组胺对星形胶质细胞炎症反应的调控在外周术后中枢炎症及神经认知障碍中的作用

Neuroinflammation, induced by peripheral surgery, is a prominent contributor to the development of postoperative cognitive disorder. Previous studies have confirmed that peripheral surgery promoted over-activation of astrocytes, increased levels of proinflammatory cytokine, suppressed production of glial cell-derived neurotrophic factor, and induced deficits in learning and memory. Notably, our recent study found that histamine could evoke the neuroprotective effect of astrocytes by negative regulation of astrocytic TNF-α and IL-1β production along with upregulation of GDNF synthesis in vitro. Based on these data, we hypothesized that histamine might play anti-inflammatory and neuroprotective roles in the inflamed CNS. Attenuation of the proinflammatory effects of astrocytes and improvement of their anti-inflammatory responses seems to be important mechanisms underlying the protective effects of histamine. We will use dividual animal model, cellular and molecular biological methods to investigate the role of histamine- mediated immune response of astrocyte in ameliorating postoperative neuroinflammation and cognitive disorder. This will provide a novel potential target for the prevention and treatment of postoperative neuroimmune diseases.

术后认知障碍与外周手术促发的中枢炎症相关。前期发现：外周手术会激活脑内星形胶质细胞，同时海马中炎症因子释放增多，胶质细胞源性神经营养因子（GDNF）表达下降，动物学习记忆能力损伤。已知组胺可下调星形胶质细胞炎症因子的表达，促GDNF的释放，发挥抗炎及神经保护作用。据此，我们提出假说：脑内组胺通过相应受体抑制术后脑内星形胶质细胞的活化，上调GDNF的表达，降低炎症因子释放，缓解中枢炎症，保护神经功能。我们拟采用组氨酸脱羧酶敲除小鼠和正常小鼠从行为学、细胞学和分子生物学层面，探讨组胺对星形胶质细胞炎症反应的调控与GDNF表达在外周创伤致中枢炎症中的作用及机制，为术后认知障碍和相关神经疾病的防治提供新思路。

围术期神经认知障碍（PND）是高龄患者术后常见的严重神经系统并发症，受到临床工作者和神经免疫学者的关注。中枢炎症现被认为是PND发生发展的主要机制。我们前期研究发现，脑内星形胶质细胞异常活化介导了术后海马区的神经炎症反应。脑内组胺在多种中枢炎症及神经退行性疾病中扮演重要角色，细胞实验发现组胺单独作用于星形胶质细胞可减少其炎症因子的释放，并促进胶质细胞源性神经营养因子的表达。本课题主要探讨组胺是否能够在中枢炎症中负向调控星形胶质细胞的激活，减轻炎症反应，保护海马神经元及此作用主要由何种组胺受体参与。离体实验发现：脂多糖（LPS）刺激原代星形胶质细胞后，H1R、H2R、H3R三种组胺受体表达明显下降,而炎症因子分泌显著增加。预先给与组胺能够上调三种组胺受体的表达，抑制LPS诱导的星形胶质细胞的过度激活，减少炎症因子的释放。单独使用各组胺受体激动剂干预发现，H1R、H2R、H3R受体激动剂均能够负向调控LPS介导的星形胶质细胞的炎症反应，其中H1R发挥主要调节作用。此外，组胺及各受体激动剂对星形胶质细胞的炎症调控作用可能与JNK/NF-κB信号通路有关。在体实验发现：外周开腹手术后24h，海马区小胶质细胞活化数目和炎症因子水平显著增加，A1神经毒性星形胶质细胞增多，海马神经元损伤，大鼠学习记忆能力受损，而侧脑室预先给与组胺可减少活化的小胶质细胞，降低炎症因子水平，下调A1型星形胶质细胞的表达，改善大鼠学习记忆。.我们的研究结果丰富了PND的中枢炎症学说，为防治POCD提供了新的思路。