Coimbra-Costa Debora, Alva Norma, Duran Mónica, Carbonell Teresa, Rama Ramón
Department of Cell Biology, Physiology and Immunology, University of Barcelona, Avda Diagonal, 643, 08028 Barcelona, Spain.
Department of Cell Biology, Physiology and Immunology, University of Barcelona, Avda Diagonal, 643, 08028 Barcelona, Spain.
Redox Biol. 2017 Aug;12:216-225. doi: 10.1016/j.redox.2017.02.014. Epub 2017 Feb 24.
Acute hypoxia increases the formation of reactive oxygen species (ROS) in the brain. However, the effect of reoxygenation, unavoidable to achieve full recovery of the hypoxic organ, has not been clearly established. The aim of the present study was to evaluate the effects of exposition to acute severe respiratory hypoxia followed by reoxygenation on the evolution of oxidative stress and apoptosis in the brain. We investigated the effect of in vivo acute severe normobaric hypoxia (rats exposed to 7% O for 6h) and reoxygenation in normoxia (21% O for 24h or 48h) on oxidative stress markers, the antioxidant system and apoptosis in the brain. After respiratory hypoxia we found increased levels of HIF-1α expression, lipid peroxidation, protein oxidation and nitric oxide in brain extracts. Antioxidant defence systems such as superoxide dismutase (SOD), reduced glutathione (GSH) and glutathione peroxidase (GPx) and the reduced/oxidized glutathione (GSH/GSSG) ratio were significantly decreased in the brain. After 24h of reoxygenation, oxidative stress parameters and the anti-oxidant system returned to control values. Regarding the apoptosis parameters, acute hypoxia increased cytochrome c, AIF and caspase 3 activity in the brain. The apoptotic effect is greatest after 24h of reoxygenation. Immunohistochemistry suggests that CA3 and dentate gyrus in the hippocampus seem more susceptible to hypoxia than the cortex. Severe acute hypoxia increases oxidative damage, which in turn could activate apoptotic mechanisms. Our work is the first to demonstrate that after 24h of reoxygenation oxidative stress is attenuated, while apoptosis is maintained mainly in the hippocampus, which may, in fact, be the cause of impaired brain function.
急性缺氧会增加大脑中活性氧（ROS）的形成。然而，复氧作为使缺氧器官完全恢复所不可避免的过程，其影响尚未明确。本研究的目的是评估急性重度呼吸性缺氧后复氧对大脑氧化应激和细胞凋亡演变的影响。我们研究了体内急性重度常压缺氧（大鼠暴露于7%氧气中6小时）以及在常氧（21%氧气）中复氧24小时或48小时对大脑氧化应激标志物、抗氧化系统和细胞凋亡的影响。呼吸性缺氧后，我们发现脑提取物中缺氧诱导因子-1α（HIF-1α）表达水平、脂质过氧化、蛋白质氧化和一氧化氮增加。大脑中的抗氧化防御系统，如超氧化物歧化酶（SOD）、还原型谷胱甘肽（GSH）和谷胱甘肽过氧化物酶（GPx）以及还原型/氧化型谷胱甘肽（GSH/GSSG）比值显著降低。复氧24小时后，氧化应激参数和抗氧化系统恢复到对照值。关于细胞凋亡参数，急性缺氧增加了大脑中细胞色素c、凋亡诱导因子（AIF）和半胱天冬酶3的活性。复氧24小时后凋亡效应最为明显。免疫组织化学表明，海马体中的CA3和齿状回似乎比皮质更容易受到缺氧的影响。严重急性缺氧会增加氧化损伤，进而可能激活细胞凋亡机制。我们的研究首次表明，复氧24小时后氧化应激减弱，而细胞凋亡主要在海马体中持续存在，这实际上可能是脑功能受损的原因。
