Introduction

What is hypoxia?

In this state, oxygen is unavailable in sufficient amounts, at the tissue level, for the maintenance of adequate homeostasis. This can be a result of inadequate oxygen delivery to the tissues either due to low blood supply or reduced oxygen content in the blood (hypoxemia).¹

In the blood, haemoglobin is a protein in red blood cells (RBC) that binds to oxygen, transporting it to tissues where it assists with nutrient breakdown as well as energy production. This process involving the delivery of oxygen to tissues is known as perfusion. If tissues do not receive enough oxygen, hypoxia will develop, which results in pain and suboptimal cellular function.²

Importance of oxygen for the central nervous system (CNS)

Oxygen is an essential requirement of most eukaryotic organisms. It functions as a scavenger for the removal of destructive electron and hydrogen ions generated as by-products of mitochondrial oxidative phosphorylation.

There is a switch of energy metabolism from oxidative phosphorylation to anaerobic glycolysis, at the cellular level. This results in increased glucose uptake and expression of stress proteins related to cell survival or death.³

Energy is consumed by neurons primarily at the synapse with a significant proportion utilized in restoration of neuronal membrane potentials following depolarization.³ In order to maintain healthy cellular and systemic function, it is essential to regulate tissue metabolite supply and cellular energy metabolism. This regulation is critical to the central nervous system (CNS) where energy consumption is highly dynamic. Increased neuronal activity drives increased energy consumption and compensatory metabolic and vasculature changes in turn enhance neuronal function.⁴ Therefore, metabolism needs to be tightly regulated, for normal brain function, both temporally and spatially from a regional level to the level of a single synapse.

How does the human body respond to hypoxia?

Oxygen concentration can be detected by all nucleated cells, in addition to responding to a reduction in oxygen availability. This takes place in one of two distinctive ways. Altered pre-existing proteins (such as phosphorylation or changing redox state) occur in response to acute hypoxia whereas transformed gene expression mainly occurs in response to chronic hypoxia. ⁵

Oxygen delivery to the brain

There are multiple routes for blood to get into the CNS, with specializations in place for the protection of that blood supply and to maximize the capability of the nervous tissue to get an uninterrupted perfusion.⁶

Mechanisms of oxygen deprivation

Oxygen is essential for the generation of aerobic adenosine triphosphate (ATP) and energy that is required to support vital cellular functions. Oxygen delivery (DO2) to the tissues is determined by convective and diffusive processes. The body’s ability to adjust oxygen extraction (ERO2) in response to changes in DO2 is crucial for the maintenance of constant tissue oxygen consumption (VO2). An increase in ERO2 is the result of the regulation of the circulation and the effects of the simultaneous activation of both central and local factors.

The endothelium plays a significant role in matching tissue oxygen supply to demand in situations of acute drop in tissue oxygenation. In case of adequate tissue oxygenation, tissue oxygen demand is met.

In the case of severely compromised DO2, a critical DO2 value is reached below which VO2 falls and becomes dependent on DO2. This results in ‘tissue hypoxia’. The different mechanisms of tissue hypoxia involve circulatory, anaemic, and hypoxic, characterised by a diminished DO2 but preserved capacity of increasing ERO2.⁷

Adaptive responses to low oxygen levels

Hypoxia can be considered a major stressor that generally destabilizes the life of aerobic species and is a prominent feature of pathological states encountered in bacterial infection, wounds, inflammation, cardiovascular defects and cancer. Therefore, mammals have evolved with key adaptive mechanisms to cope with hypoxia. Systemically, these adaptations include increased ventilation, cardiac output, blood vessel growth and circulating red blood cell numbers.

Considering the cellular level, there is suppression of ATP-consuming reactions and, metabolism is altered until the restoration of oxygen homeostasis.⁸

Effects of hypoxia on the CNS

Normal brain function significantly depends on oxygen and nutrient supply. Hypoxia is induced when the demand for oxygen exceeds its supply.

Acute episodes of hypoxia may lead to depression in synaptic activity in many regions of the brain, whilst prolonged exposure to hypoxia leads to neuronal cell loss and death. Acute inadequate supply may lead to anaerobic metabolism and, increased respiration in order to increase oxygen intake whilst chronic hypoxia may give rise to angiogenesis and erythropoiesis in order to promote oxygen delivery to peripheral tissues.⁹

Complications

Hypoxic brain damage may cause severe disability.¹⁰ A study found that intermittent hypoxia (IH) can cause a general compromise of oxidative phosphorylation and consequently poor maintenance of ion gradients of neurons. In other words, the physiological function of the neurons may be compromised before explicit neuronal apoptosis. It has been shown that in the developing nervous system, IH will influence neuronal excitability and its maturation by alterations in the expression of Na channels and ion transporters. In adult mice, IH could decrease membrane-input resistance and excitability of hippocampal CA1 neurons.

Additionally, exposure to IH during sleep does not induce substantial sleep disturbances but has an association with impaired spatial learning in the adult rat, as well as with increased apoptosis in the cortex and CA1 region of the hippocampus.¹¹

Brain damage

Hypoxia is a state of reduced oxygen supply and excessive oxygen consumption. According to the duration of the hypoxic period, it can be classified as acute and chronic hypoxia.

Both acute and chronic hypoxia could induce abundant neurological deficits. Although there have been significant advances in the pathophysiological injuries that arise due to hypoxia, few studies have focused on cognitive dysfunction.

Hypoxia can impair several cognitive domains such as attention, learning and memory, procession speed and executive function, which are similar to acute and chronic hypoxia. The severity of cognitive deficit correlates with the duration and degree of hypoxia.

Recovery can be achieved following acute hypoxia, while chronic hypoxia can cause sequelae or even dementia, perhaps due to the different molecular mechanisms. Cardiopulmonary compensatory response, glycolysis, oxidative stress, calcium overload, adenosine, mitochondrial disruption, inflammation and excitotoxicity contribute to the molecular mechanisms of cognitive deficit after acute hypoxia.

During the chronic stage of hypoxia, different adaptive responses, impaired neurovascular coupling, apoptosis, transcription factors-mediated inflammation, as well as Aβ accumulation and tau phosphorylation account for the deficit in neurocognition. Moreover, structural changes in the brain with hippocampus and cortical atrophy, ventricular enlargement, senile plaque and neurofibrillary tangle deposition can be observed under chronic hypoxia rather than acute hypoxia.¹²

Neurological symptoms

The symptoms of hypoxia include restlessness, tachycardia, tachypnea, dyspnea, confusion or loss of consciousness and clubbing.¹³

Impaired cognitive function

Both acute and chronic hypoxia could induce abundant neurological deficits. Although there have been significant advances in the pathophysiological injuries, few studies have focused on the cognitive dysfunction. Hypoxia can result in the impairment of several cognitive domains such as attention, learning and memory, procession speed and executive function, which are similar to acute and chronic hypoxia. The severity will correlate with the duration and degree of hypoxia.

Recovery can be achieved after acute hypoxia, while sequelae or even dementia can be observed after chronic hypoxia, perhaps due to the different molecular mechanisms. Cardiopulmonary compensatory response, glycolysis, oxidative stress, calcium overload, adenosine, mitochondrial disruption, inflammation and excitotoxicity contribute to the molecular mechanisms of cognitive deficit after acute hypoxia. During the chronic stage of hypoxia, different adaptive responses, impaired neurovascular coupling, apoptosis, transcription factors-mediated inflammation, as well as Aβ accumulation and tau phosphorylation account for the neurocognitive deficit. Moreover, brain structural changes with hippocampus and cortex atrophy, ventricle enlargement, senile plaque and neurofibrillary tangle deposition can be observed under chronic hypoxia rather than acute hypoxia.¹⁴

Decision-making impairments

People tend to take more risks under stressful conditions. Pighin and colleagues examined the effect of mild hypoxia, an unconscious and ongoing stressor, on decisions under uncertainty where probabilities could not be defined. As part of the study, participants completed the Balloon Analogue Risk-Taking task (BART) in both a normoxic (20.9% oxygen concentration) and a mildly hypoxic (14.1% oxygen concentration) environment. The results indicate that people take more risks in a mildly hypoxic than in a normoxic environment.¹⁵

Shared mechanisms in hypoxia, ageing and neurodegenerative diseases

Neurodegeneration and ageing are strongly linked to the mechanisms of cellular, brain and systemic responses to hypoxia. The major pathogenetic mechanisms of neurodegeneration, including neuroinflammation, oxidative stress and mitochondrial dysfunction have been implicated in “normal” ageing as well. Inflammation (“inflammaging” paradigm of ageing), oxidative stress (free radical theory of ageing) and mitochondrial dysfunction increase with ageing and are ranked among ageing’s central promotors.

Hypoxia can either provoke or suppress oxidative stress, mitochondrial dysfunction and inflammation and the HIF pathway is crucially involved, suggesting hypoxia conditioning could potentially modulate brain ageing.¹⁶

Summary

Hypoxia is a result of inadequate oxygen delivery to the tissues either due to low blood supply or reduced oxygen content in the blood. The different mechanisms of tissue hypoxia involve circulatory, anaemic, and hypoxic, characterised by a diminished DO2 but preserved capacity of increasing ERO2. Key adaptive mechanisms to cope with hypoxia include increased ventilation, cardiac output, blood vessel growth and circulating red blood cell numbers. Hypoxic brain damage may lead to neurological symptoms such as impaired cognitive function, and decision-making impairments in addition to many others.