Trifluoperazine and dibucaine-induced inhibition of glutamate-induced mitochondrial depolarization in rat cultured forebrain neurones.
Trifluoperazine and dibucaine-induced inhibition of glutamate-induced mitochondrial depolarization in rat cultured forebrain neurones.
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在大鼠培养的前脑神经元中，三氟拉嗪和地布卡因诱导抑制谷氨酸诱导的线粒体去极化。
DOI：
10.1038/sj.bjp.0701442
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发表时间：
1997
期刊：
影响因子：
--
通讯作者：
Reynolds,IJ
中科院分区：
文献类型：
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作者：
Hoyt,KR;Sharma,TA;Reynolds,IJ
谷氨酸受体的激活以前已被证明会导致线粒体去极化和激活的线粒体通透性转换孔在培养的神经元。在这项研究中，我们的特点是两个假定的通透性转换抑制剂，即三氟拉嗪和地布卡因，在大鼠完整的，培养的前脑神经元线粒体去极化的影响。渗透性转换监测以下线粒体去极化与线粒体膜电位敏感的荧光指示剂，JC-1加载的神经元。三氟拉嗪（10-20 μM）和地布卡因（50-100 μM）抑制或延迟谷氨酸诱导的渗透性转变的发生。我们还研究了三氟拉嗪和地布卡因对谷氨酸诱导的Ca 2+负荷神经元恢复的影响。三氟拉嗪以类似于线粒体Na+/Ca 2+交换抑制剂CGP-37157的方式影响Ca 2+恢复，而地布卡因对Ca 2+恢复没有明显影响。因此，渗透性转换的抑制似乎并不参与谷氨酸诱导的Ca 2+负荷的Ca 2+恢复。三氟拉嗪和地布卡因在阻止线粒体去极化的浓度下不抑制[3 H]-地佐环平结合。这些研究表明，三氟拉嗪和地布卡因抑制完整神经元的通透性转换。三氟拉嗪似乎也抑制线粒体Na+/Ca 2+交换。这些药物应被证明是有价值的工具，在进一步研究线粒体通透性转换的作用，谷氨酸诱导的神经元死亡。
Glutamate receptor activation has been previously shown to result in mitochondrial depolarization and activation of the mitochondrial permeability transition pore in cultured neurones. In this study, we characterized the effects of two putative permeability transition inhibitors, namely trifluoperazine and dibucaine, on mitochondrial depolarization in rat intact, cultured forebrain neurones. Permeability transition was monitored by following mitochondrial depolarization in neurones loaded with the mitochondrial membrane potential-sensitive fluorescent indicator, JC-1. Trifluoperazine (10–20 μM) and dibucaine (50–100 μM) inhibited or delayed the onset of glutamate-induced permeability transition. We also investigated the effects of trifluoperazine and dibucaine on neuronal recovery from glutamate-induced Ca2+ loads. Trifluoperazine affected Ca2+ recovery in a manner similar to the mitochondrial Na+/Ca2+ exchange inhibitor, CGP-37157, while dibucaine had no apparent effect on Ca2+ recovery. Therefore, inhibition of permeability transition does not appear to be involved in Ca2+ recovery from glutamate-induced Ca2+ loads. Trifluoperazine and dibucaine did not inhibit [3H]-dizocilpine binding at the concentrations that prevented mitochondrial depolarization. These studies suggest that trifluoperazine and dibucaine inhibit permeability transition in intact neurones. Trifluoperazine also appears to inhibit mitochondrial Na+/Ca2+ exchange. These drugs should prove to be valuable tools in the further study of the role of mitochondrial permeability transition in glutamate-induced neuronal death.