Glutathione is considered the most powerful endogenous antioxidant and it is distributed throughout all the tissues and cells of the human body. But what is its role in the brain?
The brain is an organ with a high metabolism: although it accounts for just 2% of body weight, it consumes 20% of all the oxygen used by the body. This means that, compared with other organs, in the brain oxygen free radicals are produced at an extremely high rate.
It is precisely for this reason that the system regulating the redox balance and neutralising free radicals needs to be highly efficient.
Despite these requirements, the glutathione content is on average low compared with other organs1. A real paradox!
The highest levels of glutathione are in fact found in the liver (5-10 mM), followed by the kidney, spleen, small intestine, brain, pancreas, lung, heart and muscle2.
Numerous studies 3-4 have confirmed the importance of this small protein complex for the antioxidant protection of the brain, and that reduced levels of glutathione (GSH) have proved to be a recurring feature in ageing and in neurodegenerative diseases.
Glutathione and detoxification of brain cells from ROS
As we have already said, one of the main properties of glutathione is precisely that of neutralising free radicals5. In practice its metabolic cycle performs a direct antioxidant function, in order to render harmless the so-called reactive oxygen species (ROS) and reactive nitrogen species (RNS), the main classes of free radicals.
This activity is a very delicate one in the brain, because this organ has two main characteristics that set it apart from other organs and make it more sensitive to oxidation:
- Its membranes are rich in polyunsaturated fatty acids (PUFAs), which are an ideal substrate for the oxidation process;
- It has practically no cell turnover: the main cells of the brain do not in fact duplicate and do not regenerate, except in particular and rare conditions. This characteristic makes it especially sensitive to the damage caused by free radicals, which ultimately turns into cell decay and death.
Another very interesting aspect, which has emerged from scientific research, is the different distribution of glutathione across the various brain cell populations. In particular, higher levels of GSH and its metabolites have been found in the primary astrocytes than in the neurons6 and in the primary endothelial cells of the blood-brain barrier7.
In vitro studies have shown that astrocytes are a decisive source of GSH for the brain; specifically, they can release up to 10% of their intracellular glutathione each hour,6 both towards the extracellular space and towards the endothelial cells of the BBB (blood-brain barrier).
To carry out this process, the multidrug resistance protein (MRP1) is used as a transporter. This flow occurs both in normal conditions and in the event of injury, but in the latter case it is accelerated6.
The astrocyte population and its correct activity therefore prove decisive for protection from free radical damage both at neuronal level and at the level of the BBB6-7.
And let us remember that the integrity both of the neurons and of the blood-brain barrier is central to preventing brain degeneration.
Can taking glutathione be useful for the wellbeing of the brain?
Reduced glutathione, GSH, had its chemical structure identified in 19298 by the Nobel Prize winner Frederick G. Hopkins and from that moment on it has been increasingly studied.
Since the 1990s, as the mechanisms of neurodegeneration induced by oxidative stress in the central nervous system have been explored in ever greater depth, decreased GSH has been increasingly associated with the brain of patients with neurodegenerative diseases.
Over the last 30 years, therefore, basic research on glutathione in the Central Nervous System has focused more and more on therapeutic strategies aimed at reducing neurodegeneration and increasing GSH levels in the brain in order to provide neuroprotective effects.
At the current state of research it seems that glutathione (GSH) is unlikely to be able to cross the blood-brain barrier intact, but that what reaches the brain cells are its constituent amino acids (Glycine, Cysteine and Glutamic acid), obtained from the breakdown of GSH in the blood, and that these are used for the synthesis of intracellular GSH9.
Further investigation could, however, lead to ever new evidence, since the blood-brain barrier does not have the same degree of permeability in all areas of the brain.
So it is not yet entirely clear whether an exogenous approach can directly affect the GSH content of the brain. But it is increasingly evident that both in conditions of ageing and in the presence of neurological disorders such as Alzheimer’s and Parkinson’s there is a decline in brain GSH.
Interest in slowing down this process and supporting the brain’s reserves of this antioxidant is therefore constantly growing.
Some research already completed shows promising results that need further confirmation.
For example, a very recent study carried out on animal models10 with an induced Alzheimer’s condition found a significant improvement in behavioural deficits, including cognitive decline and depression-like behaviour, following the oral administration of GSH. This promising result makes further exploration in future clinical studies on humans very interesting, in order to check whether the same potential may be found.
Another investigation11 from 2015 showed that after 6 months of oral intake, average GSH levels increased by 30-35% in erythrocytes, plasma and lymphocytes, and therefore that exogenous glutathione is absorbed by the body.
Following all these considerations, GSH remains the most promising antioxidant at brain level because it is selectively decreased in the brain of patients with these neurodegenerative diseases. Enriching the brain’s reserves with exogenous GSH seems to be an interesting route in supporting brain functions, including in the presence of these problems. Obviously, further studies are needed to establish the best approach for taking it.
Should glutathione be taken on its own or together with other substances?
As well as playing a leading role in the brain, let us not forget that glutathione is important for the whole body.
To optimise its benefits it is preferable to combine it with other substances that promote its action and its synthesis in the liver, such as quercetin12-13, and also with lipophilic elements, so that its structure is protected from oxidation and also from enzymes that could degrade it in the digestive tract.
Another element that goes well with glutathione supplementation is Selenium. This mineral in fact takes part in numerous processes in the human body, including antioxidant protection, and it also contributes to the physiology of the brain.
A very recent clinical study14 published in The Neurologist showed that the administration of selenium in patients with acute ischaemic stroke gave positive outcomes in terms of recovery from neurological deficits, antioxidant enzyme activity and levels of inflammatory markers.
In Italy, a mix of powerful antioxidants combined together, including reduced glutathione, can be found in Glutatione Forte. It is a food supplement in capsules, 100% natural, which contains the maximum daily amount permitted for supplements of reduced Glutathione and Quercetin, with Selenium, Naringenin and the patented plant complex OxiP®.
Dr Miriana Fabbri - Biologist