Role of polyamine metabolism in kainic acid excitotoxicity in organotypic hippocampal slice cultures
Role of polyamine metabolism in kainic acid excitotoxicity in organotypic hippocampal slice cultures
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DOI：
10.1046/j.1471-4159.2001.00650.x
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发表时间：
2001-12-01
影响因子：
4.7
通讯作者：
Baudry, M
中科院分区：
文献类型：
--
作者：
Liu, W;Liu, RL;Baudry, M
多胺是普遍存在的阳离子，对于细胞生长、再生和分化至关重要。多胺代谢的增加与多种神经病理学状况有关，包括兴奋性毒性。然而，多胺在神经元变性中的确切作用仍不清楚。为了研究多胺导致兴奋毒性神经元死亡的机制，本研究使用器官型海马切片培养物检查了多胺相互转化途径在红藻氨酸（KA）神经毒性中的作用。用多胺氧化酶不可逆抑制剂 N1,N(2)-双(2,3-丁二烯基)-1,4-丁二胺 (MDL 72527) 处理培养物，可产生部分但显着的神经元保护，特别是在 CA1 区域。此外，这种预处理还减弱了 KA 诱导的脂质过氧化、胞质细胞色素 C 释放和神经胶质细胞活化水平的增加。此外，使用环孢菌素 A（线粒体通透性转换孔抑制剂）和 MDL 72527 组合进行预处理可产生针对 KA 毒性的附加且几乎完全的神经元保护，而 MDL 72527 和 EUK-134（合成过氧化氢酶/超氧化物歧化酶模拟物）的组合则不能提供附加保护。这些数据强烈表明，多胺相互转化途径通过活性氧的产生部分促进 KA 诱导的神经变性。
Polyamines are ubiquitous cations that are essential for cell growth, regeneration and differentiation. Increases in polyamine metabolism have been implicated in several neuropathological conditions, including excitotoxicity. However, the precise role of polyamines in neuronal degeneration is still unclear. To investigate mechanisms by which polyamines could contribute to excitotoxic neuronal death, the present study examined the role of the polyamine interconversion pathway in kainic acid (KA) neurotoxicity using organotypic hippocampal slice cultures. Treatment of cultures with N1,N(2)-bis(2,3-butadienyl)-1,4-butanediamine (MDL 72527), an irreversible inhibitor of polyamine oxidase, resulted in a partial but significant neuronal protection, especially in CA1 region. In addition, this pre-treatment also attenuated KA-induced increase in levels of lipid peroxidation, cytosolic cytochrome C release and glial cell activation. Furthermore, pre-treatment with a combination of cyclosporin A (an inhibitor of the mitochondrial permeability transition pore) and MDL 72527 resulted in an additive and almost total neuronal protection against KA toxicity, while the combination of MDL 72527 and EUK-134 (a synthetic catalase/superoxide dismutase mimetic) did not provide additive protection. These data strongly suggest that the polyamine interconversion pathway partially contributes to KA-induced neurodegeneration via the production of reactive oxygen species.