症发生、发展及药物治疗中有何作用尚属未知。本项目以本课题组首次构建的靶向胍丁胺-I1咪唑啉受体（I1R）系统的一系列模式动物（包括胍丁胺合成酶、降解酶、I1R转基因小鼠和I1R基因敲除小鼠）为基础，研究胍丁胺及其受体I1R在抑郁症发生、发展以及药物治疗中的作用；进一步研究胍丁胺抗抑郁作用的受体机制，以及从"单胺假说"和"神经可塑性假说"方面研究胍丁胺参与抑郁症的神经生物学机制。本项目是我们前期工作的延续和深入，期望发现新的参与抑郁症发病及病理过程的新通路和新机制，为抑郁症的治疗提供可能的新策略- - 调控胍丁胺-I1R作用系统功能。

抑郁症是一种严重威胁人类健康的精神疾病。现有抗抑郁药均是以单胺为靶标，但治疗效果不理想，因此需要寻找新型抗抑郁潜在靶标和候选药物。胍丁胺被认为一种新的候选神经递质/调质，是咪唑啉受体的内源性配体。本项目在多种急性和亚急性抑郁动物模型中确证了胍丁胺的抗抑郁样作用；利用药理学手段基本阐明胍丁胺抗抑郁样作用的主要靶点是I1咪唑啉受体，神经机制可能与逆转海马神经再生和神经营养障碍有关。另外，利用基因敲除模式动物发现I1咪唑啉受体基因敲除影响小鼠的抑郁及焦虑样行为，进一步表明了I1咪唑啉受体在抑郁症中的重要作用。鉴于抑郁症与创伤后应激障碍（PTSD）同属于神经可塑性障碍疾病，且目前批准的PTSD治疗药物均是抗抑郁药（但效果不理想），提示二者在病理机制中可能有共同之处，因此本项目增加了胍丁胺-I1咪唑啉受体抗PTSD的研究。利用大、小鼠PTSD模型研究首次发现胍丁胺具有抗PTSD作用，其机制至少部分由I1咪唑啉受体介导、可能与逆转谷氨酸系统功能紊乱有关。综上所述，本项目研究发现了胍丁胺-I1咪唑啉受体系统在抑郁症的病理机制中具有重要作用，同时发现该系统在PTSD发生中也发挥作用，为探索抑郁症及PTSD的共性机制、寻找新的潜在治疗靶标和候选药物提供了一定的理论基础。