Signal cascade of glial apoptosis and its protection

胶质细胞凋亡的信号级联及其保护

• 批准号: 11470512
• 负责人: MATSUDA Toshio
• 金额: $ 7.17万
• 依托单位: Osaka University
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (B)
• 财政年份: 1999
• 资助国家: 日本
• 起止时间: 1999 至 2001
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-11470512/
• 关键词: apoptosis; Ca^<2+>; MAP Kinase; cyclic GMP; astrocyte; microglia; neuron; neuroprotection; 過酸化水素; ホスホジエステラーゼ; イブジラスト; ミトコンドリア; NF-κB; conditioned medium; β-アミロイド蛋白; NF-KB; カルシニューリン

The present study was carried out to clarify the mechanisms of cell death in cultured astrocytes, microglia and neurons. Incubation of cultured astrocytes in Ca^<2+>-containing medium after exposure to Ca^<2+>-free medium causes an increase in intracellular Ca^<2+> concentration followed by,delayed cell death. This injury is considered to be an in vitro model of ischaemia/reperfusion injury. This review summarizes our current studies on the mechanisms underlying the Ca^<2+>-mediated injury of cultured astrocytes and, target molecules, for drugs to prevent the reperfusion injury. Ca^<2+> reperfusion injury of astrocytes appears to be mediated by apoptosis as evidenced by DNA fragmentation and nuclear condensation. Calpain, reactive oxygen species, calcineurin, caspase-3, and NF-κB are involved in the Ca^<2+> reperfusion injury. Several neuroprotective drugs including NGF, T-588, idebenone, and ibudilast prevent astrocyte apoptosis in the reperfusion injury models using Ca^<2+> depletion or hydrogen peroxide. The protective effects of these drugs are, mediated by phosphatidylinositol-3 kinase, mitogen-activated protein/extracellular signal-regulated kinase, nerve growth factor production, and cyclic GMP-dependent protein kinase. The analysis on the mechanism for the cyclic GMP effect indicates that the mitochondrial permeability transition pore plays a key role in, apoptotic events of cultured astrocytes

本研究旨在阐明体外培养的星形胶质细胞、小胶质细胞和神经元的细胞死亡机制。将培养的星形胶质细胞暴露于无Ca^<2 +>培养基后，在含Ca^<2+>培养基中孵育，导致细胞内Ca^<2+>浓度增加，随后细胞死亡延迟。该损伤被认为是缺血/再灌注损伤的体外模型。本文综述了近年来对钙离子介导的星形胶质细胞损伤机制的研究进展，以及针对钙离子介导的星形胶质细胞再灌注损伤的药物靶分子。星形胶质细胞的Ca^<2+>再灌注损伤似乎是由细胞凋亡介导的，如DNA断裂和核浓缩所证明的。钙蛋白酶、活性氧、钙调神经磷酸酶、caspase-3和NF-κB参与Ca^<2+>再灌注损伤。几种神经保护药物，包括NGF、T-588、艾地苯醌和异丁司特，在使用Ca^2+耗竭或过氧化氢的再灌注损伤模型中防止星形胶质细胞凋亡。这些药物的保护作用由磷脂酰肌醇-3激酶、促分裂原活化蛋白/细胞外信号调节激酶、神经生长因子产生和环GMP依赖性蛋白激酶介导。对环鸟苷酸作用机制的分析表明，线粒体通透性转换孔在培养星形胶质细胞凋亡事件中起关键作用

项目成果

K.Takuma, et al.: "Signal cascade of Na^+/Ca^<2+> exchanger-involved delayed apoptosis of astrocytes"Control and Diseases of Sodium Dependent Transport Proteins and Ion Channels. 87-88 (2000)

K.Takuma等人：“Na 2 /Ca 2 交换器涉及的星形胶质细胞延迟凋亡的信号级联”钠依赖性转运蛋白和离子通道的控制和疾病。

K.Takuma et al.: "CV-2619 protects cultured astrocytes against reperfusion injury via nerve growth factor production"Eur.J.Pharmacol.. 406. 333-339 (2000)

K.Takuma 等人：“CV-2619 通过神经生长因子的产生保护培养的星形胶质细胞免受再灌注损伤”Eur.J.Pharmacol.. 406. 333-339 (2000)

K.Takuma et al.: "T-588 inhibits astrocyte apoptosis via mitogen-activated protein kinase signal pathway"European Journal of Pharmacology. 399. 1-8 (2000)

K.Takuma 等人：“T-588 通过丝裂原激活蛋白激酶信号通路抑制星形胶质细胞凋亡”欧洲药理学杂志。

K.Takuma et al.: "Signal cascade of Na^+/Ca^<2+> exchanger-involved delayed apoptosis of astrocytes"Control and Diseases of Sodium Dependent Transport Proteins and Ion Channels, (ed. By Y.Suketa, E.Carafori, M.Lazdunski, K.Mikoshiba, Y.Okada, E.M.Weight)

K.Takuma 等人：“Na ^ /Ca ^ 2 交换器涉及的星形胶质细胞延迟凋亡的信号级联”钠依赖性转运蛋白和离子通道的控制和疾病，（Y.Suketa、E.Carafori 编辑）

T.Matsuda et al.: "SEA0400, a novel and selective inhibitor of the Na^+-Ca^<2+> exchanger, attenuates reperfusion injury in the in vitro and in vivo cerebral ischemic models"J.Pharmacol.ExTher.. 298. 249-256 (2001)

T.Matsuda 等人：“SEA0400 是一种新型选择性 Na^-Ca^2 交换抑制剂，可减轻体外和体内脑缺血模型中的再灌注损伤”J.Pharmacol.ExTher.. 298。