Neuroprotective effects exerted by activated microglia

激活的小胶质细胞发挥的神经保护作用

基本信息

批准号：
16390066
负责人：
NAKATA Yoshihiro
金额：
$ 4.93万
依托单位：
HIROSHIMA UNIVERSITY
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (B)
财政年份：
2004
资助国家：
日本
起止时间：
2004 至 2005
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-16390066/
关键词：
microglia neuroprotection ATP TNF P2X_7 receptors nicotine LPS 脳虚血モデル α7受容体 MAP2 in vivo

项目摘要

Microglia perform both neuroprotective and neurotoxic functions in the brain, with this depending on their state of activation and their release of mediators. Upon a brain insult, ATP is released from damaged cells and activates microglia. The microglia that are activated in this way then release a range of bioactive substances, one of which is tumor nectosis factor (TNF). The release of TNF appears to be dependent on the P2X_7 receptor. The inhibitors, U0126, SP600125 and SB203580, which target MEK, JNK and p38, respectively, all potently suppress the production of TNF in ATP-stimulated microglia, whereas the production of TNF mRNA from accumulating in the cytoplasm. The ATP-provoked activation of JNK and p38, but not ERK, could be inhibited by brilliant blue G, a P2X_7 receptor blocker, and by genistein and PP2, general and src-family specific tyrosine kinase inhibitors, respectively. The treatment of the microglia in neurone-microglia co-cultures with the P2X_7 agonist BzATP led to … More significant neuroprotective effects. On the other hand, LPS caused massive TNF release, but did not exert any protective effects on glutamate neurotoxity. In rat primary cultured microglia, α7 nicotinic acetylcholine receptor (α7 nAChR) is expressed, and the activation of this receptor by nicotine enhanced P2X_7 receptor-mediated TNF release, whilst suppressing LPS-induced TNF release. This response was independent of extracellular Ca^<2+> and blocked by U73122 and xestospongin C, inhibitors of phospholipase C and IP_3 receptor, respectively. In addition, nicotine-induced currents were not detected, suggesting that α7 nAChR may not function as conventional ion channels. This novel α7 nAChR signal may be involved in the nicotine modification of microglia activation towards a neuroprotective role by suppressing the inflammatory state and strengthening the protective function. Furthermore, intracerebroventricular injection of microglia protected neurodegeneration in brain ischemic model rats. Less

小胶质细胞在大脑中同时执行神经保护性和神经毒性功能，这取决于它们的激活状态和介体的释放。脑损伤后，ATP从受损细胞中释放出来并激活小胶质细胞。以这种方式激活的小胶质细胞释放了一系列生物活性物质，其中一种是肿瘤内核因子（TNF）。 TNF的释放似乎取决于P2X_7受体。分别针对MEK，JNK和P38的抑制剂U0126，SP600125和SB203580都可能抑制ATP刺激的小胶质细胞中TNF的产生，而TNF mRNA的产生在细胞质中积累。 JNK和p38而非ERK的ATP发动机激活可以被Brill Blue Blue G，P2X_7受体阻滞剂以及Genastein and pp2，General and src-家族特异性酪氨酸激酶抑制剂分别抑制。与P2X_7激动剂BZATP共同培养神经元 - 微胶质细胞中的小胶质细胞的治疗导致……更重要的神经保护作用。另一方面，LPS引起了大规模的TNF释放，但对谷氨酸神经毒性没有任何保护作用。在大鼠原发性培养的小胶质细胞中，表达α7烟碱乙酰胆碱受体（α7NACHR），并通过尼古丁增强的P2X_7受体介导的TNF释放来激活该受体，同时抑制了LPS诱导的LPS诱导的TNF释放。该反应独立于细胞外Ca^<2+>，并被U73122和Xestospongin C阻塞，分别是磷脂酶C和IP_3受体的抑制剂。另外，未检测到尼古丁诱导的电流，表明α7NACHR可能无法充当常规离子通道。这种新型的α7NACHR信号可能与尼古丁的修饰小胶质细胞激活通过抑制炎症状态并增强保护功能，使小胶质细胞激活向神经保护作用。此外，脑外缺血模型大鼠的小胶质细胞保护神经退行性的注射。较少的