Intermittent Hypobaric Hypoxic Preconditioning Provides Neuroprotection by Increasing Antioxidant Activity, Erythropoietin Expression and Preventing Apoptosis and Astrogliosis in the Brain of Adult Rats Exposed to Acute Severe Hypoxia

Abstract

Background: Exposure to intermittent hypoxia has been demonstrated to be an efficient tool for hypoxic preconditioning, preventing damage to cells and demonstrating therapeutic benefits. We aimed to evaluate the effects of respiratory intermittent hypobaric hypoxia (IHH) to avoid brain injury caused by exposure to acute severe hypoxia (ASH). Methods: biomarkers of oxidative damage, mitochondrial apoptosis, and transcriptional factors in response to hypoxia were assessed by Western blot and immunohistochemistry in brain tissue. Four groups of rats were used: (1) normoxic (NOR), (2) exposed to ASH (FiO2 7% for 6 h), (3) exposed to IHH for 3 h per day over 8 days at 460 mmHg, and (4) ASH preconditioned after IHH. Results: ASH animals underwent increased oxidative-stress-related parameters, an upregulation in apoptotic proteins and had astrocytes with phenotype forms compatible with severe diffuse reactive astrogliosis. These effects were attenuated and even prevented when the animals were preconditioned with IHH. These changes paralleled the inhibition of NF-κB expression and the increase of erythropoietin (EPO) levels in the brain. Conclusions: IHH exerted neuroprotection against ASH-induced oxidative injury by preventing oxidative stress and inhibiting the apoptotic cascade, which was associated with NF-κB downregulation and EPO upregulation.

Preconditioning With Intermittent Hypobaric Hypoxia Attenuates Stroke Damage and Modulates Endocytosis in Residual Neurons

“…Moderate hypoxia (3,500–5,500 m) ( 27 ) is a feasible, economical, and effective non-invasive method of preconditioning that may enhance tissue tolerance through moderate stimulation aimed at achieving tissue protection. Numerous basic research efforts have demonstrated the neuroprotective effect of hypoxic preconditioning (HPC) from various perspectives ( 28 – 31 ). Intermittent hypobaric hypoxia was reported to improve vasodilation ( 32 ), reduce vascular sclerosis, increase left ventricular ejection fraction, and upregulate the expression of antioxidant enzymes in cardiac tissues ( 33 ).…”

“…Additionally, the upregulation of heat shock protein 70 may play a pivotal role in tissue tolerance during the hypobaric hypoxia procedure ( 34 , 35 ). Activation of hypoxia-inducible factor and its downstream target genes, including glucose transporters, vascular endothelial growth factor b, and erythropoietin, has also been demonstrated to contribute to HPC-induced ischemic tolerance ( 28 , 36 ). Hypoxic preconditioned neural stem cells improve the efficacy of stem cell therapy in brain injury ( 37 , 38 ).…”

“…Moderate hypoxia (3,500-5,500 m) (27) is a feasible, economical, and effective non-invasive method of preconditioning that may enhance tissue tolerance through moderate stimulation aimed at achieving tissue protection. Numerous basic research efforts have demonstrated the neuroprotective effect of hypoxic preconditioning (HPC) from various perspectives (28)(29)(30)(31). Intermittent hypobaric hypoxia was reported to improve vasodilation (32), reduce vascular sclerosis, increase left ventricular ejection fraction, and upregulate the expression of antioxidant enzymes in cardiac Abbreviations: CCA, common carotid artery; CDE, clathrin-dependent endocytosis; GO, Gene Ontology; HHP, hypobaric hypoxia preconditioning; HPC, hypoxic preconditioning; ICA, internal carotid artery; IHP, intermittent hypoxic preconditioning; MCAO, middle cerebral artery occlusion; mNSS, modified neurological severity score; NeuN, neuron-specific nuclear protein; PHP, persistent hypoxic preconditioning.…”

Hypoxic preconditioning induces neuroprotection against oxidative stress

“…In experimental studies, rat brains subjected to acute hypoxia exhibited increased cytochrome c and caspase 3. In contrast, when acute hypoxia was preceded by HP, no differences were found in these markers compared to normoxic rats (Coimbra-Costa et al 2021) suggesting that HP may prevent mitochondrial dysfunction and apoptosis.…”

“…This antioxidant response decreases the activity of pro-apoptotic cascades mediated by the downregulation of nuclear factor kappa-lightchain-enhancer of activated B cells (NF-κB) and the upregulation of erythropoietin (EPO) highlighting the neuroprotective effect of HP. Furthermore, sublethal hypoxic conditions stimulate neurogenesis and angiogenesis similar to what occurs during embryonic brain development (Coimbra-Costa et al 2021). Thus, the neuroprotective mechanisms triggered by HP include activation of antioxidant and anti-apoptotic pathways, suppression of excitotoxicity, promotion of cell proliferation, activation of anti-inflammatory responses, and enhancement of vascular regulation (Fan et al 2020) (Fig.…”