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Cited by 68Parkinson's Disease Mechanisms and TreatmentsGlutathione Transferases and PolymorphismsGenomics, phytochemicals, and oxidative stress

Glutathione and Related Molecules in Parkinsonism

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Asanuma, Masato, Miyazaki, Ikuko·2021·International Journal of Molecular Sciences
DOI 10.3390/ijms22168689PMC PMC8395390
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Abstract

Glutathione (GSH) is the most abundant intrinsic antioxidant in the central nervous system, and its substrate cysteine readily becomes the oxidized dimeric cystine. Since neurons lack a cystine transport system, neuronal GSH synthesis depends on cystine uptake via the cystine/glutamate exchange transporter (xCT), GSH synthesis, and release in/from surrounding astrocytes. Transcription factor nuclear factor erythroid 2-related factor 2 (Nrf2), a detoxifying master transcription factor, is expressed mainly in astrocytes and activates the gene expression of various phase II drug-metabolizing enzymes or antioxidants including GSH-related molecules and metallothionein by binding to the antioxidant response element (ARE) of these genes. Accumulating evidence has shown the involvement of dysfunction of antioxidative molecules including GSH and its related molecules in the pathogenesis of Parkinson’s disease (PD) or parkinsonian models. Furthermore, we found several agents targeting GSH synthesis in the astrocytes that protect nigrostriatal dopaminergic neuronal loss in PD models. In this article, the neuroprotective effects of supplementation and enhancement of GSH and its related molecules in PD pathology are reviewed, along with introducing new experimental findings, especially targeting of the xCT-GSH synthetic system and Nrf2–ARE pathway in astrocytes.

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  • 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.”

    From Glutathione Metabolism of the Brain—The Role of Astrocytes (2025) · cites this paper as Asanuma and Miyazaki 2021

    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

  • Oxidative stress and alterations in the GSH metabolism of the brain have been connected with many neurological and neurodegenerative diseases.

    “Oxidative stress and alterations in the GSH metabolism of the brain have been connected with many neurological and neurodegenerative diseases as recently summarized (Asanuma and Miyazaki 2021; Bell et al. 2024; Bjørklund et al. 2021, 2020; Bottino et al. 2021; Iskusnykh et al. 2022; Kim 2021; Murray et al. 2024).”

    From Glutathione Metabolism of the Brain—The Role of Astrocytes (2025) · cites this paper as Asanuma and Miyazaki 2021

    The Introduction links oxidative stress to neurodegenerative disorders and describes reduced brain GSH and dysfunction of GSH-related molecules in Parkinson’s disease. It does not establish altered brain GSH metabolism across the many neurological and neurodegenerative diseases named in the broader claim. The supplied passages have section labels but no page numbers. (LLM, conf=0.86)

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  1. [1]Jenner P. Dexter D.T. Sian J. Schapira A.H. Marsden C.D. Oxidative stress as a cause of nigral cell death in Parkinson’s disease and incidental Lewy body disease. The Royal Kings and Queens Parkinson’s Disease Research Group Ann. Neurol. 1992 32 Suppl. S1 S82 S87 10.1002/ana.410320714 1510385 · DOI
  2. [2]Riederer P. Sofic E. Rausch W.D. Schmidt B. Reynolds G.P. Jellinger K. Youdim M.B. Transition metals, ferritin, glutathione, and ascorbic acid in parkinsonian brains J. Neurochem. 1989 52 515 520 10.1111/j.1471-4159.1989.tb09150.x 2911028 · DOI · Paper page
  3. [3]Sian J. Dexter D.T. Lees A.J. Daniel S. Agid Y. Javoy-Agid F. Jenner P. Marsden C.D. Alterations in glutathione levels in Parkinson’s disease and other neurodegenerative disorders affecting basal ganglia Ann. Neurol. 1994 36 348 355 10.1002/ana.410360305 8080242 · DOI · Paper page
  4. [4]Sofic E. Lange K.W. Jellinger K. Riederer P. Reduced and oxidized glutathione in the substantia nigra of patients with Parkinson’s disease Neurosci. Lett. 1992 142 128 130 10.1016/0304-3940(92)90355-B 1454205 · DOI
  5. [5]Miyazaki I. Asanuma M. Approaches to prevent dopamine quinone-induced neurotoxicity Neurochem. Res. 2009 34 698 706 10.1007/s11064-008-9843-1 18770028 · DOI
  6. [6]Miyazaki I. Asanuma M. Therapeutic strategy of targeting astrocytes for neuroprotection in Parkinson’s disease Curr. Pharm. Design 2017 23 4936 4947 10.2174/1381612823666170710163731 28699520 · DOI
  7. [7]Cho Y. Bannai S. Uptake of glutamate and cysteine in C-6 glioma cells and in cultured astrocytes J. Neurochem. 1990 55 2091 2097 10.1111/j.1471-4159.1990.tb05800.x 1977889 · DOI
  8. [8]Qiang W. Cahill J.M. Liu J. Kuang X. Liu N. Scofield V.L. Voorhees J.R. Reid A.J. Yan M. Lynn W.S. Activation of transcription factor Nrf-2 and its downstream targets in response to moloney murine leukemia virus ts1-induced thiol depletion and oxidative stress in astrocytes J. Virol. 2004 78 11926 11938 10.1128/JVI.78.21.11926-11938.2004 15479833 PMC523278 · DOI
  9. [9]Seib T.M. Patel S.A. Bridges R.J. Regulation of the system x(C)- cystine/glutamate exchanger by intracellular glutathione levels in rat astrocyte primary cultures Glia 2011 59 1387 1401 10.1002/glia.21176 21590811 · DOI
  10. [10]Hirrlinger J. Konig J. Keppler D. Lindenau J. Schulz J.B. Dringen R. The multidrug resistance protein MRP1 mediates the release of glutathione disulfide from rat astrocytes during oxidative stress J. Neurochem. 2001 76 627 636 10.1046/j.1471-4159.2001.00101.x 11208926 · DOI · Paper page
  11. [11]Dringen R. Gutterer J.M. Hirrlinger J. Glutathione metabolism in brain metabolic interaction between astrocytes and neurons in the defense against reactive oxygen species Eur. J. Biochem. 2000 267 4912 4916 10.1046/j.1432-1327.2000.01597.x 10931173 · DOI
  12. [12]Shih A.Y. Erb H. Sun X. Toda S. Kalivas P.W. Murphy T.H. Cystine/glutamate exchange modulates glutathione supply for neuroprotection from oxidative stress and cell proliferation J. Neurosci. 2006 26 10514 10523 10.1523/JNEUROSCI.3178-06.2006 17035536 PMC6674710 · DOI
  13. [13]Wang X.F. Cynader M.S. Astrocytes provide cysteine to neurons by releasing glutathione J. Neurochem. 2000 74 1434 1442 10.1046/j.1471-4159.2000.0741434.x 10737599 · DOI · Paper page
  14. [14]Kuhn D.M. Arthur R.E. Jr. Thomas D.M. Elferink L.A. Tyrosine hydroxylase is inactivated by catechol-quinones and converted to a redox-cycling quinoprotein: Possible relevance to Parkinson’s disease J. Neurochem. 1999 73 1309 1317 10.1046/j.1471-4159.1999.0731309.x 10461926 · DOI
  15. [15]LaVoie M.J. Ostaszewski B.L. Weihofen A. Schlossmacher M.G. Selkoe D.J. Dopamine covalently modifies and functionally inactivates parkin Nat. Med. 2005 11 1214 1221 10.1038/nm1314 16227987 · DOI
  16. [16]Whitehead R.E. Ferrer J.V. Javitch J.A. Justice J.B. Reaction of oxidized dopamine with endogenous cysteine residues in the human dopamine transporter J. Neurochem. 2001 76 1242 1251 10.1046/j.1471-4159.2001.00125.x 11181843 · DOI
  17. [17]Asanuma M. Miyazaki I. Ogawa N. Dopamine- or L-DOPA-induced neurotoxicity: The role of dopamine quinone formation and tyrosinase in a model of Parkinson’s disease Neurotox. Res. 2003 5 165 176 10.1007/BF03033137 12835121 · DOI
  18. [18]Haque M.E. Asanuma M. Higashi Y. Miyazaki I. Tanaka K. Ogawa N. Apoptosis-inducing neurotoxicity of dopamine and its metabolites via reactive quinone generation in neuroblastoma cells Biochim. Biophys. Acta 2003 1619 39 52 10.1016/S0304-4165(02)00440-3 12495814 · DOI
  19. [19]Hastings T.G. Enzymatic oxidation of dopamine: The role of prostaglandin H synthase J. Neurochem. 1995 64 919 924 10.1046/j.1471-4159.1995.64020919.x 7830086 · DOI
  20. [20]Lai C.T. Yu P.H. Dopamine- and L-beta-3,4-dihydroxyphenylalanine hydrochloride (L-Dopa)-induced cytotoxicity towards catecholaminergic neuroblastoma SH-SY5Y cells. Effects of oxidative stress and antioxidative factors Biochem. Pharmacol. 1997 53 363 372 10.1016/S0006-2952(96)00731-9 9065740 · DOI
  21. [21]Miyazaki I. Asanuma M. Kikkawa Y. Takeshima M. Murakami S. Miyoshi K. Sogawa N. Kita T. Astrocyte-derived metallothionein protects dopaminergic neurons from dopamine quinone toxicity Glia 2011 59 435 451 10.1002/glia.21112 21264950 · DOI
  22. [22]Shih A.Y. Johnson D.A. Wong G. Kraft A.D. Jiang L. Erb H. Johnson J.A. Murphy T.H. Coordinate regulation of glutathione biosynthesis and release by Nrf2-expressing glia potently protects neurons from oxidative stress J. Neurosci. 2003 23 3394 3406 10.1523/JNEUROSCI.23-08-03394.2003 12716947 PMC6742304 · DOI
  23. [23]Itoh K. Wakabayashi N. Katoh Y. Ishii T. Igarashi K. Engel J.D. Yamamoto M. Keap1 represses nuclear activation of antioxidant responsive elements by Nrf2 through binding to the amino-terminal Neh2 domain Genes Dev. 1999 13 76 86 10.1101/gad.13.1.76 9887101 PMC316370 · DOI · Paper page
  24. [24]Kang M.I. Kobayashi A. Wakabayashi N. Kim S.G. Yamamoto M. Scaffolding of Keap1 to the actin cytoskeleton controls the function of Nrf2 as key regulator of cytoprotective phase 2 genes Proc. Natl. Acad. Sci. USA 2004 101 2046 2051 10.1073/pnas.0308347100 14764898 PMC357049 · DOI
  25. [25]Dinkova-Kostova A.T. Holtzclaw W.D. Cole R.N. Itoh K. Wakabayashi N. Katoh Y. Yamamoto M. Talalay P. Direct evidence that sulfhydryl groups of Keap1 are the sensors regulating induction of phase 2 enzymes that protect against carcinogens and oxidants Proc. Natl. Acad. Sci. USA 2002 99 11908 11913 10.1073/pnas.172398899 12193649 PMC129367 · DOI · Paper page
  26. [27]Delaidelli A. Richner M. Jiang L. van der Laan A. Bergholdt Jul Christiansen I. Ferreira N. Nyengaard J.R. Vægter C.B. Jensen P.H. Mackenzie I.R. α-Synuclein pathology in Parkinson disease activates homeostatic NRF2 anti-oxidant response Acta Neuropathol. Commun. 2021 9 105 10.1186/s40478-021-01209-3 34092244 PMC8183088 · DOI
  27. [28]Van Muiswinkel F.L. de Vos R.A. Bol J.G. Andringa G. Jansen Steur E.N. Ross D. Siegel D. Drukarch B. Expression of NAD(P)H:quinone oxidoreductase in the normal and Parkinsonian substantia nigra Neurobiol. Aging 2004 25 1253 1262 10.1016/j.neurobiolaging.2003.12.010 15312971 · DOI
  28. [29]Aschner M. Metallothionein (MT) isoforms in the central nervous system (CNS): Regional and cell-specific distribution and potential functions as an antioxidant Neurotoxicology 1998 19 653 660 9745925
  29. [30]Penkowa M. Metallothioneins are multipurpose neuroprotectants during brain pathology FEBS J. 2006 273 1857 1870 10.1111/j.1742-4658.2006.05207.x 16640552 · DOI
  30. [31]Chung R.S. West A.K. A role for extracellular metallothioneins in CNS injury and repair Neuroscience 2004 123 595 599 10.1016/j.neuroscience.2003.10.019 14706772 · DOI
  31. [32]Holloway A.F. Stennard F.A. Dziegielewska K.M. Weller L. West A.K. Localisation and expression of metallothionein immunoreactivity in the developing sheep brain Int. J. Dev. Neurosci. 1997 15 195 203 10.1016/S0736-5748(96)00091-3 9178038 · DOI
  32. [33]Aschner M. Astrocyte metallothioneins (MTs) and their neuroprotective role Ann. N. Y. Acad. Sci. 1997 825 334 347 10.1111/j.1749-6632.1997.tb48445.x 9369999 · DOI
  33. [34]Aschner M. Conklin D.R. Aschner J.L. Induction of metallothionein-I (MT-I) mRNA in primary astrocyte cultures is mediated by hypotonicity and not ethanol (EtOH) per se Brain Res. 1997 770 289 293 10.1016/S0006-8993(97)00772-5 9372231 · DOI
  34. [35]Choudhury M.E. Sugimoto K. Kubo M. Iwaki H. Tsujii T. Kyaw W.T. Nishikawa N. Nagai M. Tanaka J. Nomoto M. Zonisamide up-regulated the mRNAs encoding astrocytic anti-oxidative and neurotrophic factors Eur. J. Pharmacol. 2012 689 72 80 10.1016/j.ejphar.2012.05.012 22659113 · DOI
  35. [36]Kruczek C. Gorg B. Keitel V. Bidmon H.J. Schliess F. Haussinger D. Ammonia increases nitric oxide, free Zn(2+), and metallothionein mRNA expression in cultured rat astrocytes Biol. Chem. 2011 392 1155 1165 10.1515/BC.2011.199 22050230 · DOI
  36. [37]Michael G.J. Esmailzadeh S. Moran L.B. Christian L. Pearce R.K. Graeber M.B. Up-regulation of metallothionein gene expression in parkinsonian astrocytes Neurogenetics 2011 12 295 305 10.1007/s10048-011-0294-5 21800131 · DOI
  37. [38]Neal J.W. Singhrao S.K. Jasani B. Newman G.R. Immunocytochemically detectable metallothionein is expressed by astrocytes in the ischaemic human brain Neuropathol. Appl. Neurobiol. 1996 22 243 247 10.1111/j.1365-2990.1996.tb00900.x 8804026 · DOI
  38. [39]Rising L. Vitarella D. Kimelberg H.K. Aschner M. Metallothionein induction in neonatal rat primary astrocyte cultures protects against methylmercury cytotoxicity J. Neurochem. 1995 65 1562 1568 10.1046/j.1471-4159.1995.65041562.x 7561850 · DOI
  39. [40]Sawada J. Kikuchi Y. Shibutani M. Mitsumori K. Inoue K. Kasahara T. Induction of metallothionein in astrocytes by cytokines and heavy metals Biol. Signals 1994 3 157 168 10.1159/000109539 7849803 · DOI
  40. [41]Young J.K. Glial metallothionein Biol. Signals 1994 3 169 175 10.1159/000109540 7849804 · DOI
  41. [42]Young J.K. Garvey J.S. Huang P.C. Glial immunoreactivity for metallothionein in the rat brain Glia 1991 4 602 610 10.1002/glia.440040607 1720764 · DOI
  42. [43]Zambenedetti P. Giordano R. Zatta P. Metallothioneins are highly expressed in astrocytes and microcapillaries in Alzheimer’s disease J. Chem. Neuroanat. 1998 15 21 26 10.1016/S0891-0618(98)00024-6 9710146 · DOI
  43. [44]Zatta P. Zambenedetti P. Musicco M. Adorni F. Metallothionein-I-II and GFAP positivity in the brains from frontotemporal dementia patients J. Alzheimers Dis. 2005 8 109 116 10.3233/JAD-2005-8203 16308479 · DOI
  44. [45]Chung R.S. Adlard P.A. Dittmann J. Vickers J.C. Chuah M.I. West A.K. Neuron-glia communication: Metallothionein expression is specifically up-regulated by astrocytes in response to neuronal injury J. Neurochem. 2004 88 454 461 10.1046/j.1471-4159.2003.02193.x 14690533 · DOI
  45. [46]Isooka N. Miyazaki I. Kikuoka R. Wada K. Nakayama E. Shin K. Yamamoto D. Kitamura Y. Asanuma M. Dopaminergic neuroprotective effects of rotigotine via 5-HT1A receptors: Possibly involvement of metallothionein expression in astrocytes Neurochem. Int. 2020 132 104608 10.1016/j.neuint.2019.104608 31765686 · DOI
  46. [47]Kikuoka R. Miyazaki I. Kubota N. Maeda M. Kagawa D. Moriyama M. Sato A. Murakami S. Kitamura Y. Sendo T. Mirtazapine exerts astrocyte-mediated dopaminergic neuroprotection Sci. Rep. 2020 10 20698 10.1038/s41598-020-77652-4 33244123 PMC7693322 · DOI
  47. [48]Miyazaki I. Asanuma M. Murakami S. Takeshima M. Torigoe N. Kitamura Y. Miyoshi K. Targeting 5-HT(1A) receptors in astrocytes to protect dopaminergic neurons in Parkinsonian models Neurobiol. Dis. 2013 59 244 256 10.1016/j.nbd.2013.08.003 23959140 · DOI
  48. [49]Kang Y.J. Metallothionein redox cycle and function Exp. Biol. Med. (Maywood) 2006 231 1459 1467 10.1177/153537020623100903 17018867 · DOI
  49. [50]Chen P.C. Vargas M.R. Pani A.K. Smeyne R.J. Johnson D.A. Kan Y.W. Johnson J.A. Nrf2-mediated neuroprotection in the MPTP mouse model of Parkinson’s disease: Critical role for the astrocyte Proc. Natl. Acad. Sci. USA 2009 106 2933 2938 10.1073/pnas.0813361106 19196989 PMC2650368 · DOI · Paper page
  50. [51]Vargas M.R. Johnson J.A. The Nrf2-ARE cytoprotective pathway in astrocytes Expert Rev. Mol. Med. 2009 11 e17 10.1017/S1462399409001094 19490732 PMC5563256 · DOI
  51. [52]Brooks W.J. Jarvis M.F. Wagner G.C. Astrocytes as a primary locus for the conversion MPTP into MPP+ J. Neural Transm. 1989 76 1 12 10.1007/BF01244987 2785159 · DOI
  52. [53]Chuang J.I. Chen T.H. Effect of melatonin on temporal changes of reactive oxygen species and glutathione after MPP(+) treatment in human astrocytoma U373MG cells J. Pineal Res. 2004 36 117 125 10.1046/j.1600-079X.2003.00107.x 14962063 · DOI
  53. [54]Blum D. Torch S. Lambeng N. Nissou M. Benabid A.L. Sadoul R. Verna J.M. Molecular pathways involved in the neurotoxicity of 6-OHDA, dopamine and MPTP: Contribution to the apoptotic theory in Parkinson’s disease Prog. Neurobiol. 2001 65 135 172 10.1016/S0301-0082(01)00003-X 11403877 · DOI
  54. [55]Asanuma M. Miyazaki I. Murakami S. Diaz-Corrales F.J. Ogawa N. Striatal astrocytes act as a reservoir for L-DOPA PLoS ONE 2014 9 e106362 10.1371/journal.pone.0106362 25188235 PMC4154692 · DOI
  55. [56]Gupta S. Goswami P. Biswas J. Joshi N. Sharma S. Nath C. Singh S. 6-Hydroxydopamine and lipopolysaccharides induced DNA damage in astrocytes: Involvement of nitric oxide and mitochondria Mutat Res. Genet. Toxicol. Environ. Mutagen 2015 778 22 36 10.1016/j.mrgentox.2014.12.007 25726145 · DOI
  56. [57]Chinta S.J. Kumar M.J. Hsu M. Rajagopalan S. Kaur D. Rane A. Nicholls D.G. Choi J. Andersen J.K. Inducible alterations of glutathione levels in adult dopaminergic midbrain neurons result in nigrostriatal degeneration J. Neurosci. 2007 27 13997 14006 10.1523/JNEUROSCI.3885-07.2007 18094238 PMC6673525 · DOI · Paper page
  57. [58]Solano R.M. Casarejos M.J. Menendez-Cuervo J. Rodriguez-Navarro J.A. Garcia de Yebenes J. Mena M.A. Glial dysfunction in parkin null mice: Effects of aging J. Neurosci. 2008 28 598 611 10.1523/JNEUROSCI.4609-07.2008 18199761 PMC6670347 · DOI
  58. [59]Innamorato N.G. Jazwa A. Rojo A.I. Garcia C. Fernandez-Ruiz J. Grochot-Przeczek A. Stachurska A. Jozkowicz A. Dulak J. Cuadrado A. Different susceptibility to the Parkinson’s toxin MPTP in mice lacking the redox master regulator Nrf2 or its target gene heme oxygenase-1 PLoS ONE 2010 5 e11838 10.1371/journal.pone.0011838 20676377 PMC2911386 · DOI
  59. [60]Conway K.A. Rochet J.C. Bieganski R.M. Lansbury P.T. Jr. Kinetic stabilization of the a-synuclein protofibril by a dopamine-a-synuclein adduct Science 2001 294 1346 1349 10.1126/science.1063522 11701929 · DOI · Paper page
  60. [61]Miyazaki I. Asanuma M. Diaz-Corrales F.J. Miyoshi K. Ogawa N. Dopamine agonist pergolide prevents levodopa-induced quinoprotein formation in parkinsonian striatum and shows quenching effects on dopamine-semiquinone generated in vitro Clin. Neuropharmacol. 2005 28 155 160 10.1097/01.wnf.0000175523.33334.24 16062092 · DOI
  61. [62]Ogawa N. Tanaka K. Asanuma M. Bromocriptine markedly suppresses levodopa-induced abnormal increase of dopamine turnover in the parkinsonian striatum Neurochem. Res. 2000 25 755 758 10.1023/A:1007530720544 10943992 · DOI
  62. [63]Braak H. Del Tredici K. Rüb U. de Vos R.A. Jansen Steur E.N. Braak E. Staging of brain pathology related to sporadic Parkinson’s disease Neurobiol. Aging 2003 24 197 211 10.1016/S0197-4580(02)00065-9 12498954 · DOI · Paper page
  63. [64]Stockwell B.R. Friedmann Angeli J.P. Bayir H. Bush A.I. Conrad M. Dixon S.J. Fulda S. Gascon S. Hatzios S.K. Kagan V.E. Ferroptosis: A Regulated Cell Death Nexus Linking Metabolism, Redox Biology, and Disease Cell 2017 171 273 285 10.1016/j.cell.2017.09.021 28985560 PMC5685180 · DOI · Paper page
  64. [65]Wakabayashi K. Takahashi H. Takeda S. Ohama E. Ikuta F. Parkinson’s disease: The presence of Lewy bodies in Auerbach’s and Meissner’s plexuses Acta Neuropathol. 1988 76 217 221 10.1007/BF00687767 2850698 · DOI · Paper page
  65. [66]Hawkes C.H. Del Tredici K. Braak H. A timeline for Parkinson’s disease Parkinsonism Relat. Disord. 2010 16 79 84 10.1016/j.parkreldis.2009.08.007 19846332 · DOI · Paper page
  66. [67]Klingelhoefer L. Reichmann H. Pathogenesis of Parkinson disease--the gut-brain axis and environmental factors Nat. Rev. Neurol. 2015 11 625 636 10.1038/nrneurol.2015.197 26503923 · DOI · Paper page
  67. [70]Van Den Berge N. Ferreira N. Mikkelsen T.W. Alstrup A.K.O. Tamgüney G. Karlsson P. Terkelsen A.J. Nyengaard J.R. Jensen P.H. Borghammer P. Ageing promotes pathological alpha-synuclein propagation and autonomic dysfunction in wild-type rats Brain 2021 144 1853 1868 10.1093/brain/awab061 33880502 PMC8320301 · DOI
  68. [71]Arotcarena M.L. Dovero S. Prigent A. Bourdenx M. Camus S. Porras G. Thiolat M.L. Tasselli M. Aubert P. Kruse N. Bidirectional gut-to-brain and brain-to-gut propagation of synucleinopathy in non-human primates Brain 2020 143 1462 1475 10.1093/brain/awaa096 32380543 · DOI · Paper page
  69. [72]Borghammer P. Van Den Berge N. Brain-First versus Gut-First Parkinson’s Disease: A Hypothesis J. Parkinsons Dis. 2019 9 S281 S295 10.3233/JPD-191721 31498132 PMC6839496 · DOI · Paper page
  70. [73]Challis C. Hori A. Sampson T.R. Yoo B.B. Challis R.C. Hamilton A.M. Mazmanian S.K. Volpicelli-Daley L.A. Gradinaru V. Gut-seeded α-synuclein fibrils promote gut dysfunction and brain pathology specifically in aged mice Nat. Neurosci. 2020 23 327 336 10.1038/s41593-020-0589-7 32066981 PMC7065967 · DOI · Paper page
  71. [74]Kim S. Kwon S.H. Kam T.I. Panicker N. Karuppagounder S.S. Lee S. Lee J.H. Kim W.R. Kook M. Foss C.A. Transneuronal Propagation of Pathologic α-Synuclein from the Gut to the Brain Models Parkinson’s Disease Neuron 2019 103 627 641 10.1016/j.neuron.2019.05.035 31255487 PMC6706297 · DOI · Paper page
  72. [75]Sampson T.R. Debelius J.W. Thron T. Janssen S. Shastri G.G. Ilhan Z.E. Challis C. Schretter C.E. Rocha S. Gradinaru V. Gut Microbiota Regulate Motor Deficits and Neuroinflammation in a Model of Parkinson’s Disease Cell 2016 167 1469 1480 10.1016/j.cell.2016.11.018 27912057 PMC5718049 · DOI · Paper page
  73. [77]Mischley L.K. Conley K.E. Shankland E.G. Kavanagh T.J. Rosenfeld M.E. Duda J.E. White C.C. Wilbur T.K. De La Torre P.U. Padowski J.M. Central nervous system uptake of intranasal glutathione in Parkinson’s disease NPJ Parkinsons Dis. 2016 2 16002 10.1038/npjparkd.2016.2 28725693 PMC5516583 · DOI
  74. [78]Mischley L.K. Lau R.C. Shankland E.G. Wilbur T.K. Padowski J.M. Phase IIb Study of Intranasal Glutathione in Parkinson’s Disease J. Parkinsons Dis. 2017 7 289 299 10.3233/JPD-161040 28436395 PMC5438472 · DOI
  75. [79]Zeevalk G.D. Bernard L.P. Guilford F.T. Liposomal-glutathione provides maintenance of intracellular glutathione and neuroprotection in mesencephalic neuronal cells Neurochem. Res. 2010 35 1575 1587 10.1007/s11064-010-0217-0 20535554 · DOI
  76. [80]Pinnen F. Cacciatore I. Cornacchia C. Mollica A. Sozio P. Cerasa L.S. Iannitelli A. Fontana A. Nasuti C. Di Stefano A. CNS delivery of L-dopa by a new hybrid glutathione-methionine peptidomimetic prodrug Amino Acids 2012 42 261 269 10.1007/s00726-010-0804-z 21080012 · DOI
  77. [81]More S.S. Vince R. Design, synthesis and biological evaluation of glutathione peptidomimetics as components of anti-Parkinson prodrugs J. Med. Chem. 2008 51 4581 4588 10.1021/jm800239v 18651729 · DOI
  78. [82]Aoyama K. Matsumura N. Watabe M. Nakaki T. Oxidative stress on EAAC1 is involved in MPTP-induced glutathione depletion and motor dysfunction Eur. J. Neurosci. 2008 27 20 30 10.1111/j.1460-9568.2007.05979.x 18093171 · DOI
  79. [83]Berman A.E. Chan W.Y. Brennan A.M. Reyes R.C. Adler B.L. Suh S.W. Kauppinen T.M. Edling Y. Swanson R.A. N-acetylcysteine prevents loss of dopaminergic neurons in the EAAC1−/− mouse Ann. Neurol. 2011 69 509 520 10.1002/ana.22162 21446024 PMC4096233 · DOI
  80. [84]Aoyama K. Glutathione in the Brain Int. J. Mol. Sci. 2021 22 5010 10.3390/ijms22095010 34065042 PMC8125908 · DOI
  81. [85]Kraft A.D. Johnson D.A. Johnson J.A. Nuclear factor E2-related factor 2-dependent antioxidant response element activation by tert-butylhydroquinone and sulforaphane occurring preferentially in astrocytes conditions neurons against oxidative insult J. Neurosci. 2004 24 1101 1112 10.1523/JNEUROSCI.3817-03.2004 14762128 PMC6793572 · DOI
  82. [86]Gan L. Vargas M.R. Johnson D.A. Johnson J.A. Astrocyte-specific overexpression of Nrf2 delays motor pathology and synuclein aggregation throughout the CNS in the alpha-synuclein mutant (A53T) mouse model J. Neurosci. 2012 32 17775 17787 10.1523/JNEUROSCI.3049-12.2012 23223297 PMC3539799 · DOI
  83. [87]Asanuma M. Miyazaki I. 3-O-Methyldopa inhibits astrocyte-mediated dopaminergic neuroprotective effects of L-DOPA BMC Neurosci. 2016 17 52 10.1186/s12868-016-0289-0 27456338 PMC4960704 · DOI
  84. [88]Joyce J.N. Millan M.J. Dopamine D3 receptor agonists for protection and repair in Parkinson’s disease Curr. Opin. Pharmacol. 2007 7 100 105 10.1016/j.coph.2006.11.004 17174156 · DOI
  85. [89]Joyce J.N. Woolsey C. Ryoo H. Borwege S. Hagner D. Low dose pramipexole is neuroprotective in the MPTP mouse model of Parkinson’s disease, and downregulates the dopamine transporter via the D3 receptor BMC Biol. 2004 2 22 10.1186/1741-7007-2-22 15473914 PMC524509 · DOI
  86. [90]Youdim M.B. Kupershmidt L. Amit T. Weinreb O. Promises of novel multi-target neuroprotective and neurorestorative drugs for Parkinson’s disease Parkinsonism Relat. Disord. 2014 20 Suppl. S1 S132 S136 10.1016/S1353-8020(13)70032-4 24262165 · DOI
  87. [91]Du F. Li R. Huang Y. Li X. Le W. Dopamine D3 receptor-preferring agonists induce neurotrophic effects on mesencephalic dopamine neurons Eur. J. Neurosci. 2005 22 2422 2430 10.1111/j.1460-9568.2005.04438.x 16307585 · DOI
  88. [92]Imamura K. Takeshima T. Nakaso K. Ito S. Nakashima K. Pramipexole has astrocyte-mediated neuroprotective effects against lactacystin toxicity Neurosci. Lett. 2008 440 97 102 10.1016/j.neulet.2008.05.067 18555604 · DOI
  89. [93]Schapira A.H. McDermott M.P. Barone P. Comella C.L. Albrecht S. Hsu H.H. Massey D.H. Mizuno Y. Poewe W. Rascol O. Pramipexole in patients with early Parkinson’s disease (PROUD): A randomised delayed-start trial Lancet Neurol. 2013 12 747 755 10.1016/S1474-4422(13)70117-0 23726851 PMC3714436 · DOI
  90. [94]Ohta K. Fujinami A. Kuno S. Sakakimoto A. Matsui H. Kawahara Y. Ohta M. Cabergoline stimulates synthesis and secretion of nerve growth factor, brain-derived neurotrophic factor and glial cell line-derived neurotrophic factor by mouse astrocytes in primary culture Pharmacology 2004 71 162 168 10.1159/000077451 15161999 · DOI
  91. [95]Ohta K. Kuno S. Mizuta I. Fujinami A. Matsui H. Ohta M. Effects of dopamine agonists bromocriptine, pergolide, cabergoline, and SKF-38393 on GDNF, NGF, and BDNF synthesis in cultured mouse astrocytes Life Sci. 2003 73 617 626 10.1016/S0024-3205(03)00321-7 12770616 · DOI
  92. [96]Lim J.H. Kim K.M. Kim S.W. Hwang O. Choi H.J. Bromocriptine activates NQO1 via Nrf2-PI3K/Akt signaling: Novel cytoprotective mechanism against oxidative damage Pharmacol. Res. 2008 57 325 331 10.1016/j.phrs.2008.03.004 18455424 · DOI
  93. [97]Iida M. Miyazaki I. Tanaka K. Kabuto H. Iwata-Ichikawa E. Ogawa N. Dopamine D2 receptor-mediated antioxidant and neuroprotective effects of ropinirole, a dopamine agonist Brain Res. 1999 838 51 59 10.1016/S0006-8993(99)01688-1 10446316 · DOI
  94. [98]Tanaka K. Miyazaki I. Fujita N. Haque M.E. Asanuma M. Ogawa N. Molecular mechanism in activation of glutathione system by ropinirole, a selective dopamine D2 agonist Neurochem. Res. 2001 26 31 36 10.1023/A:1007672414239 11358279 · DOI
  95. [99]Yoshioka M. Tanaka K. Miyazaki I. Fujita N. Higashi Y. Asanuma M. Ogawa N. The dopamine agonist cabergoline provides neuroprotection by activation of the glutathione system and scavenging free radicals Neurosci. Res. 2002 43 259 267 10.1016/S0168-0102(02)00040-8 12103444 · DOI
  96. [100]Wei Y. Lu M. Mei M. Wang H. Han Z. Chen M. Yao H. Song N. Ding X. Ding J. Pyridoxine induces glutathione synthesis via PKM2-mediated Nrf2 transactivation and confers neuroprotection Nat. Commun. 2020 11 941 10.1038/s41467-020-14788-x 32071304 PMC7029000 · DOI
  97. [101]Shao W. Zhang S.Z. Tang M. Zhang X.H. Zhou Z. Yin Y.Q. Zhou Q.B. Huang Y.Y. Liu Y.J. Wawrousek E. Suppression of neuroinflammation by astrocytic dopamine D2 receptors via alphaB-crystallin Nature 2013 494 90 94 10.1038/nature11748 23242137 · DOI
  98. [102]Asanuma M. Miyazaki I. Diaz-Corrales F.J. Kimoto N. Kikkawa Y. Takeshima M. Miyoshi K. Murata M. Neuroprotective effects of zonisamide target astrocyte Ann. Neurol. 2010 67 239 249 10.1002/ana.21885 20225289 · DOI
  99. [103]Miyazaki I. Murakami S. Torigoe N. Kitamura Y. Asanuma M. Neuroprotective effects of levetiracetam target xCT in astrocytes in parkinsonian mice J. Neurochem. 2016 136 194 204 10.1111/jnc.13405 26485447 · DOI
  100. [104]Murata M. Novel therapeutic effects of the anti-convulsant, zonisamide, on Parkinson’s disease Curr. Pharm. Des. 2004 10 687 693 10.2174/1381612043453180 14965331 · DOI
  101. [105]Murata M. Hasegawa K. Kanazawa I. Zonisamide improves motor function in Parkinson disease: A randomized, double-blind study Neurology 2007 68 45 50 10.1212/01.wnl.0000250236.75053.16 17200492 · DOI
  102. [106]Murata M. Horiuchi E. Kanazawa I. Zonisamide has beneficial effects on Parkinson’s disease patients Neurosci. Res. 2001 41 397 399 10.1016/S0168-0102(01)00298-X 11755227 · DOI
  103. [107]Bentea E. Van Liefferinge J. Verbruggen L. Martens K. Kobayashi S. Deneyer L. Demuyser T. Albertini G. Maes K. Sato H. Zonisamide attenuates lactacystin-induced parkinsonism in mice without affecting system xc Exp. Neurol. 2017 290 15 28 10.1016/j.expneurol.2016.12.009 28024798 · DOI
  104. [108]Gower A.J. Hirsch E. Boehrer A. Noyer M. Marescaux C. Effects of levetiracetam, a novel antiepileptic drug, on convulsant activity in two genetic rat models of epilepsy Epilepsy Res. 1995 22 207 213 10.1016/0920-1211(95)00077-1 8991787 · DOI
  105. [109]Klitgaard H. Matagne A. Gobert J. Wulfert E. Evidence for a unique profile of levetiracetam in rodent models of seizures and epilepsy Eur. J. Pharmacol. 1998 353 191 206 10.1016/S0014-2999(98)00410-5 9726649 · DOI
  106. [110]Loscher W. Honack D. Rundfeldt C. Antiepileptogenic effects of the novel anticonvulsant levetiracetam (ucb L059) in the kindling model of temporal lobe epilepsy J. Pharmacol. Exp. Ther. 1998 284 474 479 9454787
  107. [111]Madeja M. Margineanu D.G. Gorji A. Siep E. Boerrigter P. Klitgaard H. Speckmann E.J. Reduction of voltage-operated potassium currents by levetiracetam: A novel antiepileptic mechanism of action? Neuropharmacology 2003 45 661 671 10.1016/S0028-3908(03)00248-X 12941379 · DOI
  108. [112]Lukyanetz E.A. Shkryl V.M. Kostyuk P.G. Selective blockade of N-type calcium channels by levetiracetam Epilepsia 2002 43 9 18 10.1046/j.1528-1157.2002.24501.x 11879381 · DOI
  109. [113]Fuks B. Gillard M. Michel P. Lynch B. Vertongen P. Leprince P. Klitgaard H. Chatelain P. Localization and photoaffinity labelling of the levetiracetam binding site in rat brain and certain cell lines Eur. J. Pharmacol. 2003 478 11 19 10.1016/j.ejphar.2003.08.033 14555179 · DOI
  110. [114]Gillard M. Fuks B. Michel P. Vertongen P. Massingham R. Chatelain P. Binding characteristics of [3H] ucb 30889 to levetiracetam binding sites in rat brain Eur. J. Pharmacol. 2003 478 1 9 10.1016/j.ejphar.2003.08.032 14555178 · DOI
  111. [115]Lynch B.A. Lambeng N. Nocka K. Kensel-Hammes P. Bajjalieh S.M. Matagne A. Fuks B. The synaptic vesicle protein SV2A is the binding site for the antiepileptic drug levetiracetam Proc. Natl. Acad. Sci. USA 2004 101 9861 9866 10.1073/pnas.0308208101 15210974 PMC470764 · DOI · Paper page
  112. [116]Ueda Y. Doi T. Takaki M. Nagatomo K. Nakajima A. Willmore L.J. Levetiracetam enhances endogenous antioxidant in the hippocampus of rats: In vivo evaluation by brain microdialysis combined with ESR spectroscopy Brain Res. 2009 1266 1 7 10.1016/j.brainres.2009.02.040 19268434 · DOI
  113. [117]Massie A. Schallier A. Kim S.W. Fernando R. Kobayashi S. Beck H. De Bundel D. Vermoesen K. Bannai S. Smolders I. Dopaminergic neurons of system x(c)(-)-deficient mice are highly protected against 6-hydroxydopamine-induced toxicity FASEB J. 2011 25 1359 1369 10.1096/fj.10-177212 21191088 · DOI
  114. [118]Ueda Y. Doi T. Nagatomo K. Tokumaru J. Takaki M. Willmore L.J. Effect of levetiracetam on molecular regulation of hippocampal glutamate and GABA transporters in rats with chronic seizures induced by amygdalar FeCl3 injection Brain Res. 2007 1151 55 61 10.1016/j.brainres.2007.03.021 17408599 · DOI
  115. [119]Iriti M. Vitalini S. Fico G. Faoro F. Neuroprotective herbs and foods from different traditional medicines and diets Molecules 2010 15 3517 3555 10.3390/molecules15053517 20657497 PMC6263339 · DOI
  116. [120]Liu R.H. Potential synergy of phytochemicals in cancer prevention: Mechanism of action J. Nutr. 2004 134 3479S 3485S 10.1093/jn/134.12.3479S 15570057 · DOI
  117. [121]Wagner A.E. Terschluesen A.M. Rimbach G. Health promoting effects of brassica-derived phytochemicals: From chemopreventive and anti-inflammatory activities to epigenetic regulation Oxid. Med. Cell. Longev. 2013 2013 964539 10.1155/2013/964539 24454992 PMC3885109 · DOI
  118. [122]Bergstrom P. Andersson H.C. Gao Y. Karlsson J.O. Nodin C. Anderson M.F. Nilsson M. Hammarsten O. Repeated transient sulforaphane stimulation in astrocytes leads to prolonged Nrf2-mediated gene expression and protection from superoxide-induced damage Neuropharmacology 2011 60 343 353 10.1016/j.neuropharm.2010.09.023 20888844 · DOI
  119. [123]Erlank H. Elmann A. Kohen R. Kanner J. Polyphenols activate Nrf2 in astrocytes via H2O2, semiquinones, and quinones Free Radic. Biol. Med. 2011 51 2319 2327 10.1016/j.freeradbiomed.2011.09.033 22037513 · DOI
  120. [124]Houghton C.A. Fassett R.G. Coombes J.S. Sulforaphane and Other Nutrigenomic Nrf2 Activators: Can the Clinician’s Expectation Be Matched by the Reality? Oxid. Med. Cell. Longev. 2016 2016 7857186 10.1155/2016/7857186 26881038 PMC4736808 · DOI
  121. [125]Zhou Q. Chen B. Wang X. Wu L. Yang Y. Cheng X. Hu Z. Cai X. Yang J. Sun X. Sulforaphane protects against rotenone-induced neurotoxicity in vivo: Involvement of the mTOR, Nrf2, and autophagy pathways Sci. Rep. 2016 6 32206 10.1038/srep32206 27553905 PMC4995453 · DOI
  122. [126]Qin S. Hou D.X. Multiple regulations of Keap1/Nrf2 system by dietary phytochemicals Mol. Nutr. Food Res. 2016 60 1731 1755 10.1002/mnfr.201501017 27523917 · DOI
  123. [127]Murakami S. Miyazaki I. Asanuma M. Neuroprotective effect of fermented papaya preparation by activation of Nrf2 pathway in astrocytes Nutr. Neurosci. 2018 21 176 184 10.1080/1028415X.2016.1253171 27841081 · DOI
  124. [128]Limanaqi F. Biagioni F. Mastroiacovo F. Polzella M. Lazzeri G. Fornai F. Merging the multi-target effects of phytochemicals in neurodegeneration: From oxidative stress to protein aggregation and inflammation Antioxidants 2020 9 1022 10.3390/antiox9101022 PMC7589770 33092300 · DOI
  125. [129]Lim G.P. Chu T. Yang F. Beech W. Frautschy S.A. Cole G.M. The curry spice curcumin reduces oxidative damage and amyloid pathology in an Alzheimer transgenic mouse J. Neurosci. 2001 21 8370 8377 10.1523/JNEUROSCI.21-21-08370.2001 11606625 PMC6762797 · DOI · Paper page
  126. [131]Terashima T. Takido J. Yokogoshi H. Time-dependent changes of amino acids in the serum, liver, brain and urine of rats administered with theanine Biosci. Biotechnol. Biochem. 1999 63 615 618 10.1271/bbb.63.615 10361674 · DOI · Paper page
  127. [132]Yamada T. Terashima T. Honma H. Nagata S. Okubo T. Juneja L.R. Yokogoshi H. Effects of theanine, a unique amino acid in tea leaves, on memory in a rat behavioral test Biosci. Biotechnol. Biochem. 2008 72 1356 1359 10.1271/bbb.70669 18460792 · DOI
  128. [134]Zukhurova M. Prosvirnina M. Daineko A. Simanenkova A. Petrishchev N. Sonin D. Galagudza M. Shamtsyan M. Juneja L.R. Vlasov T. L-theanine administration results in neuroprotection and prevents glutamate receptor agonist-mediated injury in the rat model of cerebral ischemia-reperfusion Phytother. Res. 2013 27 1282 1287 10.1002/ptr.4868 23097345 · DOI · Paper page
  129. [135]Takeshima M. Miyazaki I. Murakami S. Kita T. Asanuma M. l-Theanine protects against excess dopamine-induced neurotoxicity in the presence of astrocytes J. Clin. Biochem. Nutr. 2016 59 93 99 10.3164/jcbn.16-15 27698535 PMC5018574 · DOI · Paper page
  130. [136]Asanuma M. Okumura-Torigoe N. Miyazaki I. Murakami S. Kitamura Y. Sendo T. Region-specific neuroprotective features of astrocytes against oxidative stress induced by 6-hydroxydopamine Int. J. Mol. Sci. 2019 20 598 10.3390/ijms20030598 30704073 PMC6387089 · DOI

Cited by

Sorted by citations

Authors
Asanuma, M., & Miyazaki, I.
Affiliations
Okayama University (JP)
Corresponding author
Asanuma, Masato
ORCID
Venue
International Journal of Molecular Sciences
Publisher
MDPI AG
Published
2021-08-13
Volume
22
Issue
16
Pages
8689
ISSN
1422-0067 (ISSN-L)
DOI
10.3390/ijms22168689
PMC
PMC8395390
OpenAlex
W3192020839
Cited by
68
References
6
Citations by year
2026: 8 · 2025: 17 · 2024: 13 · 2023: 17 · 2022: 12 · 2021: 1
FWCI
1.37
Type
journal article
Language
en
Open access
Licence
Locations
  • International Journal of Molecular Sciences (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • Institutional Repositories DataBase (IRDB) (acceptedVersion)
  • Okayama University Scientific Achievement Repository (Okayama University) (submittedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Funders
  • Japan Society for the Promotion of Science (JP19K07993, JP21K07415)
  • Japanese Society of Eucommia (Research grant)
  • Okayama Medical Foundation (Research grant)
  • All Japan Coffee Association (Research grant)
Topics
  • Health Sciences › Medicine › Neurology › Parkinson's Disease Mechanisms and Treatments
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Glutathione Transferases and Polymorphisms
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Genomics, phytochemicals, and oxidative stress
Keywords
glutathione, Parkinson's disease, parkinsonism, SLC7A11, Nrf2, antioxidant response element, astrocytes, neuroprotection, glutathione synthesis, metallothionein, dopaminergic neuron loss, oxidative stress, glutathione supplementation
MeSH terms
Animals, Astrocytes, Carboxylic Ester Hydrolases, Disease Models, Animal, Gene Expression Regulation, Glutathione, Humans, Signal Transduction, Oxidative Stress, Parkinsonian Disorders, Amino Acid Transport System y+, NF-E2-Related Factor 2

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