The cell-permeable mitochondrial calcium uniporter inhibitor Ru265 preserves cortical neuron respiration after lethal oxygen glucose deprivation and reduces hypoxic/ischemic brain injury
The cell-permeable mitochondrial calcium uniporter inhibitor Ru265 preserves cortical neuron respiration after lethal oxygen glucose deprivation and reduces hypoxic/ischemic brain injury
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DOI：
10.1177/0271678x20908523
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发表时间：
2020-03-03
影响因子：
6.3
通讯作者：
Robertson, George S.
中科院分区：
文献类型：
--
作者：
Novorolsky, Robyn J.;Nichols, Matthew;Robertson, George S.
线粒体钙单向转运体（MCU）介导高容量线粒体钙摄取，参与缺血/再灌注细胞死亡。我们最近表明，诱导MCU消融Thy 1表达的神经元，使小鼠耐受感觉运动缺陷和前脑神经元的缺氧/缺血（HI）脑损伤模型的损失。这些发现鼓励我们比较Ru 360和最近发现的细胞渗透性MCU抑制剂Ru 265的神经保护作用。与Ru 360不同，Ru 265（2-10 μ M）在培养的皮层神经元中达到细胞内浓度，保持细胞活力，阻断Ca 2+依赖性钙蛋白酶的蛋白酶活性，并在氧-葡萄糖剥夺（OGD）致死期后维持线粒体呼吸和糖酵解。腹膜内（i. p.）用Ru 265（3 mg/kg）注射成年雄性C57 B1/6小鼠也抑制HI诱导的感觉运动缺陷和脑损伤。然而，较高剂量的Ru 265（10和30 mg/kg，i. p.）产生剂量依赖性增加的频率和持续时间的类似行为。Ru 265被提议通过减少高能量中间神经元中的Ca 2+缓冲和能量产生来促进惊厥，所述中间神经元抑制脑癫痫发作活动。这些发现支持MCU抑制在治疗缺血性中风中的治疗潜力，但也表明这种临床转化将需要减轻Ru 265的促惊厥作用的药物递送策略。
The mitochondrial calcium (Ca2+) uniporter (MCU) mediates high-capacity mitochondrial Ca2+ uptake implicated in ischemic/reperfusion cell death. We have recently shown that inducible MCU ablation in Thy1-expressing neurons renders mice resistant to sensorimotor deficits and forebrain neuron loss in a model of hypoxic/ischemic (HI) brain injury. These findings encouraged us to compare the neuroprotective effects of Ru360 and the recently identified cell permeable MCU inhibitor Ru265. Unlike Ru360, Ru265 (2-10 mu M) reached intracellular concentrations in cultured cortical neurons that preserved cell viability, blocked the protease activity of Ca2+-dependent calpains and maintained mitochondrial respiration and glycolysis after a lethal period of oxygen-glucose deprivation (OGD). Intraperitoneal (i.p.) injection of adult male C57Bl/6 mice with Ru265 (3 mg/kg) also suppressed HI-induced sensorimotor deficits and brain injury. However, higher doses of Ru265 (10 and 30 mg/kg, i.p.) produced dose-dependent increases in the frequency and duration of seizure-like behaviours. Ru265 is proposed to promote convulsions by reducing Ca2+ buffering and energy production in highly energetic interneurons that suppress brain seizure activity. These findings support the therapeutic potential of MCU inhibition in the treatment of ischemic stroke but also indicate that such clinical translation will require drug delivery strategies which mitigate the pro-convulsant effects of Ru265.