Abstract
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% O2 for 6h) and reoxygenation in normoxia (21% O2 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.
Highlights
There is abundant literature demonstrating that hypoxia induces increased production of reactive oxygen species (ROS) in brain [1,2,3,4,5]
The results showed that exposure to 6 h of severe hypoxia (7% FiO2) caused a significant increase in levels of hypoxia inducible factor (HIF)-1α in the brain of hypoxic rats vs. brain of normoxic rats that was sustained after 24 h of reoxygenation (Fig. 2A)
These results corroborate that this model of 6 h of experimental acute hypoxia is effective at inducing hypoxia in the brain
Summary
There is abundant literature demonstrating that hypoxia induces increased production of reactive oxygen species (ROS) in brain [1,2,3,4,5]. Hypoxia modifies the activity of the cytochrome chain responsible for mitochondrial oxidative phosphorylation, resulting in a decrease in ATP synthesis and increased ROS [9] at the same time as a decrease in the activity of the cellular antioxidant system [5,10], which may lead to oxidative stress. The mitochondria release apoptotic proteins such as cytochrome c and apoptosis inducible factor (AIF) into the cytosol [15]. The release of cytochrome c (cyt c) and other pro-apoptotic proteins can trigger caspase activation and apoptosis. Once released into the cytosol from the mitochondrial intermembrane space, cyt c binds with apoptotic protein-activating factor-1 (Apaf-1) and procaspase-9 to form an “apoptosome”, which actives caspase-9 and subsequently caspase-3. Activated caspase-3 disrupts a wide range of homeostatic, reparative and cytoskeletal proteins and leads to neuron cell death [16]. Upregulation and activation of caspase-3 have been found to precede neuron death in cerebral ischemia [15]
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