PDE4抑制剂通过调控HMGB1介导小胶质细胞活化改善抑郁样行为的作用及机制研究

小胶质细胞内HMGB1及其受体RAGE和TLR4的过度活化参与抑郁症发生。磷酸二酯酶4(PDE4) 是介导神经炎症的关键蛋白，是抗抑郁药研究的重要靶点，但PDE4抑制剂是否通过作用于小胶质细胞HMGB1及其下游通路发挥抗抑郁作用还不清楚。我们在抑郁症动物模型中发现PDE4抑制剂具有良好的抗抑郁作用并可抑制小胶质细胞活化及小胶质细胞内RAGE的表达。抑制PDE4能显著降低海马组织HMGB1表达，减少其受体RAGE及其下游NF-κB活化介导的IL-1β的生成。据此我们提出假说：抑制PDE4能显著降低小胶质细胞内HMGB1的产生及其受体介导的神经免疫反应，从而发挥抗抑郁作用。本项目拟在抑郁症模型中系统研究PDE4抑制剂对小胶质细胞中HMGB1介导的信号通路及神经炎症的影响，以及PDE4抑制剂影响小胶质细胞内HMGB1表达的机制。本项目对于探讨抑郁症发病机制及获得新型抗抑郁药物靶点具有重要意义。

Over-activation of HMGB1 and its receptors RAGE and TRL4 in microglial cells are involved in the pathology of depression. Phosphodiesterase 4 (PDE4) in microglia is a key protein that mediates neuroinflammation, and PDE4 is also an excellent target for the development of antidepressants. While whether PDE4 inhibitors exert antidepressive-like effects by acting on microglia is still unclear. We have previously found that PDE4 inhibitors inhibit microglia activation, reduce the expression of HMGB1 and its receptors, and decrease HMGB1-mediated production of IL-1β in animal models of depression. Based on these findings, we hypothesize that inhibition of PDE4 in microglia significantly inhibits HMGB1-mediated neuroimmune response and reduces cytokine production, thereby exerting antidepressant effects. However, it is unclear which signaling pathway is responsible for the regulation of HMGB1 by PDE4 inhibitors in microglia. Using both in vitro and in vivo models of depression, we aim to study the effect of PDE4 inhibitor on HMGB1-mediated signaling pathway and the mechanism by which PDE4 affects the expression of HMGB1 in microglia. The research of this project is of great significance for exploring the pathogenesis of depression and obtaining targets for new antidepressants.