Nelfinavir inhibits intra-mitochondrial calcium influx and protects brain against hypoxic-ischemic injury in neonatal mice.
Nelfinavir inhibits intra-mitochondrial calcium influx and protects brain against hypoxic-ischemic injury in neonatal mice.
复制标题
DOI：
10.1371/journal.pone.0062448
复制
发表时间：
2013
期刊：
影响因子：
3.7
通讯作者：
Ten VS
中科院分区：
文献类型：
--
作者：
Utkina-Sosunova IV;Niatsetskaya ZV;Sosunov SA;Ratner VI;Matsiukevich D;Ten VS
奈非那韦 (NLF) 是一种抗逆转录病毒药物，可保持啮齿动物线粒体膜的完整性并保护成熟大脑免受缺血性损伤。我们的研究表明，在新生小鼠中，NLF 显着限制线粒体钙内流，这一事件与保护大脑免受缺氧缺血性损伤 (HI) 相关。与媒介物处理的小鼠相比，NLF 处理的小鼠的脑线粒体对 Ca2+ 诱导的膜透化具有显着更高的耐受性，ADP 磷酸化活性更高，再灌注期间细胞色素 C 释放减少。 NLF 或钌红 (RuR) 预处理显着提高了小鼠海马 HT-22 细胞的活力，降低了氧糖剥夺 (OGD) 后线粒体中的 Ca2+ 含量并保留了膜电位 (Ψm)。组胺刺激 Ca2+ 从内质网释放后，与载体处理的细胞相比，用 NLF 或 RuR 处理的细胞也表现出线粒体中 Ca2+ 含量降低，这一事件与保存的 Ψm 相关。由于 RuR 抑制线粒体 Ca2+ 单向转运蛋白，我们测试了 NLF 是否通过与 RuR 类似的机制发挥作用。然而，与 RuR 相比，在这些药物与从幼鼠分离的线粒体直接相互作用的实验中，NLF 不会改变线粒体 Ca2+ 流入，也不会阻止 Ca2+ 诱导的 Ψm 塌陷。这些数据强烈反对 NLF 和线粒体 Ca2+ 单向转运蛋白的相互作用。尽管确切的机制尚不清楚，但我们的研究首次表明 NLF 抑制线粒体内 Ca2+ 流动并保护发育中的大脑免受 HI 再灌注损伤。 NLF 的这种新作用具有重要的临床意义，因为它针对缺血后细胞死亡的基本机制：线粒体内 Ca2+ 超载 → 线粒体膜透化 → 继发性能量衰竭。
Nelfinavir (NLF), an antiretroviral agent, preserves mitochondrial membranes integrity and protects mature brain against ischemic injury in rodents. Our study demonstrates that in neonatal mice NLF significantly limits mitochondrial calcium influx, the event associated with protection of the brain against hypoxic-ischemic insult (HI). Compared to the vehicle-treated mice, cerebral mitochondria from NLF-treated mice exhibited a significantly greater tolerance to the Ca2+-induced membrane permeabilization, greater ADP-phosphorylating activity and reduced cytochrome C release during reperfusion. Pre-treatment with NLF or Ruthenium red (RuR) significantly improved viability of murine hippocampal HT-22 cells, reduced Ca2+ content and preserved membrane potential (Ψm) in mitochondria following oxygen-glucose deprivation (OGD). Following histamine-stimulated Ca2+ release from endoplasmic reticulum, in contrast to the vehicle-treated cells, the cells treated with NLF or RuR also demonstrated reduced Ca2+ content in their mitochondria, the event associated with preserved Ψm. Because RuR inhibits mitochondrial Ca2+ uniporter, we tested whether the NLF acts via the mechanism similar to the RuR. However, in contrast to the RuR, in the experiment with direct interaction of these agents with mitochondria isolated from naïve mice, the NLF did not alter mitochondrial Ca2+ influx, and did not prevent Ca2+ induced collapse of the Ψm. These data strongly argues against interaction of NLF and mitochondrial Ca2+ uniporter. Although the exact mechanism remains unclear, our study is the first to show that NLF inhibits intramitochondrial Ca2+ flux and protects developing brain against HI-reperfusion injury. This novel action of NLF has important clinical implication, because it targets a fundamental mechanism of post-ischemic cell death: intramitochondrial Ca2+ overload → mitochondrial membrane permeabilization → secondary energy failure.
登录
查看更多内容
DOI：
10.1523/jneurosci.5249-09.2010
发表时间：
2010-02-10
期刊：
The Journal of neuroscience : the official journal of the Society for Neuroscience
影响因子：
--
作者：
Ten VS;Yao J;Ratner V;Sosunov S;Fraser DA;Botto M;Sivasankar B;Morgan BP;Silverstein S;Stark R;Polin R;Vannucci SJ;Pinsky D;Starkov AA
通讯作者：
Starkov AA
影响因子：
2.9
作者：
Caspersen, Casper S.;Sosunov, Alexander;Ten, Vadim S.
通讯作者：
Ten, Vadim S.
影响因子：
3.6
作者：
Düfer, M;Neye, Y;Drews, G
通讯作者：
Drews, G
影响因子：
3.9
作者：
Halestrap, Andrew P.
通讯作者：
Halestrap, Andrew P.
影响因子：
64.8
作者：
Nakagawa, T;Shimizu, S;Tsujimoto, Y
通讯作者：
Tsujimoto, Y