α7-nAChRs对星形胶质细胞功能的调控及与肝性脑病的相关性研究

Hepatic encephalopathy (HE) is a serious complication of acute and chronic liver diseases and has a high mortality rate. The neuropathological features of HE primarily include changes in the morphology and function of cells of the glial (rather than neuronal) lineage and have led to the suggestion that HE is a primary gliopathy. The pathogenesis of HE remains unclear, and there is no means of prevention or effective cure for the disease. Recent work on glial cell physiology has revealed that glial cells, and astrocytes in particular, are much more actively involved in brain inflammation processing than previously thought. An improved understanding of astrocyte biology and the involvement of these cells in pathogenesis of HE offers the potential for developing novel strategies to treat HE. There is now a substantial body of evidence from studies in patients and animal models demonstrating that inflammation causes worsening of encephalopathy and that proinflammatory mechanism may act synergistically with ammonia toxicity and result in the cerebral complications of acute and chronic liver failure. Recent studies suggest the implications of the α7 nicotinic acetylcholine receptors (α7-nAChRs) as a critical link in nicotinic anti-inflammatory pathway. Our previous data have demonstrated that in rat primary cultured astrocytes, pretreatment with nicotine suppressed LPS-induced astrocyte activation evidenced by both decreased production of TNF-α and inhibition of Erk1/2 and p38 activation in astrocytes, and these effects also were reversed by the α7-nAChR-selective antagonist methyllycaconitine (MLA). Therefore, the objective of the present study was to determine whether nicotine, acting at α7-nAChRs, could regulate astrocyte-mediated disfunction, and may provide some insight into changes in cholinergic signaling associated with HE pathogenesis and present valuable information for new drug therapies. We explore the regulatory effects of α7-nAChRs on astrocyte function through the neuron-astroglia co-culture system in vitro models. Further, we establish A type and C type rat HE models to investigate the roles of α7-nAChRs on astrocyte function and liver function in vivo models, and test hypothesis about α7-nAChRs providing a new therapeutic strategy for treatment of neurological disorders. Nicotinic agonists that specifically target the α7-nAChR might be developed and serve as potential therapeutic agents for HE and other neuroinflammation-related central nervous system diseases.

肝性脑病（Hepatic encephalopathy, HE）是急慢性肝病较严重的并发症，神经病理学特征主要是胶质细胞的形态学和功能学发生变化，被认为是原发性胶质病。星形胶质细胞炎性机制在HE发病机制中的地位近年来受到重视。"烟碱能抗炎通路"在免疫炎症反应中的作用与多种疾病相关，我们的预实验结果提示烟碱可显著抑制LPS诱导的大鼠星形胶质细胞的活化，选择性α7-nAChRs阻断剂MLA可逆转烟碱的抗炎效应。因此，我们提出假说：α7-nAChRs激动剂在肝性脑病中发挥神经保护作用。为了验证这一假说，我们在体外通过原代培养的星形胶质细胞及神经元，研究α7-nAChRs对星形胶质细胞的功能调控机制及与神经元的交互调节作用。体内通过HE大鼠模型，在整体水平观察α7-nAChRs对星形胶质细胞功能的影响，并同时评价其对HE大鼠模型肝脏功能的影响，为探索靶向特定烟碱受体的调节剂、防治HE提供学术依据。

肝性脑病（Hepatic encephalopathy, HE）是急慢性肝病较严重的并发症，神经病理学特征主要是胶质细胞的形态学和功能学发生变化，被认为是原发性胶质病。星形胶质细胞炎性机制在HE发病机制中的地位近年来受到重视。“烟碱能抗炎通路”在免疫炎症反应中的作用与多种疾病相关，我们的预实验结果提示烟碱可显著抑制LPS诱导的大鼠星形胶质细胞的活化，选择性α7-nAChRs阻断剂MLA可逆转烟碱的抗炎效应。因此，我们提出假说：α7-nAChRs激动剂在肝性脑病中发挥神经保护作用。为了验证这一假说，我们在体外通过原代培养的星形胶质细胞及神经元，研究α7-nAChRs对星形胶质细胞的功能调控机制及与神经元的交互调节作用，发现烟碱可以通过α7-nAChRs 抑制双氧水诱导的星形胶质细胞的凋亡和线粒体膜电位的缺失，改善双氧水对星形胶质细胞神经营养因子的抑制作用，稳定BAX/Bcl-2和抑制caspase-9的激活，在体通过HE大鼠模型，在整体水平观察α7-nAChRs对星形胶质细胞功能的影响，并同时评价其对HE大鼠模型肝脏功能的影响，为探索靶向特定烟碱受体的调节剂、防治HE提供学术依据。