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Cited by 46Sulfur Compounds in BiologyGlutathione Transferases and PolymorphismsNeuroscience and Neuropharmacology Research

Glutathione Metabolism of the Brain—The Role of Astrocytes

Open access
Dringen, Ralf, Arend, Christian·2025·Journal of Neurochemistry
DOI 10.1111/jnc.70073PMC PMC12046376
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Abstract

Astrocytes have essential functions in the brain as partners of neurons in many metabolic and homeostatic processes. The metabolism of the tripeptide GSH (γ‐L‐glutamyl‐L‐cysteinyl‐glycine) is an important example of a metabolic interaction between astrocytes and neurons. GSH is present in brain cells in millimolar concentrations and has essential functions as an antioxidant and as a substrate for detoxification reactions. A high GSH content protects astrocytes against oxidative stress and toxins and is therefore beneficial for the astrocytic self‐defense that helps to maintain the essential functions of astrocytes in the brain and will enable astrocytes to eliminate potential toxins before they may reach other brain cells. In addition, astrocytes provide neurons with the amino acids required for GSH synthesis in a process that involves the export of GSH from astrocytes by the multidrug resistance protein 1, the extracellular processing of GSH via the astrocytic γ‐glutamyl transpeptidase to generate the dipeptide cysteinyl‐glycine, and the extracellular cleavage of this dipeptide by the neuronal ectopeptidase aminopeptidase N. As GSH export from astrocytes strongly depends on the cytosolic GSH concentration, a high astrocytic GSH content will also facilitate GSH release and thereby the supply of GSH precursors to neighboring neurons. In this article, we will give an overview of the current knowledge on the GSH metabolism of astrocytes, address how a high astrocytic GSH content can help to maintain brain functions, and discuss open questions and future perspectives of research on the functions of astrocytes in the GSH metabolism of the healthy and diseased brain. image

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Written from the paper’s full text.

TL;DR

This review argues that astrocytes sit at the center of brain glutathione (GSH) metabolism: their high GSH content supports their own detoxification capacity and, via Mrp1-mediated GSH export followed by extracellular processing by astrocytic γ-glutamyl transpeptidase and neuronal aminopeptidase N, supplies neurons with the cysteine and glycine they need for GSH synthesis. It synthesizes decades of mostly cultured-cell evidence and flags the key open questions, especially whether these astrocyte–neuron interactions operate in the human brain in vivo.

Key findings

  • Astrocytes contain substantially higher GSH than neurons; the cytosolic GSH concentration of cultured astrocytes was calculated at 8 mM, and astrocytes are estimated to make up 20%–40% of all brain cells and 10%–15% of brain volume, so much of tissue GSH is likely astrocytic.
  • In unstressed cultured astrocytes, GSH export is the main consumer of GSH, with cultures releasing around 10% of their GSH per hour; export is primarily Mrp1-mediated and follows apparent Michaelis–Menten kinetics with a K_M between 25 and 50 mM, so any rise in cytosolic GSH accelerates export.
  • Two distinct mechanisms of stimulated Mrp1-mediated export are described: formaldehyde raises V_max about tenfold with unchanged K_M (suggesting recruitment of transporter-containing vesicles to the plasma membrane), whereas ritonavir lowers the K_M; basal export is inhibited only ~60% by the Mrp1 inhibitor MK571.
  • Astrocytes supply neuronal GSH precursors: co-culture with astrocytes increases neuronal GSH content, the γGT inhibitor acivicin strongly inhibits this cysteine supply, and an inactivating antibody against aminopeptidase N prevents neuronal use of CysGly. GSH depletion (e.g., by BSO) compromises astrocyte resistance to peroxides, metals, and xenobiotics (Table 1), and impaired astrocytic GSH metabolism increases neuronal vulnerability (Table 2).

Methods

  • Narrative review: the authors state they give an overview of current knowledge on astrocytic GSH metabolism, discuss why high astrocytic GSH benefits the brain, and outline open questions and future perspectives; they note the topic has been reviewed before and that they focus mainly on astrocyte functions.
  • Evidence base is the published literature, dominated by cultured murine (rat and mouse) astrocytes and neurons, co-culture experiments, transporter inhibitors/knockouts (e.g., Mrp1-deficient astrocytes), and enzyme assays (LDH, MTT, ROS staining, neurite length, cell counting) as tabulated in Tables 1 and 2.
  • No new experimental data, systematic search strategy, or meta-analysis is reported.

Limitations

  • Stated by the authors: most processes involved in shuttling GSH substrates from astrocytes to other brain cells have been studied only in cultured murine brain cells, and little information exists on astrocyte–neuron metabolic interactions in the human brain, especially for GSH metabolism; in vivo confirmation (e.g., astrocyte-specific knockdowns of Mrp1-mediated export or γGT processing) is still needed.
  • Stated by the authors: contradictory results across groups, partly from methodological differences, make it difficult to evaluate literature on brain GSH alterations in human disease, and it is currently unclear whether or to what extent disturbed astrocytic GSH metabolism contributes to reported changes in human brain GSH levels.
  • Evident from the text: the review is not systematic, so the selection and weighting of cited studies is the authors' own; several mechanistic conclusions (e.g., vesicular recruitment of Mrp1 after formaldehyde) are inferences from kinetic data rather than direct demonstration, and the relative contributions of ectoenzyme-dependent versus ectoenzyme-independent cysteine supply pathways remain unresolved.

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Integrity signals

Registry

Crossref · 10.1111/jnc.70073

Cites

167 of 167 references verified0 citation errors · 0 not checkable

Statistics

Nothing to recompute.

Claims the paper makes

25 of 77 cited sources checked · 12 supported · 0 flagged · accuracy not yet measured

  • Interpretationreasoning

    The reported loss in GSH in given brain areas in some human diseases is likely to be at least in part the consequence of a loss of astrocytic GSH and/or of alterations in the GSH metabolism of astrocytes.

    “As a consequence of the high abundance of astrocytes in the brain and of the well‐known pivotal role of astrocytes in brain GSH metabolism, it can be concluded that the reported loss in GSH in given brain areas in some human diseases (Detcheverry et al. 2024; Iskusnykh et al. 2022) is likely to be at least in part the consequence of a loss of astrocytic GSH and/or of alterations in the GSH”
    Quote in the paperSubstantial claim2 of 2 sources checked
    • cites Detcheverry et al. 2024 source
    • cites Iskusnykh et al. 2022 source
  • Premisecitation

    Astrocytes are considered to contain substantially higher GSH contents than neurons.

    “As astrocytes are considered to contain substantially higher GSH contents than neurons (Asanuma and Miyazaki 2021; Dringen et al. 2015; McBean 2017; Sedlak et al. 2019; Vázquez‐Meza et al. 2023), it can be concluded that a substantial part of the total GSH determined in brain tissue represents astrocytic GSH.”
    Quote in the paperSubstantial claim1 of 2 sources checked
    • cites Asanuma and Miyazaki 2021 source

      Section 2.1 (page unavailable) describes astrocytes synthesizing and releasing GSH that supports neuronal GSH synthesis. It does not say that astrocytes contain substantially more GSH than neurons; Section 4 discusses differences between astrocyte populations, not an astrocyte–neuron comparison. (LLM, conf=0.82)

      Experimental — accuracy not yet measured
    • cites Dringen et al. 2015

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  • Premisecitation

    The KM-values for Mrp1-mediated export of GSSG are in the micromolar range.

    “KM‐values for the Mrp1‐mediated export of GSSG and the GSH‐conjugate glutathione‐bimane (GS‐B) are in the micromolar and nanomolar range (Homma et al. 1999; Leier et al. 1996), respectively.”
    Quote in the paperNot a substantial claim1 of 2 sources checked
    • cites Homma et al. 1999 source
    • cites Leier et al. 1996 source
  • Premisecitation

    The KM-values for Mrp1-mediated export of the GSH-conjugate glutathione-bimane (GS-B) are in the nanomolar range.

    “KM‐values for the Mrp1‐mediated export of GSSG and the GSH‐conjugate glutathione‐bimane (GS‐B) are in the micromolar and nanomolar range (Homma et al. 1999; Leier et al. 1996), respectively.”
    Quote in the paperNot a substantial claim1 of 2 sources checked
    • cites Homma et al. 1999 source
    • cites Leier et al. 1996 source

      The kinetic-characterization section reports micromolar Kₘ values for GSSG transport, and the Discussion gives a nanomolar Kₘ for leukotriene C₄, not glutathione-bimane. Searches for glutathione-bimane, GS-B, and monochlorobimane found no passage in our copy reporting its transport Kₘ. (LLM, conf=0.76)

      Experimental — accuracy not yet measured
  • Premisecitation

    The cysteine shuttle between astrocytes and endothelial cells helps to maintain endothelial barrier stability and integrity.

    “A similar interaction in GSH metabolism by cysteine supply via GSH export appears to take place between astrocytes and endothelial cells, and this cysteine shuttle has been reported to help to maintain endothelial barrier stability and integrity (Huang et al. 2020).”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites Huang et al. 2020 source

      The Significance section reports that astrocyte-derived glutathione supports endothelial barrier stability and that blocking its transfer increases permeability. The Discussion says the proposed cysteine-supply mechanism—glutathione breakdown followed by cysteine uptake—was not investigated in detail and remains speculative, so the paper does not establish a cysteine shuttle specifically. (LLM, conf=0.88)

      Experimental — accuracy not yet measured
  • May combine two claims. 12
  • Classified as probably not a substantial claim. 1

  • May combine two claims.

    Premisecitation

    Improved supply of GSH precursors from astrocytes to neurons and a thereby better resistance of neurons has been reported after β-adrenergic stimulation, by exposure to interleukin 1β, or after exposure to ethanol.

    “Interestingly, improved supply of GSH precursors from astrocytes to neurons and a thereby better resistance of neurons has been reported after β‐adrenergic stimulation (Yoshioka et al. 2021), by exposure to interleukin 1β (Chowdhury et al. 2018) or after exposure to ethanol (Rathinam et al. 2006).”
    Quote in the paperNot a substantial claim1 of 3 sources checked
    • cites Yoshioka et al. 2021

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

    • cites Chowdhury et al. 2018 source
    • cites Rathinam et al. 2006 source

  • May combine two claims.

    Premisecitation

    The amino acids cysteine and glycine liberated by hydrolysis are efficiently taken up by sodium-dependent transporters into neurons and can be used as substrates for neuronal GSH synthesis.

    “The amino acids liberated by the hydrolysis, cysteine and glycine, are efficiently taken up by sodium‐dependent transporters into neurons (Aoyama and Nakaki 2013; Zafra and Giménez 2008) and can be used as substrates for neuronal GSH synthesis (Dringen, Pfeiffer, et al. 1999; Kranich et al. 1996).”
    Quote in the paperSubstantial claim3 of 3 sources checked
    • cites Aoyama and Nakaki 2013 source

      The ‘Excitatory Amino Acid Transporters’ section says that approximately 90% of neuronal cysteine uptake uses sodium-dependent systems. The ‘Thiol Source for Glutathione Synthesis in the Brain’ section says that cysteine and glycine released by hydrolysis are transported into neurons for GSH synthesis. Our copy does not establish that glycine uptake is sodium-dependent, so it supports only part of the uptake claim attributed to this citation. (LLM, conf=0.88)

      Experimental — accuracy not yet measured
    • cites Zafra and Giménez 2008 source

      The ‘Plasma Membrane Glycine Transporters: Distribution and Function’ section describes sodium-coupled glycine transport and glycine accumulation in neurons expressing GLYT2. It does not establish neuronal uptake of cysteine or identify hydrolysis as the source of the transported glycine. The GSH-synthesis clause is attributed to different citations in the citing sentence, not to this paper. (LLM, conf=0.88)

      Experimental — accuracy not yet measured
    • cites Dringen, Pfeiffer, et al. 1999 source

  • May combine two claims.

    Interpretationcitation

    Both the chemical reduction of extracellular cystine by GSH released from astrocytes and transfer via extracellular vesicles should not be affected by inhibitors of the astrocytic γGT or neuronal aminopeptidase N.

    “However, both the chemical reduction of extracellular cystine by GSH released from astrocytes as well as transfer via extracellular vesicles should not be affected by inhibitors of the astrocytic γGT or neuronal aminopeptidase N, which were shown to be involved in the supply of cysteine to neurons (Dringen, Pfeiffer, et al. 1999) and in the use of CysGly by neurons (Dringen et al. 2001).”
    Quote in the paperNot a substantial claim1 of 2 sources checked
    • cites Dringen, Pfeiffer, et al. 1999 source
    • cites Dringen et al. 2001 source

  • May combine two claims.

    Premisecitation

    The supply of GSH precursors from astrocytes appears not to be exclusive for neurons as receiving cell type; a similar interaction in GSH metabolism by cysteine supply via GSH export appears to take place between astrocytes and endothelial cells.

    “The supply of GSH precursors from astrocyte appears not to be exclusive for neurons as receiving cell type. A similar interaction in GSH metabolism by cysteine supply via GSH export appears to take place between astrocytes and endothelial cells, and this cysteine shuttle has been reported to help to maintain endothelial barrier stability and integrity (Huang et al. 2020).”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites Huang et al. 2020 source

      Split into 2 atoms — 0 confirmed, 2 partially supported, 0 disputed, 0 misattributed, 0 unverifiable. Expand the claim to see per-atom verdicts.

      Experimental — accuracy not yet measured

  • May combine two claims.

    Interpretationcitation

    The loss in astrocytic GSH content by a given treatment can be caused by four main mechanisms: impaired GSH synthesis, conjugation of GSH to electrophiles, accelerated export of GSH, and oxidation of GSH to GSSG which is subsequently exported.

    “The loss in astrocytic GSH content by a given treatment can be caused by four main mechanisms: (1) impaired GSH synthesis due to lack of substrates (Dringen and Hamprecht 1996) or impaired activity of GSH synthesizing enzymes (Giordano et al. 2008; He and Hewett 2025; Lavoie et al. 2009), (2) conjugation of GSH to electrophiles (Ehrke et al. 2015; Schmidt and Dringen 2009, 2010), (3) accelerated”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    Cultured astrocytes are able to efficiently export GSSG and GSH-conjugates via Mrp1 under conditions that induce oxidative stress and after application of given electrophiles.

    “cultured astrocytes are able to efficiently export GSSG and GSH‐conjugates via Mrp1 (Figure 2) under conditions that induce oxidative stress (Arend et al. 2024; Hirrlinger et al. 2001; Minich et al. 2006; Raabe et al. 2019;) and after the application of given electrophiles (Arend et al. 2024; Dringen et al. 2015; Raabe et al. 2019; Waak and Dringen 2006), respectively.”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites Arend et al. 2024

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

    • cites Hirrlinger et al. 2001 source
    • cites Minich et al. 2006 source

  • May combine two claims.

    Premisecitation

    Neurons appear not to take up and use substantial amounts of cystine for GSH synthesis and rely on the availability of cysteine as an extracellular precursor for the cysteine moiety of GSH.

    “In contrast to astrocytes, neurons appear not to take up and use substantial amounts of cystine for GSH synthesis and rely therefore on the availability of cysteine as an extracellular precursor for the cysteine moiety of GSH (Kranich et al. 1996).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Kranich et al. 1996 source

  • Classified as probably not a substantial claim.

    Interpretationnone given

    Most of the processes involved in the shuttling of GSH substrates from astrocytes to other types of brain cells have been studied on cultured murine brain cells.

    “Most of the processes involved in the shuttling of GSH substrates from astrocytes to other types of brain cells have been studied on cultured murine brain cells.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationreasoning

    A high GSH content is beneficial for astrocytes and will thereby help to maintain the many important physiological functions that astrocytes have in the brain.

    “Thus, a high GSH content is beneficial for astrocytes and will thereby help to maintain the many important physiological functions that astrocytes have in the brain.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationreasoning

    Astrocytes play a central role in the GSH metabolism of the brain and provide neighboring brain cells with cysteine as an essential substrate for GSH synthesis.

    “Astrocytes have been shown to play a central role in the GSH metabolism of the brain and provide neighboring brain cells with cysteine as an essential substrate for GSH synthesis.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    The supply of GSH precursors from astrocytes to neurons increases the GSH content in neurons and improves the resistance of neurons to various adverse treatments, including induction of oxidative stress and application of toxins.

    “The supply of GSH precursors from astrocytes to neurons does not only increase the GSH content in neurons but also improves the resistance of neurons to various adverse treatments, including induction of oxidative stress and application of toxins (Table 2), demonstrating the importance of the astrocytic cysteine supply for neuronal GSH synthesis.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Table 2

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  • May combine two claims.

    Premisecitation

    Extracellular GSH concentrations in the brain are very low, most likely due to the rapid metabolism of released GSH by γGT.

    “Extracellular GSH concentrations in the brain are very low (Hilgier et al. 2010; Orwar et al. 1994), most likely due to the rapid metabolism of released GSH by γGT.”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites Hilgier et al. 2010 source
    • cites Orwar et al. 1994 source

  • May combine two claims.

    Premisecitation

    PrP-deficient astrocytes have enhanced GSH contents and show accelerated GSH export and reduced γGT activity.

    “PrP‐deficient cerebellar neurons show impaired survival after exposure to hypoxia or treatments with glutamate or H2O2, while PrP‐deficient astrocytes have enhanced GSH contents and show accelerated GSH export and reduced γGT activity (Guitart et al. 2015).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Guitart et al. 2015 source
13 of 13

  • The paper relies on this without support.

    Findings from cultured astrocytes are representative of astrocytes in the intact brain.

    “Cultured rat astrocytes have the potential to synthesize the three amino acids required for GSH synthesis from intracellular metabolites, but can also use extracellular amino acids and dipeptides as precursors of the three substrates of GSH synthesis (Dringen and Hamprecht 1996, 1998).”
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Authors
Dringen, R., & Arend, C.
Affiliations
University of Bremen (DE)
Corresponding author
Dringen, Ralf
ORCID
Venue
Journal of Neurochemistry
Publisher
Wiley
Published
2025-05
Volume
169
Issue
5
Pages
e70073-e70073
ISSN
  • 0022-3042 (ISSN-L)
  • 1471-4159
DOI
10.1111/jnc.70073
PMC
PMC12046376
OpenAlex
W4410037395
Cited by
46
References
167
Citations by year
2026: 35 · 2025: 11
FWCI
4.54
Type
journal article
Language
en
Open access
Licence
Locations
  • Journal of Neurochemistry (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Biochemistry › Sulfur Compounds in Biology
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Glutathione Transferases and Polymorphisms
  • Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
Keywords
glutathione metabolism, astrocytes, oxidative stress, antioxidant defense, detoxification, multidrug resistance protein 1, gamma-glutamyl transferase, cysteinylglycine, CD13, brain homeostasis
MeSH terms
Animals, Astrocytes, Brain, Glutathione, Humans

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