What is Oxidative Stress?

All living organisms on Earth live under an oxidant atmosphere, characterized by a percentage of molecular oxygen of about 20%.  We all know the fate of a piece of iron left outside: in a short time, it becomes completely oxidized (rusted). Why does the same not happen to us? 

The reason is simple: biological lifeforms, during evolution on Earth, developed various mechanisms for sensing and counteracting the deleterious effects of free radicals or reactive oxygen species (ROS),[1] the highly reactive by-products of oxygen metabolism. Several systems have evolved in prokaryotic and eukaryotic cells to regulate ROS, and today almost all organisms control free-radical levels by maintaining a fine equilibrium, the reductive-oxidative (RedOx) balance.[2,3]

In physiological conditions, ROS are largely produced by metabolic reactions and this happens at every moment in every single cell of our body. Thus, production of oxidizing species and free radicals is a physiological process. The deleterious effects of ROS are neutralised by an ensemble of enzyme and molecules endowed with antioxidant capacity. However, when ROS production exceeds the neutralising ability of antioxidant defences, a state of oxidative stress occurs, causing cell damage and death, and eventually organ dysfunction (Figure 1).

Therefore, Oxidative stress is a disturbance of the physiological RedOx balance that is not balanced by adequate adaptive responses from the body.

Figure 1. RedOx homeostasis. The RedOX balance is preserved thanks to the existing equilibrium between ROS production rate and antioxidant defence system. Highlighted in red possible sources of ROS, while in green the antioxidant defences. Oxidative stress (OS) is a condition where there is an overproduction of ROS or a reduced ability of the antioxidant defences to counteract the production of ROS.  OS can induce cellular and tissue injury through different mechanisms.

Causes of Oxidative Stress

Nature is often drastic in its behaviour, and one has to keep in mind that living organisms are evolved to preserve genomic integrity. Individual cells can be easily sacrificed if endogenous check-point mechanisms suspect genomic damage.  When this happens, we perceive it as a tissue lesion, as a weakness, as aging and wellness unbalance.

The main causes of oxidative stress are pollution, inflammation, the immune response, and incorrect management of ROS produced in the mitochondria, as well as various metabolic reactions (Figure 1).

Consider the case of atmospheric pollution: aromatic hydrocarbon particles constantly challenge our body. These particles have a high potential to harm the cell’s DNA and thus detoxifying mechanisms based on oxidation of these aromatic hydrocarbons are constantly activated. The free radicals formed in these processes easily react with any molecule in their vicinity (lipids, proteins, nucleic acids), damaging it, often impairing its function, and propagating oxidative damage. Indeed, strong and massive oxidation produces a huge amount of ROS, which severely harm cells leading to premature aging and decline.

Why central nervous system and brain are highly susceptible to oxidative stress damage?

In the last years the signalling and damaging properties of ROS have received particular attention being implicated in central homeostatic mechanisms at the molecular, cellular, tissue and apparatus levels. Recently high impact factor journals (Nature Review, Science and Science Translational Medicine) reported comprehensive reviews about the pathophysiological role of RedOx signalling.[2,4–10] Oxidative Stress (OS) has been linked to several human diseases, including: ADHD,[11] cancer,[12] Parkinson’s disease (PD),[13] Alzheimer’s disease (AD),[14,14,15] heart failure and myocardial infarction.[16–18]

Human brain and central nervous system are characterized by distinctive features that make it highly sensitive to OS. Indeed, they are one of the organ and apparatus with the highest O2 utilisation, they have the highest content of docosahexaenoic acid, which is a polyunsaturated fatty acid extremely sensitive to lipoperoxidation processes, and in the brain, there is also a high content of RedOx-active metals (Fe, Cu). Therefore, it is not surprising that most of the neurodegenerative disorders are characterized by an OS component, also considering that OS increases with the age. Several experimental evidences suggest that ROS play crucial role in neurodegenerative disorders since increased OS levels have been observed in tissue samples of patients with AD or PD and protein modifications induced directly or indirectly by ROS and lipid peroxidation processes have also been observed.

In evaluating cerebral OS four key elements have to be considered:

  • The blood brain barrier (BBB): BBB can be considered as a neuro-vascular unit and damages of any of the elements of this unit will have repercussion on cerebral functions and performances. BBB is one of the cerebral structures mostly damaged by OS in neurodegenerative disorders. Therefore, it is relevant to protect the BBB structures, preserving the integrity of the vessels (indirect protection) and their patency (direct protection).
  • The pro-oxidant components (homocysteine and amyloid substance): at the BBB level two substances play major roles as pro-oxidants, homocysteine (HCy) and the amyloid substance. Elevated HCy plasma levels have been implicated in alteration of electroencephalogram layout of Alzheimer’s patients and damages of the endothelial structure.[19,20] HCy has been associated with oxidative damage and endothelium damages, through different mechanisms.[21–23] The other toxic component is represented by the amyloid substance. In pathological condition there is an accumulation of amyloidogenic peptides (Aβ peptide) prone to aggregate and leading to the generation of amyloid substance, which (i) increases the damages at the cellular components; (ii) increases OS; and (iii) binds to the endothelium of the vessels, reducing the vascular calibre and impair the cerebral micro-circulation.[24,25] 
  • Mitochondria: BBB endothelial cells require large amount of energy, in the form of ATP, to keep the barrier effective.[26] Therefore, BBB endothelial cells are enriched in mitochondria to satisfy such energetic demand. Unfortunately, a large production of ATP corresponds to an increased production of ROS. The RedOx balance at the BBB level is regulated by complex and sensitive mechanisms and any alterations to the mitochondrial respiratory chain can culminate into two parallel deleterious phenomena: a decrease in ATP production and an increase in ROS production.[27,28]
  • Circualting cells (mainly erythrocytes): the main activity of erythrocytes is the transportation of O2 bound to hemoglobin. Due to the elevated O2 consumption of the brain key elements to consider are: (i) the erythrocyte transport ability and (ii) the ability of the erythrocyte to properly reach cerebral structures. Erythrocyte functionalities are linked to the plasticity of the membrane which undergoes to adaptation when passing into cerebral micro-circulation and the calibre of the vessels is reduced. Lipids of erythrocytic membranes can be oxidized in condition of elevated OS levels, in this condition the membrane becomes more rigid and less prone to re-adapt in condition of reduced vessel calibre.[29–31] Moreover, amyloid substance can bind to the erythrocytic membrane generating pore-like structures, which alter the cell membrane and volume, and erythrocytes assume an elongated shape (fusiform erythrocytes). ROS and amyloid substance have a vasoconstriction effect on the vessels of the cerebral microcirculation, this phenomena together with the reduced ability of erythrocytes to adapt in condition of reduced vessel calibre strongly affects the O2 supplementation to cerebral cells and BBB components, which further exacerbates OS status and the diseases progression.[29]

Is it possible to protect the brain and the central nervous system from oxidative stress?

In light of the previous observations the protection of brain and central nervous system from oxidative stress requires specific, synergic and harmonic supplementation of ingredients able to concurrently address the main aspects of cerebral OS.

The challenge for researchers and producers is to catch this complexity and translate it into new supplements with robust validation. The challenge for consumers is to expect robust validation and trust evidence-based results. At Cor.Con. International our innovative food supplements are patented, tested in clinical studies. The use of specific ingredients promotes the normal function of the nervous system, protects the cells from oxidative stress, promotes the normal psychological function, the normal cysteine synthesis, and the normal homocysteine metabolism.[32]


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