权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

Mechanism underlying neuroprotection by activated microglia

激活小胶质细胞的神经保护机制

基本信息

批准号：
15590229
负责人：
HIDE Izumi
金额：
$ 1.79万
依托单位：
HIROSHIMA UNIVERSITY
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
2003
资助国家：
日本
起止时间：
2003 至 2004
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-15590229/
关键词：
microglia ATP P2X7 receptors TNF nicotine neuroprotection in vivo 神経保護作用 LPS IL-6

项目摘要

Microglia are the primary immune cells in the central nervous system. After a brain insult, ATP is released from injured cells and activates microglia. The microglia that are activated in this way then release a range of bioactive substances, one of which is tumor necrosis 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 is strongly inhibited by U0126 and SP600125. SB203580 did not affect the increased levels of TNF mRNA but did not prevent TNF mRNA from accumulating in the cytoplasm. The ATP-provoked activation of JNK and p38 [but not extracellular signal-regulated kinase (ERK)] could be inhibited by brilliant blue G, a P2X7 receptor blocker, and by genistein and PP-2, which are general and src-family-specific tyrosine kinase inhibitors, respectively. Most important, the treatment of the microglia in neurone-microglia cocultures with the P2X_7 agonist BzATP led to significant resuction in glutamate-induced neuronal cell death, and that either TNF-α converting enzyme inhibitor or anti-TNF readily suppressed the protective effect implied by this result. Recombinant TNF itself showed a significant neuroprotective effects. On the other hand, LPS caused massive TNF release, but did not exert any protective effects on glutamate neurotoxity. Furthermore we investigated whether microglia could exert this protective action in vivo [by collaboration with Dr.Taniguchi and Dr.Kitamura, Kyoto Pharmaceutical University]. The intracerebroventricular injection of microglia into ischemic model rats protected against focal ischemia-induced neurodegeneration, and BzATP pretreatment showed a tendency to strengthen such effects. Therefore, modulation of P2X_7 receptors of microglia might be amenable to therapeutic intervention for neurodegeneration.

小胶质细胞是中枢神经系统中的主要免疫细胞。在脑损伤后，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然后释放一系列生物活性物质，其中之一是肿瘤坏死因子（TNF）。TNF的释放似乎依赖于P2X_7受体。分别靶向MEK、JNK和p38的抑制剂U 0126、SP 600125和SB 203580均有效抑制ATP刺激的小胶质细胞中TNF的产生，而TNF mRNA的产生被U 0126和SP 600125强烈抑制。SB 203580不影响TNF mRNA水平的增加，但不阻止TNF mRNA在细胞质中的积累。ATP引起的JNK和p38 [而不是细胞外信号调节激酶（ERK）]的激活可以被P2 X7受体阻断剂亮蓝G以及分别是一般和src家族特异性酪氨酸激酶抑制剂的染料木素和PP-2抑制。最重要的是，用P2X_7激动剂BzATP处理神经元-小胶质细胞共培养物中的小胶质细胞导致谷氨酸诱导的神经元细胞死亡的显著再抽吸，并且TNF-α转化酶抑制剂或抗TNF容易抑制该结果所暗示的保护作用。重组TNF本身具有明显的神经保护作用。另一方面，LPS引起大量TNF释放，但对谷氨酸神经毒性没有任何保护作用。此外，我们研究了小胶质细胞是否可以在体内发挥这种保护作用[通过与京都药科大学的谷口博士和北村博士合作]。侧脑室注射小胶质细胞对脑缺血大鼠局灶性神经元变性有保护作用，而BzATP预处理有加强这种保护作用的趋势。因此，调节小胶质细胞的P2X_7受体可能适用于神经变性的治疗干预。