Neuroprotective effects exerted by activated microglia

激活的小胶质细胞发挥的神经保护作用

• 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

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执行神经保护和神经毒性功能，这取决于它们的激活状态和介质的释放。在脑损伤时，ATP从受损细胞释放并激活小胶质细胞。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都有效地抑制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。P2X_7受体阻断剂亮蓝G、酪氨酸激酶抑制剂genistein和src家族特异性酪氨酸激酶抑制剂PP 2均能抑制ATP诱导的JNK和p38的激活，而ERK则不能。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， ...更多信息 显著的神经保护作用。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。原代培养的大鼠小胶质细胞表达α7烟碱乙酰胆碱受体（α7 nAChR），尼古丁激活α 7 nAChR可增强P2X_7受体介导的TNF释放，同时抑制LPS诱导的TNF释放。该反应不依赖于细胞外Ca^<2+>，并分别被磷脂酶C和IP_3受体抑制剂U 73122和xestospongin C阻断。此外，未检测到尼古丁诱导的电流，表明α7 nAChR可能不具有常规离子通道的功能。这种新的α7 nAChR信号可能参与尼古丁修饰小胶质细胞活化，通过抑制炎症状态和加强保护功能而发挥神经保护作用。此外，侧脑室注射小胶质细胞保护脑缺血模型大鼠的神经变性。少

项目成果

Production and release of neuroprotective tumor necrosis factor by P2X7 receptor-activated microglia

• DOI: 10.1523/jneurosci.3792-03.2004
• 发表时间: 2004-01-07
• 期刊: JOURNAL OF NEUROSCIENCE
• 影响因子: 5.3
• 作者: Suzuki, T;Hide, I;Nakata, Y
• 通讯作者: Nakata, Y

Microglial α7 nicotinic acetylcholine receptors drive a phospholipase C/IP3 pathway and modulate the cell activation toward a neuroprotective role

• DOI: 10.1002/jnr.20850
• 发表时间: 2006-06-01
• 期刊: JOURNAL OF NEUROSCIENCE RESEARCH
• 影响因子: 4.2
• 作者: Suzuki, Tomohisa;Hide, Izumi;Nakata, Yoshihiro
• 通讯作者: Nakata, Yoshihiro

Regulation of microglia activation and neuroprotection.

小胶质细胞激活和神经保护的调节。

• 发表时间: 2004
• 期刊: Folic Pharmacogical Japonica 124
• 作者: Izumi Hide;Yoshihiro Nakata
• 通讯作者: Yoshihiro Nakata

ミクログリアの活性制御と神経保護

小胶质细胞活动控制和神经保护

• 发表时间: 2004
• 期刊: 日本薬理学雑誌 124
• 作者: 秀 和泉;仲田義啓
• 通讯作者: 仲田義啓

Microglial α7 nicotinic acetylcholine receptors drive a phospholipase C/IP3 pathway and modulate the cell activation towards a neuroprotective role

小胶质细胞 α7 烟碱乙酰胆碱受体驱动磷脂酶 C/IP3 通路并调节细胞激活以发挥神经保护作用

• 发表时间: 2006
• 期刊: J. Neurosci Res 83
• 作者: Suzuki;T.Hide;I.;Matsubara,A.Hama;C.;Harada;K.Miyano;K.;Andra;M.;Matsubayashi;H.;Sakai,N.;Kohsaka,S.;Inoue,K.;Nakata,Y
• 通讯作者: Nakata,Y