Skip to main content

Advertisement

SpringerLink
Log in

Glutathione in Brain: Overview of Its Conformations, Functions, Biochemical Characteristics, Quantitation and Potential Therapeutic Role in Brain Disorders

  • Review
  • Published:
Neurochemical Research Aims and scope Submit manuscript

Abstract

Glutathione (GSH) is an important antioxidant found abundantly and synthesized intracellularly in the cytosol in a tightly regulated fashion. It has diverse physiological functions, including protection against reactive oxygen species and nitrogen species, antioxidant defense as well as maintenance of cellular thiol status. The human brain due to the high oxygen consumption is extremely susceptible to the generation of reactive oxygen species. GSH plays a paramount role in brain antioxidant defense, maintaining redox homeostasis. The depletion of brain GSH has also been observed from both autopsies as well as in vivo MRS studies with aging and varied neurological disorders (Alzheimer’s disease, Parkinson’s disease, etc.). Therefore, GSH enrichment using supplementation is a promising avenue in the therapeutic development for these neurological disorders. This review will enrich the information on the importance of GSH synthesis, metabolism, functions, compartmentation and inter-organ transport, structural conformations and its quantitation via different techniques. The transportation of GSH in the brain via different interventional routes and its potential role in the development of therapeutic strategies for various brain disorders is also addressed. Very recent study found significant improvement of behavioral deficits including cognitive decline, depressive-like behaviors, in APP (NL−G-F/NL−G-FG-) mice due to oral GSH administration. This animal model study put an emergent need to complete GSH supplementation trial in MCI and AD patients for cognitive improvement as proposed earlier.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Fig. 7
Fig. 8
Fig. 9

The figure reproduced with permission from IOS Press [23]. b Box plot representation of GSH concentrations in the right hippocampus (RH) and left hippocampus (LH) regions among HC (green), MCI (blue) and AD (red) subjects. A significant reduction was observed in the RH and LH regions of AD and MCI patients in comparison with HC. All significant values were set at p < 0.05 (*p < 0.05, **p < 0.01, ***p < 0.001). Necessary permissions were taken to reproduce the figure from the publisher—Elsevier [14] (Color figure online)

Similar content being viewed by others

References

  1. Townsend DM, Tew KD, Tapiero H (2003) The importance of glutathione in human disease. Biomed Pharm 57:145–155

    Article  CAS  Google Scholar 

  2. Mailloux RJ, McBride SL, Harper M-E (2013) Unearthing the secrets of mitochondrial ROS and glutathione in bioenergetics. Trends Biochem Sci 38:592–602

    Article  CAS  PubMed  Google Scholar 

  3. Keszler A, Zhang Y, Hogg N (2010) Reaction between nitric oxide, glutathione, and oxygen in the presence and absence of protein: how are S-nitrosothiols formed? Free Radic Biol Med 48:55–64

    Article  CAS  PubMed  Google Scholar 

  4. Lu SC (2013) Glutathione synthesis. Biochem Biophys Acta 1830:3143–3153

    Article  CAS  PubMed  Google Scholar 

  5. Shen D, Dalton TP, Nebert DW, Shertzer HG (2005) Glutathione redox state regulates mitochondrial reactive oxygen production. J Biol Chem 280:25305–25312

    Article  CAS  PubMed  Google Scholar 

  6. Knollema S, Hom HW, Schirmer H, Korf J, Ter Horst GJ (1996) Immunolocalization of glutathione reductase in the murine brain. J Comp Neurol 373:157–172

    Article  CAS  PubMed  Google Scholar 

  7. Lubos E, Loscalzo J, Handy DE (2011) Glutathione peroxidase-1 in health and disease: from molecular mechanisms to therapeutic opportunities. Antioxid Redox Signal 15:1957–1997

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Dringen R, Gutterer JM, Hirrlinger J (2000) Glutathione metabolism in brain metabolic interaction between astrocytes and neurons in the defense against reactive oxygen species. Eur J Biochem 267:4912–4916

    Article  CAS  PubMed  Google Scholar 

  9. Franco R, Schoneveld OJ, Pappa A, Panayiotidis MI (2007) The central role of glutathione in the pathophysiology of human diseases. Arch Physiol Biochem 113:234–258

    Article  CAS  PubMed  Google Scholar 

  10. Ghezzi P (2005) Regulation of protein function by glutathionylation. Free Radic Res 39:573–580

    Article  CAS  PubMed  Google Scholar 

  11. Clark DD, Sokoloff L (1999) Circulation and energy metabolism of the brain. Lippincott, Philadelphia

    Google Scholar 

  12. Choi I-Y, Lee S, Denney DR, Lynch SG (2011) Lower levels of glutathione in the brains of secondary progressive multiple sclerosis patients measured by 1H magnetic resonance chemical shift imaging at 3 T. Multiple Scler J 17:289–296

    Article  CAS  Google Scholar 

  13. Lovell MA, Ehmann WD, Butler SM, Markesbery WR (1995) Elevated thiobarbituric acid-reactive substances and antioxidant enzyme activity in the brain in Alzheimer's disease. Neurology 45:1594–1601

    Article  CAS  PubMed  Google Scholar 

  14. Mandal PK, Saharan S, Tripathi M, Murari G (2015) Brain glutathione levels—a novel biomarker for mild cognitive impairment and Alzheimer’s disease. Biol Psychiatry 78:702–710

    Article  CAS  PubMed  Google Scholar 

  15. Pearce R, Owen A, Daniel S, Jenner P, Marsden C (1997) Alterations in the distribution of glutathione in the substantia nigra in Parkinson's disease. J Neural Transm 104:661–677

    Article  CAS  PubMed  Google Scholar 

  16. Saharan S, Mandal PK (2014) The emerging role of glutathione in Alzheimer's disease. J Alzheimer's Dis 40:519–529

    Article  CAS  Google Scholar 

  17. Gu M, Owen AD, Toffa SE, Cooper JM, Dexter DT, Jenner P, Marsden CD, Schapira AH (1998) Mitochondrial function, GSH and iron in neurodegeneration and Lewy body diseases. J Neurol Sci 158:24–29

    Article  CAS  PubMed  Google Scholar 

  18. Ansari MA, Scheff SW (2010) Oxidative stress in the progression of Alzheimer disease in the frontal cortex. J Neuropathol Exp Neurol 69:155–167

    Article  CAS  PubMed  Google Scholar 

  19. Sultana R, Piroddi M, Galli F, Butterfield DA (2008) Protein levels and activity of some antioxidant enzymes in hippocampus of subjects with amnestic mild cognitive impairment. Neurochem Res 33:2540–2546

    Article  CAS  PubMed  Google Scholar 

  20. Mandal PK, Tripathi M, Sugunan S (2012) Brain oxidative stress: detection and mapping of anti-oxidant marker 'Glutathione' in different brain regions of healthy male/female, MCI and Alzheimer patients using non-invasive magnetic resonance spectroscopy. Biochem Biophys Res Commun 417:43–48

    Article  CAS  PubMed  Google Scholar 

  21. Shukla D, Mandal PK, Tripathi M, Vishwakarma G, Mishra R, Sandal K (2020) Quantitation of in vivo brain glutathione conformers in cingulate cortex among age-matched control, MCI, and AD patients using MEGA-PRESS. Hum Brain Mapp 41:194–217

    Article  PubMed  Google Scholar 

  22. Mandal PK, Shukla D, Govind V, Boulard Y, Ersland L (2017) Glutathione conformations and its implications for in vivo magnetic resonance spectroscopy. J Alzheimer’s Dis 59:537–541

    Article  CAS  Google Scholar 

  23. Shukla D, Mandal PK, Ersland L, Gruner ER, Tripathi M, Raghunathan P, Sharma A, Chaithya GR, Punjabi K, Splaine C (2018) A Multi-center study on human brain glutathione conformation using magnetic resonance spectroscopy. J Alzheimer’s Dis 66:517–532

    Article  CAS  Google Scholar 

  24. Matsuzawa D, Obata T, Shirayama Y, Nonaka H, Kanazawa Y, Yoshitome E, Takanashi J, Matsuda T, Shimizu E, Ikehira H, Iyo M, Hashimoto K (2008) Negative correlation between brain glutathione level and negative symptoms in schizophrenia: a 3T 1H-MRS study. PLoS ONE 3:e1944

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  25. Srinivasan R, Ratiney H, Hammond-Rosenbluth KE, Pelletier D, Nelson SJ (2010) MR spectroscopic imaging of glutathione in the white and gray matter at 7 T with an application to multiple sclerosis. Magn Reson Imaging 28:163–170

    Article  CAS  PubMed  Google Scholar 

  26. Zhang R, Wu W, Luo S (2011) Different behaviors of glutathione in aqueous and DMSO solutions: molecular dynamics simulation and NMR experimental study. J Solut Chem 40:1784–1795

    Article  CAS  Google Scholar 

  27. Richie JP Jr, Nichenametla S, Neidig W, Calcagnotto A, Haley JS, Schell TD, Muscat JE (2015) Randomized controlled trial of oral glutathione supplementation on body stores of glutathione. Eur J Nutr 54:251–263

    Article  CAS  PubMed  Google Scholar 

  28. Schmitt B, Vicenzi M, Garrel C, Denis FM (2015) Effects of N-acetylcysteine, oral glutathione (GSH) and a novel sublingual form of GSH on oxidative stress markers: a comparative crossover study. Redox Biol 6:198–205

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Sinha R, Sinha I, Calcagnotto A, Trushin N, Haley JS, Schell TD, Richie JP Jr (2018) Oral supplementation with liposomal glutathione elevates body stores of glutathione and markers of immune function. Eur J Clin Nutr 72:105–111

    Article  CAS  PubMed  Google Scholar 

  30. Wink LK, Adams R, Wang Z, Klaunig JE, Plawecki MH, Posey DJ, McDougle CJ, Erickson CA (2016) A randomized placebo-controlled pilot study of N-acetylcysteine in youth with autism spectrum disorder. Mol Autism 7:26

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  31. Mai J, Sorensen PS, Hansen JC (1990) High dose antioxidant supplementation to MS patients. Effects on glutathione peroxidase, clinical safety, and absorption of selenium. Biol Trace Elem Res 24:109–117

    Article  CAS  PubMed  Google Scholar 

  32. Mischley LK, Conley KE, Shankland EG, Kavanagh TJ, Rosenfeld ME, Duda JE, White CC, Wilbur TK, De La Torre PU, Padowski JM (2016) Central nervous system uptake of intranasal glutathione in Parkinson's disease. NPJ Parkinson's Dis 2:16001–16007

    Article  CAS  Google Scholar 

  33. Kern JK, Geier DA, Adams JB, Garver CR, Audhya T, Geier MR (2011) A clinical trial of glutathione supplementation in autism spectrum disorders. Med Sci Monit 17:677–682

    Article  Google Scholar 

  34. Remington R, Bechtel C, Larsen D, Samar A, Doshanjh L, Fishman P, Luo Y, Smyers K, Page R, Morrell C, Shea TB (2015) A phase II Randomized clinical trial of a nutritional formulation for cognition and mood in Alzheimer's disease. J Alzheimer’s Dis 45:395–405

    Article  CAS  Google Scholar 

  35. Chio A, Cucatto A, Terreni AA, Schiffer D (1998) Reduced glutathione in amyotrophic lateral sclerosis: an open, crossover, randomized trial. Ital J Neurol Sci 19:363–366

    Article  CAS  PubMed  Google Scholar 

  36. Hauser RA, Lyons KE, McClain T, Carter S, Perlmutter D (2009) Randomized, double-blind, pilot evaluation of intravenous glutathione in Parkinson's disease. Mov Disord 24:979–983

    Article  PubMed  Google Scholar 

  37. Mischley LK, Lau RC, Shankland EG, Wilbur TK, Padowski JM (2017) Phase IIb study of intranasal glutathione in Parkinson's disease. J Parkinson’s Dis 7:289–299

    Article  CAS  Google Scholar 

  38. Sechi G, Deledda MG, Bua G, Satta WM, Deiana GA, Pes GM, Rosati G (1996) Reduced intravenous glutathione in the treatment of early Parkinson's disease. Prog Neuropsychopharmacol Biol Psychiatry 20:1159–1170

    Article  CAS  PubMed  Google Scholar 

  39. Holmay MJ, Terpstra M, Coles LD, Mishra U, Ahlskog M, Oz G, Cloyd JC, Tuite PJ (2013) N-Acetylcysteine boosts brain and blood glutathione in Gaucher and Parkinson diseases. Clin Neuropharmacol 36:103–106

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Remington R, Lortie JJ, Hoffmann H, Page R, Morrell C, Shea TB (2015) A nutritional formulation for cognitive performance in mild cognitive impairment: a placebo-controlled trial with an open-label extension. J Alzheimer’s Dis 48:591–595

    Article  CAS  Google Scholar 

  41. Louwerse ES, Weverling GJ, Bossuyt PM, Meyjes FE, de Jong JM (1995) Randomized, double-blind, controlled trial of acetylcysteine in amyotrophic lateral sclerosis. Arch Neurol 52:559–564

    Article  CAS  PubMed  Google Scholar 

  42. Salamon S, Kramar B, Marolt TP, Poljsak B, Milisav I (2019) Medical and dietary uses of N-acetylcysteine. Antioxidants 8:111

    Article  CAS  PubMed Central  Google Scholar 

  43. Meister A, Anderson ME (1983) Glutathione. Annu Rev Biochem 52:711–760

    Article  CAS  PubMed  Google Scholar 

  44. Njalsson R, Norgren S, Larsson A, Huang CS, Anderson ME, Luo JL (2001) Cooperative binding of gamma-glutamyl substrate to human glutathione synthetase. Biochem Biophys Res Commun 289:80–84

    Article  CAS  PubMed  Google Scholar 

  45. Lushchak VI (2012) Glutathione homeostasis and functions: potential targets for medical interventions. J Amino Acids 2012:736–837

    Article  CAS  Google Scholar 

  46. Bella DL, Hirschberger LL, Kwon YH, Stipanuk MH (2002) Cysteine metabolism in periportal and perivenous hepatocytes: perivenous cells have greater capacity for glutathione production and taurine synthesis but not for cysteine catabolism. Amino Acids 23:453–458

    Article  CAS  PubMed  Google Scholar 

  47. Reid M, Badaloo A, Forrester T, Morlese JF, Frazer M, Heird WC, Jahoor F (2000) In vivo rates of erythrocyte glutathione synthesis in children with severe protein-energy malnutrition. Am J Physiol Endocrinol Metab 278:E405–412

    Article  CAS  PubMed  Google Scholar 

  48. Lyons J, Rauh-Pfeiffer A, Yu YM, Lu XM, Zurakowski D, Tompkins RG, Ajami AM, Young VR, Castillo L (2000) Blood glutathione synthesis rates in healthy adults receiving a sulfur amino acid-free diet. Proc Natl Acad Sci USA 97:5071–5076

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Liu H, Wang H, Shenvi S, Hagen TM, Liu RM (2004) Glutathione metabolism during aging and in Alzheimer disease. Ann N Y Acad Sci 1019:346–349

    Article  CAS  PubMed  Google Scholar 

  50. Richman PG, Meister A (1975) Regulation of gamma-glutamyl-cysteine synthetase by nonallosteric feedback inhibition by glutathione. J Biol Chem 250:1422–1426

    CAS  PubMed  Google Scholar 

  51. Huang CS, Moore WR, Meister A (1988) On the active site thiol of gamma-glutamylcysteine synthetase: relationships to catalysis, inhibition, and regulation. Proc Natl Acad Sci USA 85:2464–2468

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Bannai S, Tateishi N (1986) Role of membrane transport in metabolism and function of glutathione in mammals. J Membr Biol 89:1–8

    Article  CAS  PubMed  Google Scholar 

  53. Lu SC, Ge JL, Kuhlenkamp J, Kaplowitz N (1992) Insulin and glucocorticoid dependence of hepatic gamma-glutamylcysteine synthetase and glutathione synthesis in the rat. Studies in cultured hepatocytes and in vivo. J Clin Investig 90:524–532

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Kilberg MS (1982) Amino acid transport in isolated rat hepatocytes. J Membr Biol 69:1–12

    Article  CAS  PubMed  Google Scholar 

  55. Mulcahy RT, Bailey HH, Gipp JJ (1995) Transfection of complementary DNAs for the heavy and light subunits of human gamma-glutamylcysteine synthetase results in an elevation of intracellular glutathione and resistance to melphalan. Can Res 55:4771–4775

    CAS  Google Scholar 

  56. Mulcahy RT, Gipp JJ (1995) Identification of a putative antioxidant response element in the 5'-flanking region of the human gamma-glutamylcysteine synthetase heavy subunit gene. Biochem Biophys Res Commun 209:227–233

    Article  CAS  PubMed  Google Scholar 

  57. Mulcahy RT, Untawale S, Gipp JJ (1994) Transcriptional up-regulation of gamma-glutamylcysteine synthetase gene expression in melphalan-resistant human prostate carcinoma cells. Mol Pharmacol 46:909–914

    CAS  PubMed  Google Scholar 

  58. Kim SK, Woodcroft KJ, Khodadadeh SS, Novak RF (2004) Insulin signaling regulates gamma-glutamylcysteine ligase catalytic subunit expression in primary cultured rat hepatocytes. J Pharmacol Exp Ther 311:99–108

    Article  CAS  PubMed  Google Scholar 

  59. Clancy RM, Levartovsky D, Leszczynska-Piziak J, Yegudin J, Abramson SB (1994) Nitric oxide reacts with intracellular glutathione and activates the hexose monophosphate shunt in human neutrophils: evidence for S-nitrosoglutathione as a bioactive intermediary. Proc Natl Acad Sci USA 91:3680–3684

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  60. Lobo V, Patil A, Phatak A, Chandra N (2010) Free radicals, antioxidants and functional foods: impact on human health. Pharmacogn Rev 4:118–126

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. Singh SP, Wishnok JS, Keshive M, Deen WM, Tannenbaum SR (1996) The chemistry of the S-nitrosoglutathione/glutathione system. Proc Natl Acad Sci USA 93:14428–14433

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. Winterbourn CC, Metodiewa D (1994) The reaction of superoxide with reduced glutathione. Arch Biochem Biophys 314:284–290

    Article  CAS  PubMed  Google Scholar 

  63. Chance B, Sies H, Boveris A (1979) Hydroperoxide metabolism in mammalian organs. Physiol Rev 59:527–605

    Article  CAS  PubMed  Google Scholar 

  64. Ng CF, Schafer FQ, Buettner GR, Rodgers VG (2007) The rate of cellular hydrogen peroxide removal shows dependency on GSH: mathematical insight into in vivo H2O2 and GPx concentrations. Free Radic Res 41:1201–1211

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  65. Ursini F, Maiorino M, Brigelius-Flohe R, Aumann KD, Roveri A, Schomburg D, Flohe L (1995) Diversity of glutathione peroxidases. Methods Enzymol 252:38–53

    Article  CAS  PubMed  Google Scholar 

  66. Ulusu NN, Tandogan B (2007) Purification and kinetic properties of glutathione reductase from bovine liver. Mol Cell Biochem 303:45–51

    Article  CAS  PubMed  Google Scholar 

  67. Dasuri K, Zhang L, Keller JN (2013) Oxidative stress, neurodegeneration, and the balance of protein degradation and protein synthesis. Free Radic Biol Med 62:170–185

    Article  CAS  PubMed  Google Scholar 

  68. Fukai T, Ushio-Fukai M (2011) Superoxide dismutases: role in redox signaling, vascular function, and diseases. Antioxid Redox Signal 15:1583–1606

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  69. Ray PD, Huang B-W, Tsuji Y (2012) Reactive oxygen species (ROS) homeostasis and redox regulation in cellular signaling. Cell Signal 24:981–990

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  70. Finkel T (2003) Oxidant signals and oxidative stress. Curr Opin Cell Biol 15:247–254

    Article  CAS  PubMed  Google Scholar 

  71. Smythies J (1999) The neurotoxicity of glutamate, dopamine, iron and reactive oxygen species: functional interrelationships in health and disease: a review—discussion. Neurotox Res 1:27–39

    Article  CAS  PubMed  Google Scholar 

  72. Stone JR, Yang S (2006) Hydrogen peroxide: a signaling messenger. Antioxid Redox Signal 8:243–270

    Article  CAS  PubMed  Google Scholar 

  73. Wang X, Wang W, Li L, Perry G, Lee H-G, Zhu X (2014) Oxidative stress and mitochondrial dysfunction in Alzheimer's disease. Biochimica et Biophysica Acta (BBA) 1842:1240–1247

    Article  CAS  Google Scholar 

  74. Wong HS, Dighe PA, Mezera V, Monternier PA, Brand MD (2017) Production of superoxide and hydrogen peroxide from specific mitochondrial sites under different bioenergetic conditions. J Biol Chem 292:16804–16809

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  75. Zorov DB, Filburn CR, Klotz LO, Zweier JL, Sollott SJ (2000) Reactive oxygen species (ROS)-induced ROS release: a new phenomenon accompanying induction of the mitochondrial permeability transition in cardiac myocytes. J Exp Med 192:1001–1014

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  76. Kehrer JP (2000) The Haber-Weiss reaction and mechanisms of toxicity. Toxicology 149:43–50

    Article  CAS  PubMed  Google Scholar 

  77. Thomas C, Mackey MM, Diaz AA, Cox DP (2009) Hydroxyl radical is produced via the Fenton reaction in submitochondrial particles under oxidative stress: implications for diseases associated with iron accumulation. Redox Rep 14:102–108

    Article  CAS  PubMed  Google Scholar 

  78. Sazanov LA (2007) Respiratory complex I: mechanistic and structural insights provided by the crystal structure of the hydrophilic domain. Biochemistry 46:2275–2288

    Article  CAS  PubMed  Google Scholar 

  79. Hirst J, Carroll J, Fearnley IM, Shannon RJ, Walker JE (2003) The nuclear encoded subunits of complex I from bovine heart mitochondria. Biochem Biophys Acta 1604:135–150

    CAS  PubMed  Google Scholar 

  80. Sawyer DT, Valentine JS (1981) How super is superoxide? Acc Chem Res 14:393–400

    Article  CAS  Google Scholar 

  81. Brand MD, Affourtit C, Esteves TC, Green K, Lambert AJ, Miwa S, Pakay JL, Parker N (2004) Mitochondrial superoxide: production, biological effects, and activation of uncoupling proteins. Free Radic Biol Med 37:755–767

    Article  CAS  PubMed  Google Scholar 

  82. Hirst J, King MS, Pryde KR (2008) The production of reactive oxygen species by complex I. Biochem Soc Trans 36:976–980

    Article  CAS  PubMed  Google Scholar 

  83. Andreyev AY, Kushnareva YE, Starkov AA (2005) Mitochondrial metabolism of reactive oxygen species. Biochem Biokhimiia 70:200–214

    Article  CAS  Google Scholar 

  84. Adam-Vizi V, Chinopoulos C (2006) Bioenergetics and the formation of mitochondrial reactive oxygen species. Trends Pharmacol Sci 27:639–645

    Article  CAS  PubMed  Google Scholar 

  85. Chance B, Hollunger G (1961) The interaction of energy and electron transfer reactions in mitochondria. I. General properties and nature of the products of succinate-linked reduction of pyridine nucleotide. J Biol Chem 236:1534–1543

    CAS  PubMed  Google Scholar 

  86. Turrens JF, Alexandre A, Lehninger AL (1985) Ubisemiquinone is the electron donor for superoxide formation by complex III of heart mitochondria. Arch Biochem Biophys 237:408–414

    Article  CAS  PubMed  Google Scholar 

  87. Cadenas E, Boveris A, Ragan CI, Stoppani AO (1977) Production of superoxide radicals and hydrogen peroxide by NADH-ubiquinone reductase and ubiquinol-cytochrome c reductase from beef-heart mitochondria. Arch Biochem Biophys 180:248–257

    Article  CAS  PubMed  Google Scholar 

  88. Murphy MP (2009) How mitochondria produce reactive oxygen species. Biochem J 417:1–13

    Article  CAS  PubMed  Google Scholar 

  89. Ramsay RR (2019) Electron carriers and energy conservation in mitochondrial respiration. ChemTexts 5:9

    Article  CAS  Google Scholar 

  90. Bai J, Cederbaum AI (2001) Mitochondrial catalase and oxidative injury. Biol Signals Recept 10:189–199

    Article  CAS  PubMed  Google Scholar 

  91. Nandi A, Yan LJ, Jana CK, Das N (2019) Role of catalase in oxidative stress- and age-associated degenerative diseases. Oxid Med Cell Longev 2019:9613090

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  92. Szarka A, Tomasskovics B, Banhegyi G (2012) The ascorbate-glutathione-alpha-tocopherol triad in abiotic stress response. Int J Mol Sci 13:4458–4483

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  93. National Center for Biotechnology Information (2020) PubChem Database. Glutathione, CID=124886, https://pubchem.ncbi.nlm.nih.gov/compound/Glutathione. Accessed 12 Feb 2020

  94. Ribas V, Garcia-Ruiz C, Fernandez-Checa JC (2014) Glutathione and mitochondria. Front Pharmacol 5:151

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  95. Stamler JS, Simon DI, Osborne JA, Mullins ME, Jaraki O, Michel T, Singel DJ, Loscalzo J (1992) S-nitrosylation of proteins with nitric oxide: synthesis and characterization of biologically active compounds. Proc Natl Acad Sci 89:444–448

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  96. Kolesnik B, Palten K, Schrammel A, Stessel H, Schmidt K, Mayer B, Gorren AC (2013) Efficient nitrosation of glutathione by nitric oxide. Free Radic Biol Med 63:51–64

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  97. Schrammel A, Gorren AC, Schmidt K, Pfeiffer S, Mayer B (2003) S-nitrosation of glutathione by nitric oxide, peroxynitrite, and (*)NO/O(2)(*-). Free Radic Biol Med 34:1078–1088

    Article  CAS  PubMed  Google Scholar 

  98. Chatterjee A (2013) Reduced glutathione: a radioprotector or a modulator of DNA-repair activity? Nutrients 5:525–542

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  99. Gaschler MM, Stockwell BR (2017) Lipid peroxidation in cell death. Biochem Biophys Res Commun 482:419–425

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  100. Wu G, Fang YZ, Yang S, Lupton JR, Turner ND (2004) Glutathione metabolism and its implications for health. J Nutr 134:489–492

    Article  CAS  PubMed  Google Scholar 

  101. Ferrari CK (2012) Effects of xenobiotics on total antioxidant capacity. Interdiscip Toxicol 5:117–122

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  102. Tonelli C, Chio IIC, Tuveson DA (2018) Transcriptional regulation by Nrf2. Antioxid Redox Signal 29:1727–1745

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  103. Liochev SI (1999) The mechanism of "Fenton-like" reactions and their importance for biological systems. A biologist's view. Met Ions Biol Syst 36:1–39

    CAS  PubMed  Google Scholar 

  104. Stohs SJ, Bagchi D (1995) Oxidative mechanisms in the toxicity of metal ions. Free Radic Biol Med 18:321–336

    Article  CAS  PubMed  Google Scholar 

  105. Ercal N, Gurer-Orhan H, Aykin-Burns N (2001) Toxic metals and oxidative stress part I: mechanisms involved in metal-induced oxidative damage. Curr Top Med Chem 1:529–539

    Article  CAS  PubMed  Google Scholar 

  106. Valko M, Morris H, Cronin M (2005) Metals, toxicity and oxidative stress. Curr Med Chem 12:1161–1208

    Article  CAS  PubMed  Google Scholar 

  107. Arslan A, Tüzün FA, Tamer S, Demir H, Aycan A, Demir C, Tasin M, Gönüllü E (2016) Change of antioxidant enzyme activities, some metals and lipid peroxidation in Alzheimer’s disease. Acta MedicaMediterranea 32:1643–1649

    Google Scholar 

  108. Bush AI, Tanzi RE (2008) Therapeutics for Alzheimer's disease based on the metal hypothesis. Neurotherapeutics 5:421–432

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  109. Wang W, Ballatori N (1998) Endogenous glutathione conjugates: occurrence and biological functions. Pharmacol Rev 50:335–356

    CAS  PubMed  Google Scholar 

  110. Sipos K, Lange H, Fekete Z, Ullmann P, Lill R, Kispal G (2002) Maturation of cytosolic iron-sulfur proteins requires glutathione. J Biol Chem 277:26944–26949

    Article  CAS  PubMed  Google Scholar 

  111. Couturier J, Przybyla-Toscano J, Roret T, Didierjean C, Rouhier N (2015) The roles of glutaredoxins ligating Fe-S clusters: sensing, transfer or repair functions? Biochem Biophys Acta 1853:1513–1527

    Article  CAS  PubMed  Google Scholar 

  112. Qi W, Li J, Chain CY, Pasquevich GA, Pasquevich AF, Cowan JA (2013) Glutathione-complexed iron-sulfur clusters. Reaction intermediates and evidence for a template effect promoting assembly and stability. Chem Commun 49:6313–6315

    Article  CAS  Google Scholar 

  113. Aguilera G, Colin-Gonzalez AL, Rangel-Lopez E, Chavarria A, Santamaria A (2018) Redox signaling, neuroinflammation, and neurodegeneration. Antioxid Redox Signal 28:1626–1651

    Article  CAS  PubMed  Google Scholar 

  114. Diaz-Hung ML, Yglesias-Rivera A, Hernandez-Zimbron LF, Orozco-Suarez S, Ruiz-Fuentes JL, Diaz-Garcia A, Leon-Martinez R, Blanco-Lezcano L, Pavon-Fuentes N, Lorigados-Pedre L (2016) Transient glutathione depletion in the substantia nigra compacta is associated with neuroinflammation in rats. Neuroscience 335:207–220

    Article  CAS  PubMed  Google Scholar 

  115. Mosley RL, Benner EJ, Kadiu I, Thomas M, Boska MD, Hasan K, Laurie C, Gendelman HE (2006) Neuroinflammation, oxidative stress and the pathogenesis of Parkinson’s disease. Clin Neurosci Res 6:261–281

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  116. Lee M, Cho T, Jantaratnotai N, Wang YT, McGeer E, McGeer PL (2010) Depletion of GSH in glial cells induces neurotoxicity: relevance to aging and degenerative neurological diseases. FASEB J 24:2533–2545

    Article  CAS  PubMed  Google Scholar 

  117. Jones DP (2006) Redefining oxidative stress. Antioxid Redox Signal 8:1865–1879

    Article  CAS  PubMed  Google Scholar 

  118. Schafer FQ, Buettner GR (2001) Redox environment of the cell as viewed through the redox state of the glutathione disulfide/glutathione couple. Free Radic Biol Med 30:1191–1212

    Article  CAS  PubMed  Google Scholar 

  119. Desideri E, Filomeni G, Ciriolo MR (2012) Glutathione participates in the modulation of starvation-induced autophagy in carcinoma cells. Autophagy 8:1769–1781

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  120. Cardaci S, Filomeni G, Rotilio G, Ciriolo MR (2010) p38(MAPK)/p53 signalling axis mediates neuronal apoptosis in response to tetrahydrobiopterin-induced oxidative stress and glucose uptake inhibition: implication for neurodegeneration. Biochem J 430:439–451

    Article  CAS  PubMed  Google Scholar 

  121. Lewerenz J, Ates G, Methner A, Conrad M, Maher P (2018) Oxytosis/ferroptosis-(Re-) emerging roles for oxidative stress-dependent non-apoptotic cell death in diseases of the central nervous system. Front Neurosci 12:214

    Article  PubMed  PubMed Central  Google Scholar 

  122. Friedmann Angeli JP, Schneider M, Proneth B, Tyurina YY, Tyurin VA, Hammond VJ, Herbach N, Aichler M, Walch A, Eggenhofer E, Basavarajappa D, Radmark O, Kobayashi S, Seibt T, Beck H, Neff F, Esposito I, Wanke R, Forster H, Yefremova O, Heinrichmeyer M, Bornkamm GW, Geissler EK, Thomas SB, Stockwell BR, O'Donnell VB, Kagan VE, Schick JA, Conrad M (2014) Inactivation of the ferroptosis regulator Gpx4 triggers acute renal failure in mice. Nat Cell Biol 16:1180–1191

    Article  CAS  PubMed  Google Scholar 

  123. Dixon SJ, Stockwell BR (2014) The role of iron and reactive oxygen species in cell death. Nat Chem Biol 10:9–17

    Article  CAS  PubMed  Google Scholar 

  124. Hwang C, Sinskey AJ, Lodish HF (1992) Oxidized redox state of glutathione in the endoplasmic reticulum. Science 257:1496–1502

    Article  CAS  PubMed  Google Scholar 

  125. Holmgren A, Sengupta R (2010) The use of thiols by ribonucleotide reductase. Free Radic Biol Med 49:1617–1628

    Article  CAS  PubMed  Google Scholar 

  126. Cooper AJL, Pulsinelli WA, Duffy TE (1980) Glutathione and ascorbate during ischemia and postischemic reperfusion in rat brain. J Neurochemistry 35:1242–1245

    Article  CAS  Google Scholar 

  127. Kumar C, Igbaria A, D'Autreaux B, Planson AG, Junot C, Godat E, Bachhawat AK, Delaunay-Moisan A, Toledano MB (2011) Glutathione revisited: a vital function in iron metabolism and ancillary role in thiol-redox control. EMBO J 30:2044–2056

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  128. Mari M, Morales A, Colell A, Garcia-Ruiz C, Kaplowitz N, Fernandez-Checa JC (2013) Mitochondrial glutathione: features, regulation and role in disease. Biochem Biophys Acta 1830:3317–3328

    Article  CAS  PubMed  Google Scholar 

  129. Schulz JB, Lindenau J, Seyfried J, Dichgans J (2000) Glutathione, oxidative stress and neurodegeneration. Eur J Biochem 267:4904–4911

    Article  CAS  PubMed  Google Scholar 

  130. Krahenbuhl S, Krahenbuhl-Glauser S, Stucki J, Gehr P, Reichen J (1992) Stereological and functional analysis of liver mitochondria from rats with secondary biliary cirrhosis: impaired mitochondrial metabolism and increased mitochondrial content per hepatocyte. Hepatology 15:1167–1172

    Article  CAS  PubMed  Google Scholar 

  131. Purucker E, Winograd R, Roeb E, Matern S (1998) Glutathione status in liver and plasma during development of biliary cirrhosis after bile duct ligation. Res Exp Med 198:167–174

    Article  CAS  Google Scholar 

  132. Meister A, Tate SS (1976) Glutathione and related gamma-glutamyl compounds: biosynthesis and utilization. Annu Rev Biochem 45:559–604

    Article  CAS  PubMed  Google Scholar 

  133. Bartoli GM, Sies H (1978) Reduced and oxidized glutathione efflux from liver. FEBS Lett 86:89–91

    Article  CAS  PubMed  Google Scholar 

  134. Anderson ME, Meister A (1980) Dynamic state of glutathione in blood plasma. J Biol Chem 255:9530–9533

    CAS  PubMed  Google Scholar 

  135. Griffith OW, Meister A (1979) Glutathione: interorgan translocation, turnover, and metabolism. Proc Natl Acad Sci USA 76:5606–5610

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  136. Inoue M (2016) Glutathionists in the battlefield of gamma-glutamyl cycle. Arch Biochem Biophys 595:61–63

    Article  CAS  PubMed  Google Scholar 

  137. Kannan R, Chakrabarti R, Tang D, Kim KJ, Kaplowitz N (2000) GSH transport in human cerebrovascular endothelial cells and human astrocytes: evidence for luminal localization of Na+-dependent GSH transport in HCEC. Brain Res 852:374–382

    Article  CAS  PubMed  Google Scholar 

  138. Lash LH (2005) Role of glutathione transport processes in kidney function. Toxicol Appl Pharmacol 204:329–342

    Article  CAS  PubMed  Google Scholar 

  139. Sun X, Shih AY, Johannssen HC, Erb H, Li P, Murphy TH (2006) Two-photon imaging of glutathione levels in intact brain indicates enhanced redox buffering in developing neurons and cells at the cerebrospinal fluid and blood-brain interface. J Biol Chem 281:17420–17431

    Article  CAS  PubMed  Google Scholar 

  140. Michelet F, Gueguen R, Leroy P, Wellman M, Nicolas A, Siest G (1995) Blood and plasma glutathione measured in healthy subjects by HPLC: relation to sex, aging, biological variables, and life habits. Clin Chem 41:1509–1517

    Article  CAS  PubMed  Google Scholar 

  141. Richie JP Jr, Skowronski L, Abraham P, Leutzinger Y (1996) Blood glutathione concentrations in a large-scale human study. Clin Chem 42:64–70

    Article  CAS  PubMed  Google Scholar 

  142. Cantin AM, North SL, Hubbard RC, Crystal RG (1987) Normal alveolar epithelial lining fluid contains high levels of glutathione. J Appl Physiol 63:152–157

    Article  CAS  PubMed  Google Scholar 

  143. Huang J, Philbert MA (1995) Distribution of glutathione and glutathione-related enzyme systems in mitochondria and cytosol of cultured cerebellar astrocytes and granule cells. Brain Res 680:16–22

    Article  CAS  PubMed  Google Scholar 

  144. Langeveld CH, Schepens E, Jongenelen CA, Stoof JC, Hjelle OP, Ottersen OP, Drukarch B (1996) Presence of glutathione immunoreactivity in cultured neurones and astrocytes. NeuroReport 7:1833–1836

    Article  CAS  PubMed  Google Scholar 

  145. Raps SP, Lai JC, Hertz L, Cooper AJ (1989) Glutathione is present in high concentrations in cultured astrocytes but not in cultured neurons. Brain Res 493:398–401

    Article  CAS  PubMed  Google Scholar 

  146. Rice ME, Russo-Menna I (1998) Differential compartmentalization of brain ascorbate and glutathione between neurons and glia. Neuroscience 82:1213–1223

    Article  CAS  PubMed  Google Scholar 

  147. Dringen R, Kranich O, Hamprecht B (1997) The γ-glutamyl transpeptidase inhibitor acivicin preserves glutathione released by astroglial cells in culture. Neurochem Res 22:727–733

    Article  CAS  PubMed  Google Scholar 

  148. Li X, Wallin C, Weber SG, Sandberg M (1999) Net efflux of cysteine, glutathione and related metabolites from rat hippocampal slices during oxygen/glucose deprivation: dependence on gamma-glutamyl transpeptidase. Brain Res 815:81–88

    Article  CAS  PubMed  Google Scholar 

  149. Rae CD, Williams SR (2017) Glutathione in the human brain: review of its roles and measurement by magnetic resonance spectroscopy. Anal Biochem 529:127–143

    Article  CAS  PubMed  Google Scholar 

  150. Aoyama K, Nakaki T (2013) Neuroprotective properties of the excitatory amino acid carrier 1 (EAAC1). Amino Acids 45:133–142

    Article  CAS  PubMed  Google Scholar 

  151. Aoyama K, Suh SW, Hamby AM, Liu J, Chan WY, Chen Y, Swanson RA (2006) Neuronal glutathione deficiency and age-dependent neurodegeneration in the EAAC1 deficient mouse. Nat Neurosci 9:119–126

    Article  CAS  PubMed  Google Scholar 

  152. Shashidharan P, Huntley GW, Murray JM, Buku A, Moran T, Walsh MJ, Morrison JH, Plaitakis A (1997) Immunohistochemical localization of the neuron-specific glutamate transporter EAAC1 (EAAT3) in rat brain and spinal cord revealed by a novel monoclonal antibody. Brain Res 773:139–148

    Article  CAS  PubMed  Google Scholar 

  153. Allaman I, Belanger M, Magistretti PJ (2011) Astrocyte-neuron metabolic relationships: for better and for worse. Trends Neurosci 34:76–87

    Article  CAS  PubMed  Google Scholar 

  154. Bradaia A, Schlichter R, Trouslard J (2004) Role of glial and neuronal glycine transporters in the control of glycinergic and glutamatergic synaptic transmission in lamina X of the rat spinal cord. J Physiol 559:169–186

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  155. Aoyama K, Watabe M, Nakaki T (2008) Regulation of neuronal glutathione synthesis. J Pharmacol Sci 108:227–238

    Article  CAS  PubMed  Google Scholar 

  156. Massucci FA, DiNuzzo M, Giove F, Maraviglia B, Castillo IP, Marinari E, De Martino A (2013) Energy metabolism and glutamate-glutamine cycle in the brain: a stoichiometric modeling perspective. BMC Syst Biol 7:103

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  157. Liu B, Teschemacher AG, Kasparov S (2017) Astroglia as a cellular target for neuroprotection and treatment of neuro-psychiatric disorders. Glia 65:1205–1226

    Article  PubMed  PubMed Central  Google Scholar 

  158. Abbott NJ, Romero IA (1996) Transporting therapeutics across the blood-brain barrier. Mol Med Today 2:106–113

    Article  CAS  PubMed  Google Scholar 

  159. Abbott NJ, Ronnback L, Hansson E (2006) Astrocyte-endothelial interactions at the blood-brain barrier. Nat Rev Neurosci 7:41–53

    Article  CAS  PubMed  Google Scholar 

  160. Goti D, Hrzenjak A, Levak-Frank S, Frank S, van der Westhuyzen DR, Malle E, Sattler W (2001) Scavenger receptor class B, type I is expressed in porcine brain capillary endothelial cells and contributes to selective uptake of HDL-associated vitamin E. J Neurochem 76:498–508

    Article  CAS  PubMed  Google Scholar 

  161. Chen Y, Liu L (2012) Modern methods for delivery of drugs across the blood-brain barrier. Adv Drug Deliv Rev 64:640–665

    Article  CAS  PubMed  Google Scholar 

  162. Kannan R, Kuhlenkamp JF, Ookhtens M, Kaplowitz N (1992) Transport of glutathione at blood-brain barrier of the rat: inhibition by glutathione analogs and age-dependence. J Pharmacol Exp Ther 263:964–970

    CAS  PubMed  Google Scholar 

  163. Kannan R, Mittur A, Bao Y, Tsuruo T, Kaplowitz N (1999) GSH transport in immortalized mouse brain endothelial cells: evidence for apical localization of a sodium-dependent GSH transporter. J Neurochem 73:390–399

    Article  CAS  PubMed  Google Scholar 

  164. Kannan R, Yi JR, Tang D, Li Y, Zlokovic BV, Kaplowitz N (1996) Evidence for the existence of a sodium-dependent glutathione (GSH) transporter. Expression of bovine brain capillary mRNA and size fractions in Xenopus laevis oocytes and dissociation from gamma-glutamyltranspeptidase and facilitative GSH transporters. J Biol Chem 271:9754–9758

    Article  CAS  PubMed  Google Scholar 

  165. Mandal PK, Shukla D (2020) KALPANA: advanced spectroscopic signal processing platform for improved accuracy to aid in early diagnosis of brain disorders in clinical setting. J Alzheimer’s Dis 75:22–28

    Google Scholar 

  166. Delalande O, Desvaux H, Godat E, Valleix A, Junot C, Labarre J, Boulard Y (2010) Cadmium-glutathione solution structures provide new insights into heavy metal detoxification. FEBS J 277:5086–5096

    Article  CAS  PubMed  Google Scholar 

  167. Mandal PK, Ersland L (2019) Editorial: Predictive imagable biomarkers for neurodegenerative and neurodevelopmental diseases. Front Neurol 10:583

    Article  PubMed  PubMed Central  Google Scholar 

  168. Perry TL, Berry K, Hansen S, Diamond S, Mok C (1971) Regional distribution of amino acids in human brain obtained at autopsy. J Neurochem 18:513–519

    Article  CAS  PubMed  Google Scholar 

  169. Calabrese V, Scapagnini G, Ravagna A, Fariello RG, Giuffrida Stella AM, Abraham NG (2002) Regional distribution of heme oxygenase, HSP70, and glutathione in brain: relevance for endogenous oxidant/antioxidant balance and stress tolerance. J Neurosci Res 68:65–75

    Article  CAS  PubMed  Google Scholar 

  170. Gawryluk JW, Wang JF, Andreazza AC, Shao L, Young LT (2011) Decreased levels of glutathione, the major brain antioxidant, in post-mortem prefrontal cortex from patients with psychiatric disorders. Int J Neuropsychopharmacol 14:123–130

    Article  CAS  PubMed  Google Scholar 

  171. Harrison FE, Hosseini AH, Dawes SM, Weaver S, May JM (2009) Ascorbic acid attenuates scopolamine-induced spatial learning deficits in the water maze. Behav Brain Res 205:550–558

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  172. Rahman I, Kode A, Biswas SK (2006) Assay for quantitative determination of glutathione and glutathione disulfide levels using enzymatic recycling method. Nat Protoc 1:3159–3165

    Article  CAS  PubMed  Google Scholar 

  173. Tumati S, Opmeer EM, Marsman JC, Martens S, Reesink FE, De Deyn PP, Aleman A (2018) Lower choline and myo-inositol in temporo-parietal cortex is associated with apathy in amnestic MCI. Front Aging Neurosci 10:106

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  174. Frantseva MV, Velazquez JL, Hwang PA, Carlen PL (2000) Free radical production correlates with cell death in an in vitro model of epilepsy. Eur J Neurosci 12:1431–1439

    Article  CAS  PubMed  Google Scholar 

  175. Mueller SG, Trabesinger AH, Boesiger P, Wieser HG (2001) Brain glutathione levels in patients with epilepsy measured by in vivo (1)H-MRS. Neurology 57:1422–1427

    Article  CAS  PubMed  Google Scholar 

  176. Arlt S, Muller-Thomsen T, Beisiegel U, Kontush A (2012) Effect of one-year vitamin C- and E-supplementation on cerebrospinal fluid oxidation parameters and clinical course in Alzheimer's disease. Neurochem Res 37:2706–2714

    Article  CAS  PubMed  Google Scholar 

  177. Galasko DR, Peskind E, Clark CM, Quinn JF, Ringman JM, Jicha GA, Cotman C, Cottrell B, Montine TJ, Thomas RG, Aisen P, Alzheimer's Disease Cooperative S (2012) Antioxidants for Alzheimer disease: a randomized clinical trial with cerebrospinal fluid biomarker measures. Arch Neurol 69:836–841

    Article  PubMed  PubMed Central  Google Scholar 

  178. Hardan AY, Fung LK, Libove RA, Obukhanych TV, Nair S, Herzenberg LA, Frazier TW, Tirouvanziam R (2012) A randomized controlled pilot trial of oral N-acetylcysteine in children with autism. Biol Psychiatry 71:956–961

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  179. Adair JC, Knoefel JE, Morgan N (2001) Controlled trial of N-acetylcysteine for patients with probable Alzheimer's disease. Neurology 57:1515–1517

    Article  CAS  PubMed  Google Scholar 

  180. Coles LD, Tuite PJ, Oz G, Mishra UR, Kartha RV, Sullivan KM, Cloyd JC, Terpstra M (2018) Repeated-dose oral N-acetylcysteine in Parkinson's disease: pharmacokinetics and effect on brain glutathione and oxidative stress. J Clin Pharmacol 58:158–167

    Article  CAS  PubMed  Google Scholar 

  181. Allen J, Bradley RD (2011) Effects of oral glutathione supplementation on systemic oxidative stress biomarkers in human volunteers. J Altern Complement Med 17:827–833

    Article  PubMed  PubMed Central  Google Scholar 

  182. Farr SA, Poon HF, Dogrukol-Ak D, Drake J, Banks WA, Eyerman E, Butterfield DA, Morley JE (2003) The antioxidants alpha-lipoic acid and N-acetylcysteine reverse memory impairment and brain oxidative stress in aged SAMP8 mice. J Neurochem 84:1173–1183

    Article  CAS  PubMed  Google Scholar 

  183. Anderson ME, Luo JL (1998) Glutathione therapy: from prodrugs to genes. Semin Liver Dis 18:415–424

    Article  CAS  PubMed  Google Scholar 

  184. Atkuri KR, Mantovani JJ, Herzenberg LA, Herzenberg LA (2007) N-Acetylcysteine—a safe antidote for cysteine/glutathione deficiency. Curr Opin Pharmacol 7:355–359

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  185. Mokhtari V, Afsharian P, Shahhoseini M, Kalantar SM, Moini A (2017) A review on various uses of N-acetyl cysteine. Cell J 19:11–17

    PubMed  Google Scholar 

  186. Bains JS, Shaw CA (1997) Neurodegenerative disorders in humans: the role of glutathione in oxidative stress-mediated neuronal death. Brain Res Brain Res Rev 25:335–358

    Article  CAS  PubMed  Google Scholar 

  187. Huang WJ, Zhang X, Chen WW (2016) Role of oxidative stress in Alzheimer's disease. Biomed Rep 4:519–522

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  188. Honda Y, Kessoku T, Sumida Y, Kobayashi T, Kato T, Ogawa Y, Tomeno W, Imajo K, Fujita K, Yoneda M, Kataoka K, Taguri M, Yamanaka T, Seko Y, Tanaka S, Saito S, Ono M, Oeda S, Eguchi Y, Aoi W, Sato K, Itoh Y, Nakajima A (2017) Efficacy of glutathione for the treatment of nonalcoholic fatty liver disease: an open-label, single-arm, multicenter, pilot study. BMC Gastroenterol 17:96

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  189. Kovacs-Nolan J, Rupa P, Matsui T, Tanaka M, Konishi T, Sauchi Y, Sato K, Ono S, Mine Y (2014) In vitro and ex vivo uptake of glutathione (GSH) across the intestinal epithelium and fate of oral GSH after in vivo supplementation. J Agric Food Chem 62:9499–9506

    Article  CAS  PubMed  Google Scholar 

  190. Weschawalit S, Thongthip S, Phutrakool P, Asawanonda P (2017) Glutathione and its antiaging and antimelanogenic effects. Clin Cosmet Investig Dermatol 10:147–153

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  191. Arjinpathana N, Asawanonda P (2012) Glutathione as an oral whitening agent: a randomized, double-blind, placebo-controlled study. J Dermatol Treat 23:97–102

    Article  CAS  Google Scholar 

  192. Cleary M (1991) Peripheral intravenous cannulation. Aust Fam Phys 20:1285–1288

    CAS  Google Scholar 

  193. Djupesland PG, Messina JC, Mahmoud RA (2014) The nasal approach to delivering treatment for brain diseases: an anatomic, physiologic, and delivery technology overview. Ther Deliv 5:709–733

    Article  CAS  PubMed  Google Scholar 

  194. Illum L (2004) Is nose-to-brain transport of drugs in man a reality? J Pharm Pharmacol 56:3–17

    Article  CAS  PubMed  Google Scholar 

  195. Narang N, Sharma J (2011) Sublingual mucosa as a route for systemic drug delivery. Int J Pharm Pharm Sci 3:18–22

    CAS  Google Scholar 

  196. Cocoman A, Murray J (2008) Intramuscular injections: a review of best practice for mental health nurses. J Psychiatr Ment Health Nurs 15:424–434

    Article  CAS  PubMed  Google Scholar 

  197. Tardiolo G, Bramanti P, Mazzon E (2018) Overview on the effects of N-Acetylcysteine in neurodegenerative diseases. Molecules 23:3305

    Article  PubMed Central  CAS  Google Scholar 

  198. Marcus DL, Thomas C, Rodriguez C, Simberkoff K, Tsai JS, Strafaci JA, Freedman ML (1998) Increased peroxidation and reduced antioxidant enzyme activity in Alzheimer's disease. Exp Neurol 150:40–44

    Article  CAS  PubMed  Google Scholar 

  199. Sofic E, Lange KW, Jellinger K, Riederer P (1992) Reduced and oxidized glutathione in the substantia nigra of patients with Parkinson's disease. Neurosci Lett 142:128–130

    Article  CAS  PubMed  Google Scholar 

  200. Jensen GE, Clausen J (1984) Glutathione peroxidase and reductase, glucose-6-phosphate dehydrogenase and catalase activities in multiple sclerosis. J Neurol Sci 63:45–53

    Article  CAS  PubMed  Google Scholar 

  201. Jensen GE, Clausen J (1986) Glutathione peroxidase activity, associated enzymes and substrates in blood cells from patients with multiple sclerosis—effects of antioxidant supplementation. Acta Pharmacol Toxicol 59(Suppl 7):450–453

    Google Scholar 

  202. James SJ, Cutler P, Melnyk S, Jernigan S, Janak L, Gaylor DW, Neubrander JA (2004) Metabolic biomarkers of increased oxidative stress and impaired methylation capacity in children with autism. Am J Clin Nutr 80:1611–1617

    Article  CAS  PubMed  Google Scholar 

  203. Moumen R, Nouvelot A, Duval D, Lechevalier B, Viader F (1997) Plasma superoxide dismutase and glutathione peroxidase activity in sporadic amyotrophic lateral sclerosis. J Neurol Sci 151:35–39

    Article  CAS  PubMed  Google Scholar 

  204. Mandal PK, Shukla D, Tripathi M, Ersland L (2019) Cognitive Improvement with glutathione supplement in Alzheimer's disease: a way forward. J Alzheimer’s Dis 68:531–535

    Article  Google Scholar 

  205. Pocernich CB, Butterfield DA (2012) Elevation of glutathione as a therapeutic strategy in Alzheimer disease. Biochem Biophys Acta 1822:625–630

    CAS  PubMed  Google Scholar 

  206. Schachter AS, Davis KL (2000) Alzheimer's disease. Dialogues Clin Neurosci 2:91–100

    CAS  PubMed  PubMed Central  Google Scholar 

  207. DeMaagd G, Philip A (2015) Parkinson's disease and Its management: part 1: disease entity, risk factors, pathophysiology, clinical presentation, and diagnosis. P & T 40:504–532

    Google Scholar 

  208. Hwang O (2013) Role of oxidative stress in Parkinson's disease. Exp Neurobiol 22:11–17

    Article  PubMed  PubMed Central  Google Scholar 

  209. Markesbery WR (1997) Oxidative stress hypothesis in Alzheimer's disease. Free Radic Biol Med 23:134–147

    Article  CAS  PubMed  Google Scholar 

  210. Calabresi PA (2004) Diagnosis and management of multiple sclerosis. Am Fam Phys 70:1935–1944

    Google Scholar 

  211. Park HR, Lee JM, Moon HE, Lee DS, Kim BN, Kim J, Kim DG, Paek SH (2016) A Short review on the current understanding of autism spectrum disorders. Exp Neurobiol 25:1–13

    Article  PubMed  PubMed Central  Google Scholar 

  212. Rowland LP, Shneider NA (2001) Amyotrophic lateral sclerosis. N Engl J Med 344:1688–1700

    Article  CAS  PubMed  Google Scholar 

  213. Izumi H, Sato K, Kozima K, Sainto, T, Saido T, Fukunag, K (2020) Oral glutathione administration inhibits the oxidative stress and the inflammatory responses in AppNL−G-F/NL−G-F knock-in mice. Neuropharmacology 168:108026–108036

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

Dr. Pravat Kumar Mandal (Principal Investigator) is thankful to the Department of Biotechnology, Ministry of Science and Technology, Government of India (Award no. BT/PR7361/MED/30/953/2013), Indo-Australia Biotechnology Fund (Grant no. BT/Indo-Aus/10/31/2016) and Ministry of Electronics and Information Technology, Govt. of India (Grant No 4(5)2019 ITEA) for funding this project. Partial financial support from Tata Innovation Fellowship (No. BT/HRD/35/01/05/2014) awarded to Dr. Pravat Kumar Mandal from the Department of Biotechnology, Ministry of Science and Technology, Government of India is highly appreciated. We would also like to thank Dr. Deepika Shukla (Scientist, NINS laboratory) and Ms. Khushboo Punjabi (Ph. D scholar, NINS laboratory) for discussion as well as Ms. Kanika Sandal (R&D Engineer I, NINS laboratory) for her help in arranging the copyright permission from various publishers. Thanks to Ms. Shubhangi Tripathi for proof reading.

Author information

Author notes

  1. Divya Dwivedi, Kanu Megha and Ritwick Mishra refers to equal first author.

Authors and Affiliations

  1. Neuroimaging and Neurospectroscopy (NINS) Laboratory, National Brain Research Centre, Manesar, Gurgaon, Haryana, India

    Divya Dwivedi, Kanu Megha, Ritwick Mishra & Pravat K. Mandal

  2. Florey Institute of Neuroscience and Mental Health, Melbourne School of Medicine Campus, Parkville, Melbourne, Australia

    Pravat K. Mandal

Authors
  1. Divya Dwivedi
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Kanu Megha
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Ritwick Mishra
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Pravat K. Mandal
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

Dr. PKM (Professor) conceptualized the research idea and was involved in writing the manuscript, figure preparation, critically reviewing and finalization of the manuscript. Ms. DD (R&D Engineer), Dr. KM (Research Associate) and Mr. RM (Clinical Coordinator) contributed equally to the literature search, critically reviewing the literature, writing and reviewing the manuscript as well as designing the figures.

Corresponding author

Correspondence to Pravat K. Mandal.

Ethics declarations

Conflict of interest

All the authors agree with the content of the article and declare no conflict of interest (personal, academic or financial) associated with this study.

Additional information

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Dwivedi, D., Megha, K., Mishra, R. et al. Glutathione in Brain: Overview of Its Conformations, Functions, Biochemical Characteristics, Quantitation and Potential Therapeutic Role in Brain Disorders. Neurochem Res 45, 1461–1480 (2020). https://doi.org/10.1007/s11064-020-03030-1

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11064-020-03030-1

Keywords

Search

Navigation