Introduction
Hypoxia, from hypo and oxygenium, means reduced tissue oxygen, arising from low inspired oxygen or certain diseases. It is usually considered pathological, and many physicians regard oxygen as always beneficial and deficiency as harmful. Yet V.V. Pashutin in 1881 noted that hypoxia periodically occurs during natural bodily activity, attributing physiological hypoxia to heavy work and mountain exposure. Later work showed it also occurs at relative rest, evidenced by persistent blood lactate (A.D. Bershtein, 1965). Periodic hypoxia at rest or during functional exertion continually trains compensatory reactions that relieve oxygen deprivation. Since tissue hypoxia causes or contributes to pathological states, training these antihypoxic reserves is a principal non-drug approach in adaptation medicine.
Hypoxic training refers to healthy-person conditioning; hypoxic therapy refers to patient treatment and rehabilitation [1].
Mountain-climate treatment, whose principal factor is natural hypobaric hypoxia, has millennia of history in Indian and Chinese texts and works of Plutarch, Hippocrates and Paracelsus. It is gentle, physiological and sometimes highly effective because multiple natural factors act on the whole body [2]. Hypobaric therapy also uses stationary or mobile chambers, lowering barometric pressure to simulate ascent. Normobaric therapy supplies low-oxygen nitrogen–oxygen mixtures through tubing and a mask from cylinders, breathing bags or hypoxicators that precisely control inspired oxygen. Mixtures containing 10–12% oxygen are applied for varying intervals. Interval normobaric hypoxic therapy avoids chamber-related rarefied-atmosphere effects, barotrauma, baroreceptor stimulation and claustrophobia.
Plakhatnyuk and colleagues reported poor normobaric tolerance 3.7 times less frequently than hypobaric intolerance [3]. Dosing and immediate functional monitoring can be strictly controlled.
Objective
The objective is to examine mechanisms through which hypoxic adaptation affects the brain.
Mechanisms of hypoxic therapy
Hypoxia reorganises multiple systems to maintain tissue oxygen delivery and adapt tissues to oxygen shortage. Mechanisms sustain environmental oxygen uptake, delivery to vital organs during hypoxaemia, utilisation at low tension, and ATP generation by glycolytic substrate-level phosphorylation [2, 4, 5].
Adaptation increases erythropoietin secretion, stimulating red-marrow erythropoiesis, erythrocytes and haemoglobin concentration and improving pulmonary oxygen binding and tissue release. Besides adult HbA, fetal HbF appears with greater oxygen affinity and binding at lower alveolar tension. Blood oxygen capacity and physical or aerobic performance increase [6, 7, 8]. Erythrocyte 2,3-diphosphoglycerate rises, facilitating oxygen release. More myocardial and skeletal-muscle myoglobin transports oxygen at lower partial pressures than haemoglobin [9].
Pulmonary surface area and alveolar number increase, respiratory-muscle mass rises and respiratory-centre neurons hypertrophy, improving ventilation [10, 11, 12].
Interval hypoxic training induces HSP70 expression in type-II alveolar epithelial cells. Heat-shock proteins protect cells and organs against oxidants, nitric oxide, tumour necrosis factor and endotoxin [13].
Adaptation reduces hyperlipidaemia and dyslipidaemia. Adapted animals on a high-cholesterol diet had significantly lower cholesterol than unadapted animals [14]. Periodic hypoxic adaptation after myocardial infarction also significantly reduced total cholesterol, triacylglycerides and atherogenic index [15].
Chamber-hypoxia adaptation lowers hepatic cytochrome P450, amidopyrine N-demethylase and aniline o-hydroxylase activity. The monooxygenase system shares functional features with immunity and interacts reciprocally: P450 inducers inhibit immunity, while immune stimulants suppress monooxygenases. The biological meaning is unclear. Lower P450 might accompany increased immunity during adaptation [16].
Periodic adaptation strengthens antioxidant membrane defence: catalase and SOD rise, malondialdehyde and lipid peroxidation fall. Membrane permeability declines and enzyme systems improve. Calcium pumps become more resistant to peroxidation products [17, 18]. Two weeks of adaptation in rats produced some radical-oxidation activation but a stronger rise in endogenous antioxidant capacity, likely relevant to preventive and therapeutic effects [19].
In dyscirculatory encephalopathy, ten-day hypoxic adaptation reduced total oxidative activity and thiobarbituric-acid-reactive substances while erythrocyte SOD, catalase and glutathione peroxidase increased. The findings demonstrated correction of disturbed oxidative homeostasis [20].
Environmental adaptation gradually attenuates stress responses and forms protection [21]. Chronic high corticosterone doses worsen NMDA-mediated brain injury; low doses mimicking moderate-stress adaptation reduce NMDA-induced neurodegeneration [22].
Hypoxic and exercise adaptation increase NO production [23], mainly through eNOS activity and expression [24, 25, 26]. This may explain cardiovascular benefits where endothelial dysfunction is present. Adaptation that stimulates endothelial NO simultaneously prevents excessive NO production and limits its adverse effects [23].
Two mechanisms may protect against both NO excess and deficiency. NO inhibits its own overproduction by negative feedback [27], so prior adaptation-induced synthesis may prevent later excess. Adaptation also forms vascular NO stores, NO-containing complexes [28, 29]. These appear to protect against excess toxicity and supply additional nonenzymatic free NO to partly compensate deficiency [29].
Effects on the brain
Improved cerebral circulation is important protection. Besides NO synthesis, vascular density rises in many organs during hypobaric adaptation, including brain [30, 31], particularly cortex, striatum and hippocampus [32].
Neovascularisation reflects HIF-1 activation. Discovered in the early 1990s, it is a master oxygen-homeostasis regulator controlling proteins responsible for cellular delivery and adaptation to oxygenation [33]. Over 60 direct targets have been identified, promoting erythropoiesis, angiogenesis, glucose transport, glycolytic ATP, ion transport and proliferation. Their products act at multiple functional levels, ultimately increasing cellular oxygen entry [34].
Other hypoxia-sensitive transcription factors include MTF-1, NF-κB, c-Fos and c-Jun [35].
The CNS also remodels. Nucleic-acid and protein synthesis increases in neurons and glia, neurons hypertrophy, and enzymes and mitochondria increase. Cortex shows 50% more RNA and doubled protein synthesis. Electron microscopy of adapted cat somatosensory cortex found denser pyramidal dendritic spines, more complex spine apparatus, longer active synapses and denser cytoplasmic matrix [17]. Function improves: conditioned reflexes develop faster and persist better. In conflict tests, adapted rats perform a vital drinking reflex despite electrical pain that previously drove them away. Resistance to intense sound-induced seizures rises and audiogenic epilepsy disappears [10].
EEG during 10% oxygen breathing and acute adaptation showed moderate generalised changes described as slow undulating inhibition. Long-term adaptation instead produced cortical stimulation and CNS activation [36]. Urmancheeva and Khasabova’s implanted-electrode monkey experiments identified frontal cortex, hippocampus and hypothalamus as most oxygen-sensitive [37], probable hypoxic targets. Because cortex and limbic systems organise emotional responses, intermittent normobaric hypoxia may influence psychoemotional reactions. Prolonged periodic adaptation under extreme conditions equalised aggression thresholds in low- and high-tolerance groups. High-tolerance rats improved task performance; low-tolerance rats had the strongest and longest neocortical and ancient-brain EEG changes [38].
Brain capacity increases, improving mental work, short-to-long-term memory transfer and resistance to overfatigue and epileptogenic stressors. GABAergic, serotonergic and endogenous opioid stress-limiting systems are activated, protecting against diverse damaging factors [39].
Low-frequency pulsed hypoxic adaptation activates physiological processes of different rates and energy demands. Neuronal energy production in vivo is reflected by oxygen tension PO₂, consumption by electrical firing, and cortical-tissue consumption by electrocorticogram amplitude σ. In adapted sensorimotor cortex these functional algorithms favour production over consumption. At simulated 10 km, neuronal PO₂ remains 2.13 times control while firing-based consumption falls 2.05-fold; tissue consumption by σ falls 8.6-fold. More reliable neuronal oxygen homeostasis improves survival under profound hypoxia [40].
Adaptation stimulates melatonin through pineal structural changes [41]. Melatonin limits CNS oxidative injury as an indirect antioxidant, stimulates antioxidant enzymes [42] and protects neurons through antiamyloidogenic properties [43].
Long adaptation increases respiratory-chain NADPH–cytochrome-c oxidoreductase activity and lowers its NADPH affinity, increasing mitochondrial oxygen resistance. This matters when flow returns and reperfusion risk is high. A more efficient chain despite reduced oxidation is described as the paradoxical adaptation effect [44].
A single moderate hypoxic session, 10% oxygen in hypobaric, normobaric or interval modes, acts through preconditioning. Acute mechanisms activate during hypoxia; periodic oxygenation delays and suppresses them. Across repeated courses, however, oxygenated intervals temper hypoxia and prevent stimulus overdose, regulating the dose and optimising long-term adaptation [45].
Three moderate hypobaric preconditioning exposures increase vulnerable neurons’ tolerance to severe hypoxia and other injury. Immunocytochemistry showed greater NF-κB and phosphorylated CREB reactivity in hippocampal CA1–CA4 and dentate gyrus, with increased expression 3–24 hours after severe hypobaric hypoxia. NF-κB and CREB therefore participate in induced brain tolerance [46].
Neuroprotection includes antioxidant induction, notably mitochondrial manganese-dependent SOD. Severe hypobaric hypoxia slightly raises hippocampal Mn-SOD by hour 3. Three moderate preconditioning sessions markedly enhance subsequent expression in CA2 and CA3, not CA1 or dentate gyrus. Immunocytochemistry of preconditioning alone found increased Mn-SOD at 24 hours in CA1 and dentate gyrus, not CA2/CA3. Thus enhanced post-severe-hypoxia expression occurs where preconditioning alone does not increase the protein. Early protection reflects modification of the severe-hypoxia response rather than prior Mn-SOD accumulation [47].
Adaptation remodels sympathoadrenal regulation: sympathetic neurons hypertrophy, catecholamine synthesis and adrenal stores rise, and cardiac adrenergic responsiveness increases, enlarging sympathetic reserves. IHT also strengthens resting autonomic heart regulation through parasympathetic activation and optimises heart-rate-variability changes during simulated acute hypoxia. Preconditioning reduces desaturation and heart-rate rise. Training effects are greater in initially low-tolerance subjects than in those already resistant [48].
Conclusion
Adaptation substantially affects CNS function, central haemodynamics, organ microcirculation, oxygen metabolism, radical lipid oxidation, detoxification enzymes and immunity. Compensatory mechanisms chiefly aim to:
1. Reduce arterial hypoxaemia and maintain near-normal pulmonary oxygen entry by greater minute and alveolar ventilation, diffusion and less shunting.
2. Increase arterial oxygen mass transfer from lungs to tissues through greater blood oxygen capacity and flow.
3. Supply cells through stronger microcirculation, shorter microvascular-to-cell diffusion distances and larger myoglobin oxygen stores.
4. Improve utilisation through more mitochondria and respiratory assemblies, greater respiratory-enzyme and antioxidant activity.
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Full main-text translation of: Солкин А.А., Белявский Н.Н., Кузнецов В.И., Николаева А.Г. Основные механизмы формирования защиты головного мозга при адаптации к гипоксии. Вестник ВГМУ. 2012;11(1):6–14.
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