Therapeutic potential of glutathione-enhancers in stress-related psychopathologies
Graphical abstract
Section snippets
The link between psychogenic stress, brain energetics and oxidative stress
Psychogenic stress is defined as a state of imminent or perceived threat to homeostasis, where the brain and body invoke various physiological responses to adapt (de Kloet and Joels, 2005; de Kloet et al., 2019). In acute situations, the stress response helps the organism mobilize the resources needed to either meet or prepare for a physical or psychological challenge (Herman and Tasker, 2016). For instance, during stress, cerebral energy metabolism, including the oxidation of glucose and the
Evidence of GSH decrease under conditions of psychogenic stress
A number of preclinical studies have reported a link between exposure to stress and decreased levels of GSH and GSH-related enzymes. Glucocorticoids, the main hormone from the hypothalamic-pituitary-adrenal (HPA) axis secreted in response to stress, have been shown to negatively impact the levels of antioxidants, including GSH. in vitro, glucocorticoids were found to decrease GSH levels and inhibit GPx activity in hippocampal neuronal cultures (Patel et al., 2002). Additionally, several studies
Compounds with potential to modulate brain GSH levels
Identifying treatments that enhance brain GSH levels may help develop therapies against stress-related neuropsychiatric diseases. In this section, we explore possible methods of increasing GSH levels in the brain.
Although a fraction of dietary GSH can cross the intestinal barrier and enter the blood stream directly, this process is inefficient and most GSH in humans is thought to be synthesized endogenously. Direct supplementation with GSH is a challenging approach, because it can be rapidly
Alternative strategies to increase glutathione levels
Apart from the main strategies to increase GSH levels through precursor supplementation or activation of Nrf2 pathway, there is substantial evidence that shows the ability of other antioxidants to increase or rescue GSH levels under conditions of oxidative stress. Ergothioneine, l-carnitine, and puerarin are discussed below, as novel possibilities for therapeutic applications. While the exact mechanism of action for some of these antioxidants is not yet well characterized, we include this
Safety and tolerability of GSH precursors and Nrf2 activators
One major aspect in using GSH precursors and Nrf2 activators as potential therapeutic approaches to treat anxiety and stress disorders is their safety and tolerability profile. As one of the main reasons for therapy discontinuation of antidepressant treatments is their severe side effects (van Geffen et al., 2007), the compounds discussed here may offer an attractive alternative or complementary option. Indeed, several GSH precursors have been tested in clinical trials for safety and
Conclusions and discussion
GSH is the main antioxidant in the brain (Dringen, 2000). Its action is essential to neutralize excessive ROS production and prevent oxidative damage under conditions of high energy demand in the brain. Stress-related and anxiety disorders have been associated with reduced levels of GSH, increased levels of oxidative damage and/or reduced levels of expression of enzymes involved in GSH synthesis or recycling (Krömer et al., 2005; Brocardo et al., 2012; Krolow et al., 2014). We propose in this
Authors' contributions
IZ, FH, ER-F, CS and LM drafted the original manuscript, designed tables and figures. IZ, FH, ER-F, LT, SS, EG, NP, PS, CS and LM critically reviewed the drafts. All authors approved the final version.
Declaration of Competing Interest
Laura Trovo, Sarah Sonnay, Eveline Geiser, Nicolas Preitner, and Pascal Steiner are employees of Société des Produits Nestlé S.A.
Acknowledgements
This work was supported by grants from the Swiss National Science Foundation [(grants 31003A-152614 and 51NF40-158776 (NCCR Synapsy)] to the EFPL team.
References (373)
- et al.
Age-associated changes in protein oxidation and proteasome activities in rat brain: modulation by antioxidants
Biochem. Biophys. Res. Commun.
(2005) - et al.
Resveratrol and dimethyl fumarate ameliorate depression-like behaviour in a rat model of chronic unpredictable mild stress
Brain Res.
(2018) - et al.
Treatment of negative symptoms: Where do we stand, and where do we go?
Schizophr. Res.
(2017) - et al.
Antioxidant enzyme and malondialdehyde levels in patients with social phobia
Psychiatry Res.
(2008) - et al.
l-carnitine in the lipid and protein protection against ethanol-induced oxidative stress
Alcohol
(2009) - et al.
Monitoring Keap1–Nrf2 interactions in single live cells
Biotechnol. Adv.
(2014) - et al.
Curcumin and hesperidin improve cognition by suppressing mitochondrial dysfunction and apoptosis induced by D-galactose in rat brain
Food Chem. Toxicol.
(2014) - et al.
Melatonin stimulates brain glutathione peroxidase activity
Neurochem. Int.
(1995) - et al.
Protective effects of melatonin against ethanol-induced reactive gliosis in hippocampus and cortex of young and aged rats
Exp. Neurol.
(2005) - et al.
Brain energy metabolism: focus on astrocyte-neuron metabolic cooperation
Cell Metab.
(2011)
Repeated transient sulforaphane stimulation in astrocytes leads to prolonged Nrf2-mediated gene expression and protection from superoxide-induced damage
Neuropharmacology
N-acetyl cysteine for depressive symptoms in bipolar disorder—a double-blind randomized placebo-controlled trial
Biol. Psychiatry
The promise of N-acetylcysteine in neuropsychiatry
Trends Pharmacol. Sci.
The possible protective effects of vitamin E and selenium administration in oxidative stress caused by high doses of glucocorticoid administration in the brain of rats
J. Trace Elem. Med. Biol.
Antioxidative enzyme activities and lipid peroxidation in major depression: alterations by antidepressant treatments
J. Affect. Disord.
Is depression associated with increased oxidative stress? A systematic review and meta-analysis
Psychoneuroendocrinology
Melatonin: action as antioxidant and potential applications in human disease and aging
Toxicology
Anxiety- and depression-like behaviors are accompanied by an increase in oxidative stress in a rat model of fetal alcohol spectrum disorders: Protective effects of voluntary physical exercise
Neuropharmacology
The Nrf2 cell defence pathway: Keap1-dependent and -independent mechanisms of regulation
Biochem. Pharmacol.
Structural basis of Keap1 interactions with Nrf2
Free Radic. Biol. Med.
Ergothioneine; antioxidant potential, physiological function and role in disease
Biochimica et Biophysica Acta (BBA) – Mol. Basis Dis.
Possible anxiolytic effects of taurine in the mouse elevated plus-maze
Life Sci.
). A standardized protocol for comparable analysis of GSH/GSSG by UHPLC-ESI-MSMS for human plasma
J. Chromatogr. B Analyt. Technol. Biomed. Life Sci.
13 reasons why the brain is susceptible to oxidative stress
Redox Biol.
Invited review: whey proteins as antioxidants and promoters of cellular antioxidant pathways
J. Dairy Sci.
Safety, tolerability and symptom outcomes associated with l-carnitine supplementation in patients with Cancer, fatigue, and carnitine deficiency: a phase I/II study
J. Pain Symptom Manage.
Oral administration of curcumin relieves behavioral alterations and oxidative stress in the frontal cortex, hippocampus, and striatum of ovariectomized Wistar rats
J. Nutr. Biochem.
Genetically altered mice to evaluate glutathione homeostasis in health and disease
Free Radic. Biol. Med.
Curcumin alleviates oxidative stress and mitochondrial dysfunction in astrocytes
Neuroscience
Pre and post treatment with curcumin and resveratrol protects astrocytes after oxidative stress
Brain Res.
Glutathione catalysis and the reaction mechanisms of glutathione-dependent enzymes
Biochim. Biophys. Acta
Increased plasma levels of 8-iso-PGF2alpha and IL-6 in an elderly population with depression
Psychiatry Res.
Melatonin stimulates antioxidant enzymes and reduces oxidative stress in experimental traumatic brain injury: the Nrf2–ARE signaling pathway as a potential mechanism
Free Radic. Biol. Med.
Involvement of the glutamate/glutamine cycle and glutamate transporter GLT-1 in antidepressant-like effects of Xiao Yao san on chronically stressed mice
BMC Complement. Altern. Med.
The emerging role of Nrf2 in mitochondrial function
Free Radic. Biol. Med.
Keap1, the cysteine-based mammalian intracellular sensor for electrophiles and oxidants
Arch. Biochem. Biophys.
Curcumin plays neuroprotective roles against traumatic brain injury partly via Nrf2 signaling
Toxicol. Appl. Pharmacol.
Metabolism and functions of glutathione in brain
Prog. Neurobiol.
Reduced glutathione regenerating enzymes undergo developmental decline and sexual dimorphism in the rat cerebral cortex
Brain Res.
Glutamine protects mitochondrial structure and function in oxygen toxicity
Am. J. Physiol. Lung Cell. Mol. Physiol.
Roles of glutamine in neurotransmission
Neuron Glia Biol.
Effects of dimethyl fumarate on neuroprotection and immunomodulation
J. Neuroinflammation
The role of curcumin administration in patients with major depressive disorder: mini meta-analysis of clinical trials
Phytother. Res.
Effects of oral glutathione supplementation on systemic oxidative stress biomarkers in human volunteers
J. Altern. Complement. Med.
Role of mitochondrial ROS in the brain: from physiology to neurodegeneration
FEBS Lett.
N-acetylcysteine and neurodegenerative diseases: basic and clinical pharmacology
Cerebellum
Antioxidant enzyme and malondialdehyde valuesin social phobia before and after citalopram treatment
Eur. Arch. Psychiatry Clin. Neurosci.
A diet enriched with curcumin promotes resilience to chronic social defeat stress
Neuropsychopharmacology
Carnosine and taurine treatments diminished brain oxidative stress and apoptosis in D-galactose aging model
Metab. Brain Dis.
Glutathione degradation
Antioxid. Redox Signal.
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