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首页> 外文期刊>Neurochemistry International: The International Journal for the Rapid Publication of Critical Reviews, Preliminary and Original Research Communications in Neurochemistry >Protection of PC12?cells from cocaine-induced cell death by inhibiting mitochondrial permeability transition
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Protection of PC12?cells from cocaine-induced cell death by inhibiting mitochondrial permeability transition

机译：通过抑制线粒体渗透率转变，保护PC12的保护来自可卡因诱导的细胞死亡

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Abstract Cocaine abuse induces brain injury and neurodegeneration by a mechanism that has not yet been fully elucidated. Mitochondria play a key role in cell death processes, notably through the opening of the permeability transition pore (PTP). In this work, we examined the involvement of the PTP in cocaine-induced toxicity in PC12?cell lines. We used two different PTP inhibitors -i.e. cyclosporin A (CsA) and metformin-to assess their ability to counteract the cocaine induced effects. We first observed that a 48?h exposure to cocaine strongly sensitized cells to calcium overload, as measured by the calcium retention capacity. CsA and metformin significantly decreased the cocaine-induced PTP opening sensitization. We next showed by confocal microscopy that cocaine induced a permanent PTP opening in intact living cells, a phenomenon characterized by the collapse of the mitochondrial membrane potential and the relocation of the NAD(P)H from the mitochondrial matrix to the cytosol. As expected, a cocaine-induced PTP opening was prevented by PTP inhibitors. Finally, a flow cytometry analysis revealed that cocaine induced cell death while CsA and metformin promoted cell survival. Our results demonstrate that cocaine induces PC12?cell death through a mechanism involving permanent PTP opening. Highlights ? Cocaine induces cell death by a mechanism that involves mitochondria. ? Exposure of PC12?cells to cocaine led to mitochondrial permeability transition. ? Inhibition of permeability transition decreased cocaine toxicity in PC12?cells.
机译：摘要可卡因滥用诱导尚未完全阐明的机制诱导脑损伤和神经变性。线粒体在细胞死亡过程中发挥关键作用，特别是通过开放渗透性过渡孔（PTP）。在这项工作中，我们检查了PTP在PC12中可卡因诱导的毒性中的参与。细胞系。我们使用了两种不同的PTP抑制剂-i.e.环孢素A（CSA）和二甲双胍 - 评估它们抵消可卡因诱导效果的能力。我们首先观察到48？H暴露于可卡因强烈敏化的细胞到钙过载，通过钙保留容量测量。 CSA和二甲双胍显着降低了可卡因诱导的PTP开度敏化。接下来通过共聚焦显微镜显示，可卡因在完整的活细胞中诱导永久性PTP开口，其特征在于线粒体膜电位的塌陷的现象以及NAD（P）H从线粒体基质到细胞溶胶的迁移。如预期，通过PTP抑制剂防止了可卡因诱导的PTP开口。最后，流式细胞术分析显示可卡因诱导细胞死亡，而CSA和二甲双胍促进细胞存活。我们的结果表明，可卡因通过涉及永久性PTP开放的机制诱导PC12？细胞死亡。强调 ？可卡因通过涉及线粒体的机制诱导细胞死亡。还PC12的暴露于可卡因的细胞导致线粒体渗透率转变。还渗透性转变的抑制降低了PC12中的可卡因毒性。

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