Zaprinast inhibits hydrogen peroxide-induced lysosomal destabilization and cell death in astrocytes
Zaprinast inhibits hydrogen peroxide-induced lysosomal destabilization and cell death in astrocytes
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DOI：
10.1016/j.ejphar.2007.06.042
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发表时间：
2007-10-01
影响因子：
5
通讯作者：
Choi, Sang-Hyun
中科院分区：
文献类型：
--
作者：
Choi, Jae-Hyuck;Kim, Dong-Hoon;Choi, Sang-Hyun
线粒体凋亡变化之前的溶酶体失稳是细胞死亡，特别是氧化性细胞死亡的重要步骤。本研究描述了cGMP升高的磷酸二酯酶抑制剂扎匹司特在抑制星形胶质细胞培养中氧化细胞死亡方面的新药理作用。通过监测乳酸脱氢酶(LDH)的释放，可以很大程度上衡量H_2O_2诱导的氧化细胞毒性，发现H_2O_2诱导的氧化细胞毒性与溶酶体吖啶橙重定位、溶酶体组织蛋白酶D释放到胞浆中以及线粒体电位降低有关。此外，扎匹司特(100 MU M)可抑制所有这些细胞毒现象。此外，8-PCPT-cGMP不抑制H_2O_2诱导的乳酸脱氢酶的释放，而蛋白激酶G抑制剂RP-8-PCPT-cGMP不影响扎普司特对这种释放的抑制作用。扎匹司特可抑制鞘氨醇诱导的溶酶体吖啶橙重定位和诱导的线粒体电位下降，但对鱼藤酮诱导的线粒体崩溃无影响，这与溶酶体失稳无关。然而，扎匹司特不能抑制H_2O_2诱导的细胞内氧自由基的增加，这表明其保护机制与去铁胺不同，去铁胺确实能抑制细胞内氧自由基的增加。我们认为，扎匹司特对过氧化氢诱导的细胞氧化死亡的新的保护作用主要与其抑制溶酶体失稳有关。(C)2007 Elsevier B.V.保留所有权利。
The lysosomal destabilization that precedes mitochondrial apoptotic changes is an important step in cell death, particularly in oxidative cell death. This study describes the novel pharmacological effects of zaprinast, a cGMP-elevating phosphodiesterase inhibitor, on the inhibition of oxidative cell death in astrocyte cultures. H2O2-induced oxidative cytotoxicity was measured grossly by monitoring lactate dehydrogenase (LDH) release, and was found to be associated with lysosomal acridine orange relocation, lysosomal cathepsin D release into cytosol, and reduced mitochondrial potentials. Moreover, zaprinast (100 mu M) inhibited all of these cytotoxic phenomena. In addition, H2O2-induced LDH release was not inhibited by 8-pCPT-cGMP, and the inhibition of this release by zaprinast was unaffected by Rp-8-pCPT-cGMP, a protein kinase G inhibitor. Zaprinast was found to inhibit sphingosine-induced lysosomal acridine orange relocation and the induced decrease in mitochondrial potential, but zaprinast had no effect on rotenone-induced mitochondrial collapse, which was not associated with lysosomal destabilization. However, zaprinast did not inhibit the cellular increase of reactive oxygen species induced by H2O2, which suggests that its protective mechanism differs from that of desferrioxamine, which does inhibit such cellular increase of oxygen free radicals. We suggest that the novel protective effect of zaprinast on H2O2-induced oxidative cell death is primarily associated with its inhibition of lysosomal destabilization. (C) 2007 Elsevier B.V. All rights reserved.