Glutathione in the human brain: Review of its roles and measurement by magnetic resonance spectroscopy

Rae, Caroline; Williams, S. R.

doi:10.1016/j.ab.2016.12.022

Cited by 142 publications

(110 citation statements)

References 149 publications

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“…). Systemic free radical formation coincided with the selective oxidation of GSH, the most abundant intracellular thiol found in the brain, which probably reflects an attempt to constrain OXINOS through the targeted scavenging of reactive oxygen, nitrogen and carbon‐centred species (Rae & Williams, ).…”

Section: Discussionmentioning

confidence: 99%

Exaggerated systemic oxidative‐inflammatory‐nitrosative stress in chronic mountain sickness is associated with cognitive decline and depression

Bailey

Brugniaux

Filipponi

et al. 2018

The Journal of Physiology

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Key points Chronic mountain sickness (CMS) is a maladaptation syndrome encountered at high altitude (HA) characterised by severe hypoxaemia that carries a higher risk of stroke and migraine and is associated with increased morbidity and mortality. We examined if exaggerated oxidative‐inflammatory‐nitrosative stress (OXINOS) and corresponding decrease in vascular nitric oxide bioavailability in patients with CMS (CMS+) is associated with impaired cerebrovascular function and adverse neurological outcome. Systemic OXINOS was markedly elevated in CMS+ compared to healthy HA (CMS−) and low‐altitude controls. OXINOS was associated with blunted cerebral perfusion and vasoreactivity to hypercapnia, impaired cognition and, in CMS+, symptoms of depression. These findings are the first to suggest that a physiological continuum exists for hypoxaemia‐induced systemic OXINOS in HA dwellers that when excessive is associated with accelerated cognitive decline and depression, helping identify those in need of more specialist neurological assessment and targeted support. Abstract Chronic mountain sickness (CMS) is a maladaptation syndrome encountered at high altitude (HA) characterised by severe hypoxaemia that carries a higher risk of stroke and migraine and is associated with increased morbidity and mortality. The present cross‐sectional study examined to what extent exaggerated systemic oxidative‐inflammatory‐nitrosative stress (OXINOS), defined by an increase in free radical formation and corresponding decrease in vascular nitric oxide (NO) bioavailability, is associated with impaired cerebrovascular function, accelerated cognitive decline and depression in CMS. Venous blood was obtained from healthy male lowlanders (80 m, n = 17), and age‐ and gender‐matched HA dwellers born and bred in La Paz, Bolivia (3600 m) with (CMS+, n = 23) and without (CMS−, n = 14) CMS. We sampled blood for oxidative (electron paramagnetic resonance spectroscopy, HPLC), nitrosative (ozone‐based chemiluminescence) and inflammatory (fluorescence) biomarkers. We employed transcranial Doppler ultrasound to measure cerebral blood flow (CBF) and reactivity. We utilised psychometric tests and validated questionnaires to assess cognition and depression. Highlanders exhibited elevated systemic OXINOS (P < 0.05 vs. lowlanders) that was especially exaggerated in the more hypoxaemic CMS+ patients (P < 0.05 vs. CMS−). OXINOS was associated with blunted cerebral perfusion and vasoreactivity to hypercapnia, impaired cognition and, in CMS+, symptoms of depression. Collectively, these findings are the first to suggest that a physiological continuum exists for hypoxaemia‐induced OXINOS in HA dwellers that when excessive is associated with accelerated cognitive decline and depression, helping identify those in need of specialist neurological assessment and support.

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Section: Discussionmentioning

confidence: 99%

Exaggerated systemic oxidative‐inflammatory‐nitrosative stress in chronic mountain sickness is associated with cognitive decline and depression

Bailey

Brugniaux

Filipponi

et al. 2018

The Journal of Physiology

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“…Methionine is crucial for the synthesis of cysteine and glutathione, both of which are essential antioxidants in protecting against the formation of reactive oxygen species (ROS) (reviewed in [ 108 , 109 ]). Decreased brain methionine in MSUD patients may result in depletion of antioxidants, with a consequent elevation of cellular vulnerability towards oxidative stress.…”

Section: Potential Impacts Of Decreased Brain Phenylalanine Tyrosmentioning

confidence: 99%

Brain Branched-Chain Amino Acids in Maple Syrup Urine Disease: Implications for Neurological Disorders

Jakher

Ahrens‐Nicklas

2020

IJMS

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Maple syrup urine disease (MSUD) is an autosomal recessive disorder caused by decreased activity of the branched-chain α-ketoacid dehydrogenase complex (BCKDC), which catalyzes the irreversible catabolism of branched-chain amino acids (BCAAs). Current management of this BCAA dyshomeostasis consists of dietary restriction of BCAAs and liver transplantation, which aims to partially restore functional BCKDC activity in the periphery. These treatments improve the circulating levels of BCAAs and significantly increase survival rates in MSUD patients. However, significant cognitive and psychiatric morbidities remain. Specifically, patients are at a higher lifetime risk for cognitive impairments, mood and anxiety disorders (depression, anxiety, and panic disorder), and attention deficit disorder. Recent literature suggests that the neurological sequelae may be due to the brain-specific roles of BCAAs. This review will focus on the derangements of BCAAs observed in the brain of MSUD patients and will explore the potential mechanisms driving neurologic dysfunction. Finally, we will discuss recent evidence that implicates the relevance of BCAA metabolism in other neurological disorders. An understanding of the role of BCAAs in the central nervous system may facilitate future identification of novel therapeutic approaches in MSUD and a broad range of neurological disorders.

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“…The studies that have considered brain GSH have focused on the cortex, which represents the greatest concentration of brain GSH, with the cerebellum, hippocampus and striatum following in descending order of GSH concentration (Kang et al, ). The location of GSH in the brain is highly tissue specific (Rae & Williams, ), with a report of 30% higher GSH in cortical white matter (WM) compared with grey matter dominated PFC (An et al, ). Grey matter (GM) demonstrates increased metabolite concentrations (Srinivasan, Ratiney, Hammond‐Rosenbluth, Pelletier, & Nelson, ), and this tissue also consumes oxygen in a 4:1 ratio to WM, despite only comprising 40% of the total brain volume (Mintun et al, ), rendering the GM more susceptible to oxidative insult.…”

Section: Resultsmentioning

confidence: 99%

Role of magnetic resonance spectroscopy in cerebral glutathione quantification for youth mental health: A systematic review

Fisher

Gillam

Upthegrove

et al. 2019

Early Intervention Psych

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Aim Oxidative stress is strongly implicated in many psychiatric disorders, which has resulted in the development of new interventions to attempt to perturb this pathology. A great deal of attention has been paid to glutathione, which is the brain's dominant antioxidant and plays a fundamental role in removing free radicals and other reactive oxygen species. Measurement of glutathione concentration in the brain in vivo can provide information on redox status and potential for oxidative stress to develop. Glutathione might also represent a marker to assess treatment response. Methods This paper systematically reviews studies that assess glutathione concentration (measured using magnetic resonance spectroscopy) in various mental health conditions. Results There is limited evidence showing altered brain glutathione concentration in mental disorders; the best evidence suggests glutathione is decreased in depression, but is not altered in bipolar disorder. The review then outlines the various methodological options for acquiring glutathione data using spectroscopy. Conclusions Analysis of the minimum effect size measurable in existing studies indicates that increased number of participants is required to measure subtle but possibly important differences and move the field forward.

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Glutathione in the human brain: Review of its roles and measurement by magnetic resonance spectroscopy

Cited by 142 publications

References 149 publications

Exaggerated systemic oxidative‐inflammatory‐nitrosative stress in chronic mountain sickness is associated with cognitive decline and depression

Exaggerated systemic oxidative‐inflammatory‐nitrosative stress in chronic mountain sickness is associated with cognitive decline and depression

Brain Branched-Chain Amino Acids in Maple Syrup Urine Disease: Implications for Neurological Disorders

Role of magnetic resonance spectroscopy in cerebral glutathione quantification for youth mental health: A systematic review

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