胡椒碱通过抑制IL-1β介导的炎症反应在预防烟雾病进展中的作用及其相关机制探讨

Although the symptoms and neurological conditions of most patients with moyamoya disease (MMD) improved after their surgical treatments, a number of MMD patients will experience deterioration. The searches for effective drugs to prevent the postoperative development of MMD are very urgent.. According to some reported data, the immunizing inflammatory reaction was found to play an important role in the development of MMD. Our preliminary study is the first to have demonstrated the upregulation of COX-2 and mPGES-1 in the wall of the middle cerebral artery (MCA) from MMD patients. Our further study indicated that greater amounts of COX-2 protein expression were found in the MCA smooth muscle cells (SMCs) after stimulated by IL-1β. Combined with the fact that the high plasma concentration of IL-1β in MMD patients, we speculate that both IL-1β and COX-2 may play critical roles in the inflammatory response of MMD.. Piperine is a new drug and has been proved to have anti-inflammatory effect on the organism by downregulating the expression levels of IL-1β and COX-2. In our preliminary experiment, we found the elevated expression of COX-2 by IL-1β in the SMCs was significantly downregulated by the piperine. One purpose of the present project is to explore the effect of piperine on the development of MMD based on the results of in vitro and in vivo experiments. During the course of the project, the change of several MMD related inflammatory factors after using piperine will be detected by many commonly used molecular biology methods. The mechanism of the effect of piperine on the development of MMD will also be clarified. The data generated from this novel study are highly expected to provide theoretical and experimental basis for the development of new drugs for the treatment of MMD.

手术治疗是目前烟雾病的主要治疗手段，但部分患者在术后仍然出现病情复发或恶化，寻找有效的辅助药物防治烟雾病的进展非常重要。近年来研究表明免疫炎症反应可能是导致烟雾病进展的重要因素，本研究组首先发现烟雾病颅内血管壁上存在COX-2和mPGES-1的阳性表达，用IL-1β刺激颅内血管平滑肌细胞(SMCs)可以导致COX-2的表达增高，结合IL-1β在烟雾病患者血浆中含量增加，推断IL-1β介导的炎症反应在烟雾病进展中起重要作用。多项研究表明胡椒碱能通过下调IL-1β和COX-2的水平在机体起明确的抗炎作用，在预实验中我们也发现胡椒碱能明显抑制烟雾病颅内血管平滑肌细胞上COX-2的表达，据此本项目拟通过分析使用胡椒碱前后烟雾病各种相关炎性因子表达的变化，探讨胡椒碱能否起到防止烟雾病的进展的作用，并试图阐明其分子机制，为寻找烟雾病新型术后辅助药物提供理论和实验依据。

烟雾病发病机制复杂，目前主要靠手术治疗，无有效内科治疗手段。本项目主要研究胡椒碱通过抑制炎症反应对烟雾病发病中的作用，由于烟雾病动物模型构建失败临时改为研究炎症在烟雾病中的作用及胡椒碱对脑缺血再灌注损伤中的作用。研究发现COX-2、mPGES-1和PGE2在烟雾病颅内血管中表达显著上升，同时本课题组发现胡椒碱能明显下调脑缺血再灌注损伤大鼠脑梗死体积，起到神经保护作用，二者可能与其抑制补体和凝血级联反应有关。另外，本课题组还发现了锁骨旁皮质动脉血流动力学与术后脑过度灌注率的关系，提出了烟雾病治疗的新理念。本课题组共在在SCI上发表文章5篇，包括神经外科领域权威期刊Journal of Neurosurgery以及2篇JCR2区杂志文章，同时培养了博士研究生1名以及硕士研究生3名，均取得了相应学位。