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Molecular mechanisms of glial activation and cell death

胶质细胞活化和细胞死亡的分子机制

基本信息

批准号：
09470504
负责人：
BABA Akemichi
金额：
$ 8.45万
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：
1997
资助国家：
日本
起止时间：
1997 至 1999
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-09470504/
关键词：
astroglia neuron cell death endothelin ischemia NaィイD1+ィエD1-CaィイD12+ィエD1 antiporter calcineurin gliosis

项目摘要

This study was aimed to clarify the functional roles of glial cells in neuron-glia interactions in pathological situations, such as ischemic brain injury. The following results were obtained.1. A stab wound injury on rat cerebral cortex increased immunoreactive endothelin-1 and reactive astrocytes at the injured site, and this was reversed by a endothelin B receptor antagonist.2. Endothelin induced cytoskeletal actin re-organization in cultured astrocytes, and this action was dependent on activation of the small GTP-binding protein Rho, and tyrosine phosphorylation of focal adhesion proteins.3. CaィイD12+ィエD1depletion followed by reperfusion with CaィイD12+ィエD1-containing medium causes cell death in cultured astrocytes (CaィイD12+ィエD1paradox-like injury), but not in neurons. This was triggered by an increased CaィイD12+ィエD1 influx through NCX in the reverse mode followed by generation of reactive oxygen species and activation of calcineurin and NF-κB.4. The CaィイD12+ィエD1 paradox-like injury was attenuated by inhibitors of NCX, calcineurin, caspase, or cathepsine, and also by cognitive enhancers, and nerve growth factor (NGF).In the present study, we revealed that endothelin signalling are involved in morphological astrocytic changes and cellular actions (activation). We also investigated the mechanisms underlying delayed glial cell death with respect to NCX activation and intracellular signaling molecules, and revealed that the CaィイD12+ィエD1paradox injury of cultured astrocytes is considered to be an in vitro model of ischemia/reperfusion injury. It is anticipated that these studies on activation and cell injury of astrocytes will contribute to development of new drugs that modulate the function of astrocytes.

本研究旨在阐明神经胶质细胞在缺血性脑损伤等病理情况下神经元-胶质细胞相互作用中的功能作用。得到了以下结果：大鼠大脑皮层的刀伤损伤增加了损伤部位的免疫反应性内皮素-1和反应性星形胶质细胞，内皮素B受体拮抗剂可逆转这种情况。内皮素在培养的星形胶质细胞中诱导细胞骨架肌动蛋白重组，这种作用依赖于小gtp结合蛋白Rho的激活和局灶黏附蛋白的酪氨酸磷酸化。在培养的星形胶质细胞中，再灌注含有Ca D12+ d1的培养基可导致细胞死亡（Ca D12+ d1悖论样损伤），但在神经元中不会。这是由Ca γ γ γ + γ γ γ以反向模式通过NCX内流增加引发的，随后是活性氧的产生和钙调磷酸酶和NF-κB.4的激活。NCX、calcalineurin、caspase或cathepine抑制剂以及认知增强剂和神经生长因子（NGF）均可减轻Ca γ γ - D12+ γ γ - D1似是而非的损伤。在本研究中，我们发现内皮素信号参与星形细胞的形态变化和细胞活动（激活）。我们还从NCX激活和细胞内信号分子方面研究了延迟胶质细胞死亡的机制，并发现培养的星形胶质细胞的Ca γ γ γ - D12+ γ γ - d1悖论损伤被认为是缺血/再灌注损伤的体外模型。这些关于星形胶质细胞活化和细胞损伤的研究将有助于开发调节星形胶质细胞功能的新药。