Glutathione in Mental Disorders: Mechanisms and Therapies

Yawei Liang

School of Materials and Energy, South China Agricultural University, Guangzhou, 510642, China

Keywords:

Glutathione Homeostasis, Oxidative Stress, Glutathione Peroxidase, Glutathione S-Transferase, Mental

Disorders, Therapeutic Potential.

Abstract: In recent decades, topics related to mental diseases have gradually become important, and the treatments for

mental diseases have also attracted attention from increasing number of researchers. Research directions have

been focused on glutathione metabolism and oxidative stress. Appreciable number of reports have suggested

that the content of reduced glutathione in patients with mental diseases, including Alzheimer's disease,

depression, anxiety disorder, autism, bipolar disorder and schizophrenia, is lower than that in normal people,

suggesting that the dysregulation of glutathione redox may be one of leading the pathogeneses of these mental

diseases. Regulation of glutathione metabolism involves many enzymes, such as GPx1 and GST, which have

been comprehensively analyzed in this paper. Additionally, the potential of targeting glutathione metabolism

balance as a breakthrough point for the treatment of psychiatric disorders will be discussed, listing some

reported that have proven therapeutic effects of N-Acetyl-L-cysteine (NAC), minocycline and dimethyl

fumarate (DMF) on mental disorders as well as their further therapeutic potential. The general purpose of this

paper aims to study the recent progress focusing on glutathione metabolism in mental disorders mechanism

and treatment, highlighting that GSH redox problems for mental illness is indispensable and outlook the

potential development of treatments for mental disorders that target glutathione metabolism.

1 INTRODUCTION

Glutathione (GSH), a kind of tripeptide composed of

glutamic acid, cysteine and glycine, exists in

practically every cell inside human bodies.

Glutathione system acts as the most essential

antioxidant defense that maintaining cellular viability

and function. Normally, glutathione in healthy human

body mainly exists in the reduced form, while

Oxidized glutathione (GSSG) takes merely a tiny part

as the inactive state (Tao, 2014). Meanwhile, the

GSH:GSSG ratio in vivo should be within a

reasonable range and defined as a reliable biomarker

of cellular redox homeostasis (Geir Bjørklund, 2020).

Serving as an antioxidant, glutathione has the

function of eliminating free radicals in vivo. Free

radicals are considered as unstable substances that

can cause cell damage, especially when they

accumulate at higher content than antioxidants.

Oxidative stress will be caused when redox

dysregulation of glutathione occurs, meanwhile

reactive oxygen species (ROS) and reactive nitrogen

species (RNS) become overproduced, leading to the

inhibition of the activity of endogenous antioxidant

system, in which the circumstance may engender

over-loading free radicals damaging cell (Javier

Toro-Pérez, 2021). Then a series of psychiatric

disorders, such as bipolar disorder (Lagopoulos,

2013), depression (Kyle, 2014), autism (Xi, 2015),

Alzheimer's disease (Tandra Ghosh, 2012),

obsessive-compulsive disorder, post-traumatic stress

disorder (PTSD), schizophrenia, etc. can be caused.

To maintain the homeostasis of glutathione, impacts

of peroxidase enzymes are indispensable, which will

be discussed in this paper.

Increasing evidence and achievements about

therapies on mental disorders targeting glutathione

pathway are emerging. The function of glutathione

that can influence and regulate DNA methylation and

epigenetics is highlighted, which can cause the cell

and organ perturbations, particularly in the brain

(Geir Bjørklund, 2020). In response to the association

between dysregulation in glutathione metabolism and

bipolar disorder, Murrough et al. have found that

Minocycline can effectively treat symptoms of

bipolar disorder by modulating oxidative stress in

patients with bipolar disorder (Murrough, 2018).

Therefore, taking glutathione metabolism as the

Liang, Y.

Glutathione in Mental Disorders: Mechanisms and Therapies.

DOI: 10.5220/0012000800003625

In Proceedings of the 1st International Conference on Food Science and Biotechnology (FSB 2022), pages 18-25

ISBN: 978-989-758-638-5

 2023 by SCITEPRESS – Science and Technology Publications, Lda. Under CC license (CC BY-NC-ND 4.0)

breakthrough point to study the pathogenesis and

treatment of mental diseases has considerable value.

This passage aiming to dig deeper into the value of

glutathione, homeostasis of glutathione and

oxidative, as well as biological enzymes which

regulate glutathione metabolism, including GPx1 and

GST. In addition, the pathogenesis and therapeutic

potential of mental disorders focusing on the

glutathione pathway will also be depicted in detail.

2 COMPOSITION OF

GLUTATHIONE SYSTEM

2.1 Oxidative Stress and Homeostasis

Oxidative stress of glutathione has been implicated in

the pathogenesis of several neuropsychiatric

disorders, which is considered as a mechanism

linking genetic, immune and external pathogenic

factors in mental disorders (Xi, 2015). Under normal

circumstances, intracellular ROS and antioxidant

capacity are in a dynamic balance (Currenti, 2010).

As an antioxidant produced by human cells,

glutathione has a limited ability to remove active

oxides. When the content of active oxides exceeds the

reducing capacity of glutathione, imbalance between

cellular oxidation and antioxidant effects will occur.

This oxidative stress can hinder or disrupt cell

signaling and affect cell proliferation as well as gene

expression (Betancur, 2011). In addition to

glutathione, glutathione peroxidase (GPX) also acts

as antioxidant effects, which will be discussed in

detail in the following parts.

In order to illustrate glutathione homeostasis

systematically, normal state of glutathione redox and

glutathione metabolism under oxidative stress are

shown in Fig 1 and Fig 2 respectively. Under normal

circumstance, methionine cycling, and sulfur transfer

are the main factors regulating methylation and redox

buffering activities (Xi, 2015). When oxidative stress

occurs, a variety of regulatory mechanisms are

activated to reduce methionine synthase and cysteine

plus dioxygenase activity, as well as to increase

cystathionine synthase activity to attain the purpose

of changing sulfur flux in response to glutathione

synthesis. Low methionine synthase can reduce

methylation, including methylation of dopamine

receptor phospholipids.

In recent decades, increasing number of studies on

neurological diseases have focused on the glutathione

pathway, from which the fact that glutathione and

oxygen can affect the activities of enzymes

controlling genetics and transcription has been

generally accepted (Geir Bjørklund, 2020). The

maintenance of redox homeostasis is of great

significance for the central nervous system (CNS).

Once homeostasis is disrupted, the nervous system

can be harmed. Dysfunction of mitochondrial can be

one of the reasons that elevated levels of oxidative

stress, which was a phenomenon observed in autism

spectrum disorders (ASD) individuals (Xi, 2015). A

study carried out by ZHANG in 2018 had proved that

GSH can restrain the cell damage by oxidative stress

(Zhang, 2018). In this research, MPP+ was applied to

MES 23.5 dopamine neuron cells, which results in

increasing levels of ROS and MDA while CAT

activity declines in cell MES 23.5, inducing abnormal

mitochondrial function as well as oxidative stress to

create models of oxidative damage cells.

Figure 1: Normal redox status of glutathione. Adapted from (Xi, 2015).

Glutathione in Mental Disorders: Mechanisms and Therapies

Figure 2: Glutathione metabolism under oxidative stress. Adapted from (Xi, 2015).

GSH was then applied to cells model, so the activity

of MES 23.5 recovered considerably, indicating that

GSH has the function of antioxidant protection. So,

what contributes in keeping the glutathione

homeostasis? Answer should be enzymes related to

the metabolism of glutathione such as glutathione

peroxidase and glutathione S-transferase.

2.2 GPx1

Glutathione peroxidase (GPx) can be divided into

four major categories, including cytosolic GPx,

plasma GPx, phospholipid hydroperoxide GPx and

gastrointestinal specific GPx. It was recognized that

the first vertebrate protein depends on selenium was

GPx (Little C, 1968). Glutathione peroxidase family

belongs to the antioxidant enzymes, of which GPx1 is

one of the family.

1) Role of GPx1 in mental disorder. Until 1968,

scientists claimed that GPx can lessen various kinds

of organic peroxides, nucleic acids and

hydroperoxides produced by unsaturated fatty acids

(Little C, 1968). Existing as an important antioxidant

enzyme, GPx1 can be found in both mitochondria and

cytoplasm of mammalian cells (Leopold Flohé,

2022). The main function of GPx1 is to oxidate

cellular GSH along with the reduction of hydrogen

peroxide, which can control the thiol redox state

while keeping necessary and harmful states of

oxidants in balance (Diane E. Handy, 2022). One

study by Zorov et al. showed that if dysfunction and

damage occur in mitochondrial membranes or

proteins, production of ATP and uncoupling of

electron transport may happened, which can stimulate

the mitochondria releasing ROS (Zorov D.B, 2014).

In addition, GPx1 also has the potential ability to

regulate the forming of these kinds of extra ROS.

GPx1 is able to protect neurocyte against ROS-related

neurotoxicity (Crack P.J., 2006). When gene

expression of GPx1 dysregulates, the oxidative stress

caused by this case can be related to

neurodegeneration which is a considerable factor of

chronic neurodegenerative diseases like Alzheimer’s

disease (Diane E. Handy, 2022).

Indeed, GPx1 helps to keep glutathione redox

stable and provides neuroprotection. If expression of

GPx1 increases, however, cellular dysfunction and

other diseases can also be stimulated because some

essential reactive oxygen species are removed in this

case (Diane E. Handy, 2022). Superfluous oxidant

like GPx1 can damage cellular DNA, proteins and

lipid. Study by Martini et al. had found that

upregulating GPx1 can mitigate suppression of

ERK1/2 and memory impairment (Martini F, 2019).

The process is illustrated in Figure 3. Interestingly,

the activation of ERK1/2 can also be inhibited when

GPx1 overexpressing, which may possibly be

promoted by ROS production (Diane E. Handy,

2022). These results provide reasonable evidence to

see the connection between GPx1 expression and

psychiatric disorders, but also highlight the

complexities of regulating antioxidant for therapies.

FSB 2022 - The International Conference on Food Science and Biotechnology

Figure 3: Process illustrating how the increase of GPx1 lead to inhibition of ERK1/2. Adapted from (Diane E. Handy, 2022).

2) Regulation of GPx1 expression. It was claimed

that not all the glutathione peroxidases are

selenoproteins but GPx1 is, which includes the amino

acid selenocysteine at the active site (Floh´e L.,

1973). Selenium deficiency may not result in a

defective GSH regeneration but cause the utilized

impairment (Leopold Flohé, 2022). Another research

by Smesny et al. revealed how omega-3 PUFA affects

the glutathione antioxidant defense system (AODS)

in individuals with ultra-high risk of psychosis

(Stefan Smesny, 2015). Result of this study had

shown the mechanisms underlying clinical

effectiveness, of which the effects were not specific.

Contrarily, it is certain that omega-3 PUFA can

influence the antioxidative effects in AODS,

decreasing the demand of glutathione. However,

there is no absolute association between omega-3

PUFA and GPx1.Therefore, it is reasonable to give an

opinion that GSH levels in vivo can be indirectly

influenced by selenium, also further study about

substances that can affect the production of GPx1 is

needed.

2.3 GST

1)Role of GST in mental disorder. Comparing with

GPx1, GST has different chemical properties and

biological effects. Details are listed in Table 1. With

detoxification, GST mainly helps to promote the

electrophilic groups from endogenous substances or

xenobiotics coupling to the sulfhydryl group of

reduced glutathione, increasing the hydrophobicity of

the combination to cross the cell membrane,

decompose and then be excreted (Sen Ma, 2008). In

this way, GST can remove peroxide as well as

detoxify xenobiotics. However, mechanism of GST

may be affected by GPx. When the activity of GPx

decreases, GST can only eliminate the lipid peroxides

(LPO), losing the ability of detoxification.

As one of the members of family of phase-II

isoenzymes, GST protect human cells from

electrophiles and substances produced by oxidative

stress, playing a critical role in pathogenesis of

Alzheimer’s disease. In 2012, Ghosh et al. digged into

the relationship between GST and Alzheimer’s

disease, indicating that gene deletion of GSTM1(Mu)

and GSTT1(theta) which are belong to GST family,

can decline the expression of related enzymes

(Tandra Ghosh, 2012). Result shown that deletion of

GSTT1 was dramatically related to Alzheimer’s

disease. Probability of people getting Alzheimer’s

disease with gene deletion of GSTT1 was 2.47 times

higher than that of people with positive GSTT1. Also,

study by Spalletta et al. found that patients with

schizophrenia who carry the GSTA1*B allele were

facing to higher risk of damage by oxidative stress

than non-B carriers, displaying severer symptoms of

illusion (Gianfranco Spalletta, 2012).

2) Factors influence metabolism of GST. Several

factors can affect the metabolism of GST. Activity,

inner concentration, issue localization of GST varies

in different people. Gene expression of GST reveals

polymorphism in people who are not living in the

same geographical area (Buratti F.M, 2021). GST

exists in practically all parts of human body, with

highest levels in the cytoplasm of liver, kidney and

blood, in which the elimination of peroxide and

detoxification of xenobiotics mainly take place.

Certain product of metabolism can also influence

GST expression. In 2021, Crawford et al. found that

3,4-dihydroxyphenylacetaldehyde (DOPAL), an

aldehyde metabolite of dopamine can inhibit the

Glutathione in Mental Disorders: Mechanisms and Therapies

Table 1: Comparison between GPx1 and GST.

GPx1 GST

can catalyze the reduction of H

and organic

dro

eroxide com

ounds

cannot decompose H

removing peroxide only removing peroxide and detoxifying

poor thermal stability better thermal stability

activity and function of GST, but 1 mM carnosine can

completely protect GST from DOPAL (Crawford

R.A., 2021).

3 ROLE OF GLUTATHIONE IN

MENTAL DISORDER

3.1 Pathogenesis

At present, a fair amount of research has been done to

probe how glutathione metabolism associates with

psychiatric disorders. However, there is still no clear

evidence to confirm that metabolic disorders of

glutathione can always cause psychiatric problems,

but it is considerable to take glutathione as a

biological indicator to analyze certain disease. Lack

of glutathione and oxidative stress can be considered

as primary symbols of some mental problems, but the

precise and specific pathogenesis concerning

glutathione remains uncertain.

Redox dysregulation act as a non-negligible factor

in autism spectrum disorder (ASD). By affecting

redox environment and redox-independent

mechanisms, glutathione metabolism impacts

multiple pathogenesis of ASD (Geir Bjørklund,

2020). N-methyl-Daspartate receptor, a glutamate

receptor regulated by glutathione may contribute to

glutamate excitotoxicity, in which case that

synergistic and antagonistic interactions of

glutathione and glutamate will lead to neuronal

dysfunction (Geir Bjørklund, 2021). These kinds of

synergistic and antagonistic interactions are likely to

involve transcription factors in immune pathway,

changing neuroinflammatory mechanisms and then

neuronal damage emerges.

Pathogenesis of depression implicates oxidative

stress as an essential mechanism. Lapidus et al. used

proton magnetic resonance spectroscopy (1H MRS)

to obtain the glutathione in vivo level of occipital

cortex of patients with major depressive disorder and

came to a conclusion that anhedonia severity shown

negative relation to occipital glutathione level, which

indicated glutathione and oxidative stress have

similar pathogenesis in anhedonia and major

depressive disorder (Kyle A.B. Lapidus, 2014). This

may increase a support to the importance of oxidative

stress of glutathione in pathogenesis of depression,

which means low level of glutathione becoming

potential symbols in the early state of major

depressive disorder. Also, in vivo level of GST is one

of the biomarkers to show the possibility of suffering

from depression. Savushkina et al. found that people

with depression have less platelet GST and

erythrocyte glutathione reductase than normal people

(Olga Savushkina, 2022). Interestingly, research by

Lagopoulos et al. argued that no decline was found in

baseline GSH concentration of the young with bipolar

disorder, while no prominent result to support

glutathione oxidative stress involved in mania

(Lagopoulos J., 2013). Therefore, further study may

be requested, but existing research has provided

human-oriented information that may contribute to

prospective clinical study and therapies.

3.2 Protective Effects

Disturbances in glutathione in the hippocampus can

lead to some of the mental diseases. A mass of

glutathione is needed in hippocampal neurons in

order to protect and maintain dendrite integrity and

cognitive function. In 2022, Ho et al. emphasized the

interactions of glutathione and copper on physiology

and Alzheimer’s disease (Talia Ho, 2022). It was

indicated that effects of glutathione and copper on

Alzheimer’s disease have been studied separately in

previous researches, of which the fact that these two

substances are actually more effective and regulate

each other when interacting. To give details of

mechanism of the interaction of glutathione and

copper, a simplified illustration by Ho is shown in

Figure 4. It can be observed from the figure that

copper is imported into the cell by copper transporter

1 (Ctr1). Then glutathione chelates the copper almost

immediately. Copper can be stored and passed by

glutathione to different chaperones and

metallothionein that functions as a storage molecule.

FSB 2022 - The International Conference on Food Science and Biotechnology

Figure 4: A simplified illustration for the overview of copper importation, utilization, and exportation within the cell.

Referring to (Talia Ho, 2022).

4 THERAPEUTIC POTENTIAL

Although the aforementioned associations of

glutathione homeostasis and oxidative stress with

psychiatric disorders are preliminary results,

targeting glutathione pathway for the treatment of

mental disorders still possess prospective

development. Appling N-Acetyl-L-cysteine (NAC)

as a drug with pharmacological targeting of

glutathione system can be a significant example.

Yang et al. executed clinical studies with

schizophrenics and found that after 8 weeks of

treatment with NAC, prefrontal cortical levels of

glutathione in schizophrenics have been raised (Yang,

2022). As a glutathione precursor, NAC has already

shown adjunctive value in therapies of schizophrenia,

of which the curative effect has been proved to be

apparent (Schiavone S., 2016). In fact, NAC can also

be effective in alleviating depressive symptoms or

anxiety symptoms, but the condition under which

NAC can work is limited. Porcu et al. conducted a 12-

week clinical experiment in 2018, in which patients

were assigned to receive the same daily dose of

placebo or 1.8g NAC (Porcu M., 2018). It has been

proved that only when high sensitivity C-reactive

protein levels exceed 3 mg/L, can the therapeutic

effect of NAC be observed.

Most of the reports about targeting glutathione

pathway to treat psychiatric disorders are by applying

NAC to schizophrenics. There is one sample study

that rarely mentioned, which focused on minocycline

for the treatment of bipolar depression. In 2018,

Murrough et al. treated 20 people with bipolar

disorder with minocycline at a daily dose of 256 mg

(SD: 71 mg) and measuring the cortical glutathione

within a voxel prescribed in the precuneus by proton

magnetic resonance spectroscopy (1H MRS)

(Murrough J.W., 2018). Results by this study proved

that applying minocycline to patients with bipolar

disorder, especially those with high baseline

glutathione levels, is considered as a significant

adjuvant treatment.

In addition, targeting the regulation of glutathione

expression is also a potential therapeutic approach.

Nrf2 can control the expression of various antioxidant

enzymes, including those involved in GSH synthesis,

such as GST and GPx1. As early in 2004, Chen et al.

proposed to enhance the antioxidant capacity of GSH

in response to oxidative stress by increasing Nrf2

activity (Chen, 2004). Dimethyl fumarate (DMF), a

fumarate ester, was thought to have an ability to

activate the action of Nrf2 (Linker, 2011). The

principle for this is that DMF can modify the cysteine

residues on Keapl, so that Nrf2 can be stabilized and

transferred to the nucleus to activate ARE targets,

thus reducing oxidative stress. In 2018, El-Fattah

conducted experiments on mice in which DMF was

administered orally at a dose of 25mg/kg 1 h before

each exposure to stress and found that depressive

symptoms due to oxidative stress in mice were

Glutathione in Mental Disorders: Mechanisms and Therapies

reduced (Abd El-Fattah, 2018). Although the results

were collected from animal model, this study also

provides us with considerable evidence and potential

that DMF may be beneficial for the treatment of

depression in humans.

Consequently, further study is required to

discover and evaluate novel drug targeting

glutathione pathway as therapy or adjuvant treatment

to various sorts of mental disorders.

5 CONCLUSION

It is undoubted that oxidative stress caused by

glutathione redox dysregulation is involved in the

pathogenesis of a variety of psychiatric diseases.

Studying the metabolic pathway of glutathione and

factors influencing glutathione homeostasis is quite

significant. Targeting the pharmacology of the redox

regulatory system as a therapeutic modality is

believed to be a promising approach for the treatment

of psychiatric disorders. The treatment of mental

disorders centered on glutathione metabolism is not

yet fully developed, but the development of such

topic may show great potential.

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Glutathione in Mental Disorders: Mechanisms and Therapies