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Study of the molecular mechanism by which microglia are activated in the brain

大脑小胶质细胞激活的分子机制研究

基本信息

批准号：
10680734
负责人：
NAKAJIMA Kazuyuki
金额：
$ 1.92万
依托单位：
Soka University (1999-2000)National Center of Neurology and Psychiatry (1998)
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
1998
资助国家：
日本
起止时间：
1998 至 2000
项目状态：
已结题

项目摘要

Since the activation of microglia in vivo has been believed to affect largely the state of neuronal degeneration and/or regeneration, we analyzed the mechanism by which microglia are activated in the brain.(1) Brain-derived neurotrophic factor (BDNF) and ATP were selected as candidates for neuron-derived microglial activation factors from the observation of rat facial nerve transection model. The in vitro study revealed that BDNF enhanced the secretion of plasminogen (PGn) and urokinase (UK), and ATP induced morphological change and enhanced the secretion of PGn and tumor necrosis factor α (TNFα) from microglia. Therefore, it is suggested that neurotrophins and/or ATP are released to extracellular spaces from injured neurons and activate microglia in vivo.(2) Among factors which can suppress microglial functions, glial cell line-derived neurotrophic factor (GDNF) was found to show the strongest activity. This factor did not affect survival, morphology and proliferative activity, but suppressed the secretion of PGn and UK from microglia. GDNF was considered to play a role on the suppression of microglial activation which was observed in later stage of brain injury including facial nerve transection.(3) To analyze the signal transduction mechanism in the induction of microglial activation, lipopolysaccharide (LPS)-stimulating system was used for in vitro model. LPS induced the release of nitric oxide (NO) and TNFα in microglia. These secretions were suppressed by the pretreatment with specific protein kinase C (PKC) inhibitor, suggesting the strong association of PKC with NO and TNFα releases. Although MAP kinases including ERK, JNK and p38 were all activated by the stimulation with LPS, specific inhibitor of p38 inhibited strongly the release of TNFα, suggesting the association of p38 with TNFα release. The release of these cytotoxic factors from activated microglia was suggested to be regulated by PKC signaling pathway and the associated MAP kinase activity.

由于小胶质细胞在体内的激活被认为在很大程度上影响神经元退化和/或再生的状态，我们分析了小胶质细胞在大脑中激活的机制。(1)通过对大鼠面神经横断模型的观察，选择脑源性神经营养因子（BDNF）和ATP作为神经元源性小胶质细胞活化因子的候选因子。体外实验表明，BDNF可促进小胶质细胞纤溶酶原（PGn）和尿激酶（UK）的分泌，ATP可诱导小胶质细胞形态改变，促进PGn和肿瘤坏死因子α (TNFα)的分泌。因此，提示神经营养因子和/或ATP从损伤的神经元释放到细胞外空间，激活体内的小胶质细胞。(2)在抑制小胶质细胞功能的因子中，神经胶质细胞系源性神经营养因子（GDNF）的活性最强。该因子不影响小胶质细胞的存活、形态和增殖活性，但抑制小胶质细胞PGn和UK的分泌。GDNF被认为在包括面神经横断在内的脑损伤后期抑制小胶质细胞的激活中起作用。(3)为分析诱导小胶质细胞活化的信号转导机制，采用脂多糖（LPS）刺激系统建立体外模型。LPS诱导小胶质细胞释放一氧化氮（NO）和TNFα。这些分泌物被特异性蛋白激酶C （PKC）抑制剂预处理抑制，表明PKC与NO和TNFα的释放密切相关。虽然MAP激酶包括ERK、JNK和p38都被LPS激活，但特异性的p38抑制剂强烈抑制TNFα的释放，提示p38与TNFα的释放有关。这些细胞毒性因子从活化的小胶质细胞释放被认为受PKC信号通路和相关MAP激酶活性的调节。