运动的抗抑郁机制——线粒体介导的炎症反应与神经元胰岛素抵抗研究

The presence of a proinflammatory state activates the tryptophan- and serotonin-degrading enzyme indoleamin 2,3-dioxygenase (IDO), leading to increased consumption of tryptophan. Stimulation of IDO and kynurenine monooxygenase by pro-inflammatory states further results in the production of tryptophan, which is involved in major depression. This also cause lowered mitochondrial energy metabolism, the generation of ROS and lipid peroxidation, and an increase in neuroexcitatory and neurotoxic effects. Mitochondrial dysfucntion is implicated in the pathology of both depression and type 2 diabetes(T2DB), however, continuing use of antidepressant medication is associated with an increased relative risk of T2DB. Concurrent effects of AICAR (a pharmacological activator of AMPK) on brain insulin action and mitochondrial function suggest a potential of neural insulin resistance, which may further increase our understanding on the link between depression and T2DB. Fortunately, regular exercise is often regarded as an effective treatment of depression and diabetes for its role in mitochondrial remodeling. Therefore, the current study aims to explore: 1) whether and how cytokines and mitochondrial dysfunction are involved in the effects of exercise on depressive-like behaviors; 2) whether and how AICAR and exercise, as a drug or physical therapy, have an antidepressant effect on depression; 3) whether and how neural insulin resistance induces drpressive-like behaviors. The prospective findings are supposed to further understand the pathophysiology of depression, and suggest a new target or guide for pharmacological research and development against depression.

细胞因子（CK）激活吲哚胺2,3-双加氧酶（IDO），IDO活化可使色氨酸循犬尿氨酸途径分解代谢，进而诱发ROS的产生，ROS可导致神经元线粒体DNA缺失、功能异常，从而介入抑郁症的发生。线粒体功能异常与抑郁症（CNS）及其2型糖尿病（外周组织）的发病密切相关，常用抗抑郁药物会增加糖尿病的发病风险。AMPK激活剂AICAR对大脑胰岛素信号和线粒体功能的促进作用揭示神经系统胰岛素抵抗的可能性，这将有助于深入理解抑郁症与糖尿病间的病理关系。运动可能通过线粒体重塑防治糖尿病和抑郁症。本项目拟探讨：1）海马与前额皮质的线粒体功能与促炎细胞因子在运动改善抑郁行为中的关联机制；2）线粒体功能激活剂AICAR与运动对抑郁行为的防治作用及其神经生化机制；3）神经元胰岛素抵抗诱导抑郁行为的可能性及改善机制。预期成果将进一步阐明抑郁症与炎症反应、线粒体功能相关的发病机制，为抗抑郁的药物研发和行为干预提供靶点。

(一).背景与主要研究内容.线粒体功能异常与抑郁症（CNS）及2 型糖尿病（外周组织）的发病密切相关，常用抗抑郁药物会增加糖尿病的发病风险。AMPK 激活剂AICAR 对大脑胰岛素信号和线粒体功能的促进作用揭示神经系统胰岛素抵抗的可能性，这将有助于深入理解抑郁症与糖尿病间的病理关系。本项目构建了抑郁症与糖尿病共病动物模型，探讨了AICAR和运动对抑郁症与糖尿病共病的改善作用，以及AICAR、运动锻炼改善慢性应激（CUMS）所致抑郁行为的炎症反应机制。.(二).重要结果与关键数据.1、运动改善慢性应激大鼠抑郁行为与促炎细胞因子以及IDO激活有关。研究发现：运动锻炼改善了CUMS所致抑郁行为，吲哚胺2,3-双加氧酶（IDO）介导的神经炎症反应减轻。.2、AICAR与运动改善高脂膳食+皮质酮联合干预导致的小鼠抑郁行为。研究发现：高脂膳食和皮质酮联合处理导致胰岛素抵抗和抑郁行为同时发生，游泳与AMPK激活剂AICAR都能改善小鼠的抑郁行为及其胰岛素抵抗状态。.3、NO对AICAR改善胰岛素抵抗小鼠抑郁行为必不可少。研究发现，AICAR增加了前额皮质NO的释放和总NOS活性，NOS抑制剂L-NAME和7-NI都会导致在联合开场实验和强迫游泳实验中AICAR抗抑郁作用的完全阻断。运动不仅增加了前额皮质中AMPK、NOS的活性和NO的生成，也同时增加了其在骨骼肌中的水平。.4、代谢因子激活的炎症反应介导运动的抗抑郁作用。研究发现，CUMS刺激前额皮质Ghrelin及其受体的表达，但是抑制leptin及其受体表达。运动可以通过GSK-3beta、STAT3的磷酸化修饰，进而改善CUMS小鼠中枢系统代谢与炎症反应。.(三).科学意义.本研究揭示：抑郁症可能也是一种代谢疾病或代谢疾病的并发症，靶向代谢改善是治疗和预防抑郁症的新方向。NO非但不是抑郁样行为障碍的罪魁祸首，反而对AICAR的抗抑郁作用至关重要。运动可能通过代谢、炎症反应的改善发挥抗抑郁作用。以上研究为慢性应激、糖皮质激素所致的抑郁行为的运动改善机制提供了更确切的分子依据。