黄连碱通过miR-874调控IDO改善脓毒症后认知功能障碍的机制研究

Post-sepsis Cognitive Dysfunction (PCD) is one of the most common nerve system complications in critically ill patients, and is associated with substantially increased morbidity, mortality, and cost of care. Our study has demonstrated that indoleamine 2,3-dioxygenase (IDO), a rate-limiting enzyme of kynurenine pathway which converts tryptophan into kynurenine in extrahepatic tissues, can contribute to the development of PCD. Accumulation of IDO induced by pro-inflammatory cytokines in sepsis, can produce neurotoxic metabolites, which results in ROS-associated mitochondrial pathway of neuron apoptosis, contributing to PCD pathogenesis and leading to impairment of learning and memory. However, the underlying mechanism what and how increase expression of IDO is unknown. Our preliminary studies in vitro (primary neurons), further have found that pro-inflammatory cytokines could down-regulate the level of miR-874, which complementarily pair with IDO mRNA. Consistent with the notion that coptisine, which is a main pharmacological active constituent of the traditional Chinese medicinal prescription huanglianjiedutang, have a good blood brain barrier permeability. Collectively, the hypothesis of the proposed studies is that coptisine can decrease neuron apoptosis and alleviate PCD via miR-874 down-regulating IDO. We will use in vitro (primary neurons) and in vivo (mice) approach, with genetic tools to test the hypothesis and to determine the underlying miR-874/IDO mechanism. The outcomes from the proposed studies would significantly contribute to our understanding of the PCD neuropathogenesis, leading to targeted interventions of PCD in the future.

脓毒症后认知功能障碍(PCD) 是脓毒症患者最常见的远期神经系统并发症，其发病机制不明。本课题组前期研究发现，脓毒症时吲哚胺2，3-双加氧酶(IDO)上调介导的神经损伤效应是导致PCD的重要原因。同时， miR-874表达下降，而黄连碱可逆转以上改变。在此基础上，本项目拟利用小鼠及原代培养神经元首先验证：黄连碱通过减少神经元凋亡改善PCD。进而从细胞、动物、患者三个层面验证miR-874及IDO与PCD发生发展的关系。通过过表达/沉默miR-874和/或IDO证明：1)脓毒症时miR-874下调导致 IDO过表达，是诱导神经元凋亡，小鼠罹患PCD的重要原因； 2)黄连碱通过上调miR-874，调控IDO逆转以上病理过程。以上问题的解决将使我们从新的角度和深度揭示PCD的作用机制，而创新性使用黄连碱改善PCD，既是对祖国医药的传承和发展，也为临床开辟一个全新的、具有良好应用前景的治疗方向。

本课题组通过系列研究进一步验证了脓毒症时吲哚胺2，3-双加氧酶(IDO)上调介导的神经损伤效应是导致PCD的重要原因。同时，miR-874表达下降，而黄连碱干预可逆转以上改变。在此基础上，本 项目利用小鼠及原代培养神经元首先验证了：（1）黄连碱通过减少神经元凋亡改善PCD；（2）进而从细胞、动物、患者三个层面验证了miR-874及IDO与PCD发生发展的关系；（3）通过过表达/沉默miR-874 和/或IDO证明了：脓毒症时miR-874下调导致 IDO过表达，是诱导神经元凋亡，小鼠罹患PCD的重要原；黄连碱通过上调miR-874，调控IDO逆转以上病理过程从而减少神经元凋亡进一步减少了PCD的发生。该课题从新的角度和深度揭示PCD的作用机制，进而通过一些列研究验证了使用黄连碱干预改善PCD，既是对祖国医药的传承和发展， 也为临床开辟一个全新的、具有良好应用前景的治疗方向。..