Pathophysiological studies on Na^+-Ca^<2+> exchanger in the central nervous system

中枢神经系统Na^-Ca^<2>交换体的病理生理学研究

• 批准号: 08672606
• 负责人: MATSUDA Toshio
• 金额: $ 1.34万
• 依托单位: Osaka University
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (C)
• 财政年份: 1996
• 资助国家: 日本
• 起止时间: 1996 至 1997
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-08672606/
• 关键词: Na^+-Ca^<2+> exchanger; antiporter; cell death; reperfusion injury; astrocyte; calcineurin; FK506; FK506; 一酸化窒素

This studies were aimed to clarify the pathophysiological roles of the Na^+-Ca^<2+> exchanger (NCX) in glial cells. The following results were obtained. 1) Receptor operated Ca^<2+> signal is regulated by NCX in the forward mode. 2) Ca^<2+> repletion after Ca^<2+> depletion causes an increase in intracellular Ca^<2+> concentration followed by cell death in cultured astrocytes. 3) This injury (Ca^<2+> paradox-like injury) is mediated by an activation of NCX in the reverse mode. 4) The Ca^<2+> paradox-like injury is attenuated by NCX inhibitors, heat shock protein and calcineurin inhibitors. 5) Heat shock protein and calcineurin inhibitors do not affect the change in intracellular Ca^<2+> induced by Ca^<2+> paradox. 6) Novel compounds inhibit NCX activity in astrocytes at nM level. 7) Hydrogen peroxide is involved in the Ca^<2+> paradox-like injury. 8) mRNA levels of rat brain NCX isoforms (NCX1, NCX2 and NCX3) are not changed by ischemia/reperfusion. 9) Competitive PCR analysis shows that main isoform of the NCX differs between neurons and astrocytes, and they have the different sensitivity to Na^+.

本研究旨在阐明神经胶质细胞中Na^+-Ca^2+交换器(NCX)的病理生理学作用。得到以下结果。 1)受体操作的Ca^2+信号在正向模式下由NCX调节。 2)Ca 2+ 耗尽后Ca 2+ 补充导致细胞内Ca 2+ 浓度增加，随后培养的星形胶质细胞死亡。 3)这种损伤(Ca ^ 2+ 悖论样损伤)是由NCX以相反模式激活介导的。 4)NCX抑制剂、热休克蛋白和钙调神经磷酸酶抑制剂可减轻Ca 2+ 悖论样损伤。 5)热休克蛋白和钙调神经磷酸酶抑制剂不影响Ca^2+悖论引起的细胞内Ca^2+的变化。 6) 新型化合物可在 nM 水平上抑制星形胶质细胞中的 NCX 活性。 7)过氧化氢参与Ca ^ 2+ 悖论样损伤。 8) 大鼠脑NCX亚型（NCX1、NCX2和NCX3）的mRNA水平不因缺血/再灌注而改变。 9) 竞争性PCR分析表明，神经元和星形胶质细胞的NCX主要亚型不同，并且它们对Na^+具有不同的敏感性。

项目成果

Toshio Matsuda: "Possible role of Na^+-Ca^<2+> exchanger in nitric oxide-induced serotonin release in the striatum of freely moving rats." Preclin.Clin.Strat.Treat.Neurodeg.Cerebrovas.Ment.Dis.11. 129-132 (1996)

Toshio Matsuda：“Na ^ -Ca ^ 2 交换器在自由活动大鼠纹状体中一氧化氮诱导的血清素释放中的可能作用。”

松田敏夫: "グリア細胞におけるCa^<2+>アンチポーターによる細胞内Ca^<2+>調節" 日薬理誌. 108. 109P-114P (1996)

Toshio Matsuda：“神经胶质细胞中 Ca^2+ 逆向转运蛋白对细胞内 Ca^2+ 的调节”，《日本药理学杂志》108. 109P-114P (1996)。

松田敏夫: "Na^+/Ca^<2+>交換輸送蛋白" 日本臨床. 54. 36-41 (1996)

Toshio Matsuda：“Na^+/Ca^<2+>交换转运蛋白”日本临床研究 54. 36-41 (1996)。

Kazuhiro Takuma: "Heat chock protects cultured rat astrocytes in a model of reperfusion injury." Brain Res.735. 265-270 (1996)

Kazuhiro Takuma：“热休克可以保护再灌注损伤模型中培养的大鼠星形胶质细胞。”

Toshio Matsuda: "Possible role of Na^+-Ca^<2+> exchanger in nitric oxide-induced serotonin release in the striatum of freely moving rats." Preclinical and Clinical Strategies for the Treatment of Neurodegenerative,Cerebrovas. Mental Disorders. 11. 129-132

Toshio Matsuda：“Na ^ -Ca ^ 2 交换器在自由活动大鼠纹状体中一氧化氮诱导的血清素释放中的可能作用。”