Skip to main content

Advertisement

Log in

Ergothioneine and central nervous system diseases

  • Original Paper
  • Published:
Neurochemical Research Aims and scope Submit manuscript

Abstract

Ergothioneine (ERGO) is a thiol contained in the food that exhibits an excellent antioxidant effect similar to that of glutathione. Although mammals lack a biosynthetic pathway for ERGO, the carnitine/organic cation transporter OCTN1/SLC22A4, which transports ERGO in vivo, is expressed throughout the body, and ERGO is distributed to various organs after oral intake. ERGO is a stable compound that remains in the body for a long time after ingestion. OCTN1 is also expressed in brain parenchymal cells, including neurons, and ERGO in the blood permeates the blood–brain barrier and is distributed to the brain, exhibiting a neuroprotective effect. Recently, the association between central nervous system (CNS) diseases and ERGO has become a research focus. ERGO concentrations in the blood components are lower in patients with cognitive impairment, Parkinson’s disease, and frailty than in healthy subjects. ERGO exerts a protective effect against various neurotoxins and improves the symptoms of cognitive impairment, depression, and epilepsy in animal models. The promotion of neurogenesis and induction of neurotrophic factors, in addition to the antioxidant and anti-inflammatory effects, may be involved in the neuroprotective effect of ERGO. This review shows the association between ERGO and CNS diseases, discusses the possible biomarkers of peripheral ERGO in CNS diseases, and the possible preventive and improvement effects of ERGO on CNS diseases.

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

Access this article

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

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1

Similar content being viewed by others

Data Availability

Not applicable.

Code Availability

Not applicable.

Abbreviations

Aβ:

amyloid beta

ACh:

acetylcholine

AD:

Alzheimer’s disease

BBB:

blood–brain barrier

BDNF:

brain-derived neurotrophic factor

CIND:

cognitive impairment, no dementia

CNS:

central nervous system

ERGO:

ergothioneine

GABA:

γ-amino butyric acid

MCI:

mild cognitive impairment

mTOR:

mammalian target of rapamycin

NMDA:

N-Methyl-D-aspartate

NT5:

neurotrophin 4/5

PD:

Parkinson’s disease

References

  1. Halliwell B, Cheah IK, Tang RMY (2018) Ergothioneine - a diet-derived antioxidant with therapeutic potential. FEBS Lett 592:3357–3366

    Article  CAS  PubMed  Google Scholar 

  2. Ey J, Schömig E, Taubert D (2007) Dietary sources and antioxidant effects of ergothioneine. J Agric Food Chem 55:6466–6474

    Article  CAS  PubMed  Google Scholar 

  3. Sugiura T, Kato S, Shimizu T, Wakayama T, Nakamichi N, Kubo Y, Iwata D, Suzuki K, Soga T, Asano M, Iseki S, Tamai I, Tsuji A, Kato Y (2010) Functional expression of carnitine/organic cation transporter OCTN1/SLC22A4 in mouse small intestine and liver. Drug Metab Dispos 38:1665–1672

    Article  CAS  PubMed  Google Scholar 

  4. Kato Y, Kubo Y, Iwata D, Kato S, Sudo T, Sugiura T, Kagaya T, Wakayama T, Hirayama A, Sugimoto M, Sugihara K, Kaneko S, Soga T, Asano M, Tomita M, Matsui T, Wada M, Tsuji A (2010) Gene knockout and metabolome analysis of carnitine/organic cation transporter OCTN1. Pharm Res 27:832–840

    Article  CAS  PubMed  Google Scholar 

  5. Tang RMY, Cheah IK, Yew TSK, Halliwell B (2018) Distribution and accumulation of dietary ergothioneine and its metabolites in mouse tissues. Sci Rep 8:1601

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  6. Paul BD (2021) Ergothioneine: A Stress Vitamin with Antiaging, Vascular, and Neuroprotective. Roles? Antioxid Redox Signal

  7. Gründemann D, Harlfinger S, Golz S, Geerts A, Lazar A, Berkels R, Jung N, Rubbert A, Schömig E (2005) Discovery of the ergothioneine transporter. Proc Natl Acad Sci U S A 102:5256–5261

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  8. Tokuhiro S, Yamada R, Chang X, Suzuki A, Kochi Y, Sawada T, Suzuki M, Nagasaki M, Ohtsuki M, Ono M, Furukawa H, Nagashima M, Yoshino S, Mabuchi A, Sekine A, Saito S, Takahashi A, Tsunoda T, Nakamura Y, Yamamoto K (2003) An intronic SNP in a RUNX1 binding site of SLC22A4, encoding an organic cation transporter, is associated with rheumatoid arthritis. Nat Genet 35:341–348

    Article  CAS  PubMed  Google Scholar 

  9. Taubert D, Grimberg G, Jung N, Rubbert A, Schömig E (2005) Functional role of the 503F variant of the organic cation transporter OCTN1 in Crohn’s disease. Gut 54:1505–1506

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Borodina I, Kenny LC, McCarthy CM, Paramasivan K, Pretorius E, Roberts TJ, van der Hoek SA, Kell DB (2020) The biology of ergothioneine, an antioxidant nutraceutical. Nutr Res Rev 33:190–217

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Cheah IK, Halliwell B (2021) Ergothioneine, recent developments. Redox Biol 42:101868

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Turck D, Bresson JL, Burlingame B, Dean T, Fairweather-Tait S, Heinonen M, Hirsch-Ernst KI, Mangelsdorf I, McArdle HJ, Naska A, Neuhäuser-Berthold M, Nowicka G, Pentieva K, Sanz Y, Siani A, Sjödin A, Stern M, Tomé D, Vinceti M, Willatts P, Engel KH, Marchelli R, Pöting A, Poulsen M, Schlatter JR, Ackerl R, van Loveren H (2017) Statement on the safety of synthetic l-ergothioneine as a novel food - supplementary dietary exposure and safety assessment for infants and young children, pregnant and breastfeeding women. Efsa j 15:e05060

    PubMed  PubMed Central  Google Scholar 

  13. Cheah IK, Tang RM, Yew TS, Lim KH, Halliwell B (2017) Administration of Pure Ergothioneine to Healthy Human Subjects: Uptake, Metabolism, and Effects on Biomarkers of Oxidative Damage and Inflammation. Antioxid Redox Signal 26:193–206

    Article  CAS  PubMed  Google Scholar 

  14. Turck D, Bresson JL, Burlingame B, Dean T, Fairweather-Tait S, Heinonen M, Hirsch‐Ernst KI, Mangelsdorf I, McArdle HJ, Naska A, Neuhäuser‐Berthold M, Nowicka G, Pentieva K, Sanz Y, Siani A, Sjödin A, Stern M, Tomé D, Vinceti M, Willatts P, Engel KH, Marchelli R, Pöting A, Poulsen M, Schlatter J, Ackerl R, van Loveren H (2016) Safety of synthetic l‐ergothioneine (Ergoneine®) as a novel food pursuant to Regulation (EC) No 258/97. EFSA Journal 14

  15. Nakamichi N, Nakao S, Nishiyama M, Takeda Y, Ishimoto T, Masuo Y, Matsumoto S, Suzuki M, Kato Y (2021) Oral Administration of the Food-Derived Hydrophilic Antioxidant Ergothioneine Enhances Object Recognition Memory in Mice. Curr Mol Pharmacol 14:220–233

    Article  CAS  PubMed  Google Scholar 

  16. Aw TY, Wierzbicka G, Jones DP (1991) Oral glutathione increases tissue glutathione in vivo. Chem Biol Interact 80:89–97

    Article  CAS  PubMed  Google Scholar 

  17. Njålsson R (2005) Glutathione synthetase deficiency. Cell Mol Life Sci 62:1938–1945

    Article  PubMed  CAS  Google Scholar 

  18. Crossland J, Woodruff GN, Mitchell JF (1964) IDENTITY OF THE CEREBELLAR FACTOR. Nature 203:1388–1389

    Article  CAS  PubMed  Google Scholar 

  19. Krnjevic K, Randic M, Straughan DW (1965) ERGOYHIONEINE AND CENTRAL NEURONES. Nature 205:603–604

    Article  CAS  PubMed  Google Scholar 

  20. Crossland J, Mitchell J, Woodruff GN (1966) The presence of ergothioneine in the central nervous system and its probable identity with the cerebellar factor. J Physiol 182:427–438

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Briggs I (1972) Ergothioneine in the central nervous system. J Neurochem 19:27–35

    Article  CAS  PubMed  Google Scholar 

  22. Nakamichi N, Taguchi T, Hosotani H, Wakayama T, Shimizu T, Sugiura T, Iseki S, Kato Y (2012) Functional expression of carnitine/organic cation transporter OCTN1 in mouse brain neurons: possible involvement in neuronal differentiation. Neurochem Int 61:1121–1132

    Article  CAS  PubMed  Google Scholar 

  23. Lamhonwah AM, Hawkins CE, Tam C, Wong J, Mai L, Tein I (2008) Expression patterns of the organic cation/carnitine transporter family in adult murine brain. Brain Dev 30:31–42

    Article  PubMed  Google Scholar 

  24. Goldsteins G, Hakosalo V, Jaronen M, Keuters MH, Lehtonen Å, Koistinaho J (2022) CNS Redox Homeostasis and Dysfunction in Neurodegenerative Diseases.Antioxidants (Basel)11

  25. Asslih S, Damri O, Agam G (2021) Neuroinflammation as a Common Denominator of Complex Diseases (Cancer, Diabetes Type 2, and Neuropsychiatric Disorders).Int J Mol Sci22

  26. Nezu J, Tamai I, Oku A, Ohashi R, Yabuuchi H, Hashimoto N, Nikaido H, Sai Y, Koizumi A, Shoji Y, Takada G, Matsuishi T, Yoshino M, Kato H, Ohura T, Tsujimoto G, Hayakawa J, Shimane M, Tsuji A (1999) Primary systemic carnitine deficiency is caused by mutations in a gene encoding sodium ion-dependent carnitine transporter. Nat Genet 21:91–94

    Article  CAS  PubMed  Google Scholar 

  27. Cheah IK, Feng L, Tang RMY, Lim KHC, Halliwell B (2016) Ergothioneine levels in an elderly population decrease with age and incidence of cognitive decline; a risk factor for neurodegeneration? Biochem Biophys Res Commun 478:162–167

    Article  CAS  PubMed  Google Scholar 

  28. Hatano T, Saiki S, Okuzumi A, Mohney RP, Hattori N (2016) Identification of novel biomarkers for Parkinson’s disease by metabolomic technologies. J Neurol Neurosurg Psychiatry 87:295–301

    Article  PubMed  Google Scholar 

  29. Ishimoto T, Nakamichi N, Hosotani H, Masuo Y, Sugiura T, Kato Y (2014) Organic cation transporter-mediated ergothioneine uptake in mouse neural progenitor cells suppresses proliferation and promotes differentiation into neurons. PLoS ONE 9:e89434

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  30. Ishimoto T, Nakamichi N, Nishijima H, Masuo Y, Kato Y (2018) Carnitine/Organic Cation Transporter OCTN1 Negatively Regulates Activation in Murine Cultured Microglial Cells. Neurochem Res 43:116–128

    Article  CAS  PubMed  Google Scholar 

  31. Li RW, Yang C, Sit AS, Kwan YW, Lee SM, Hoi MP, Chan SW, Hausman M, Vanhoutte PM, Leung GP (2014) Uptake and protective effects of ergothioneine in human endothelial cells. J Pharmacol Exp Ther 350:691–700

    Article  PubMed  CAS  Google Scholar 

  32. Shimizu T, Masuo Y, Takahashi S, Nakamichi N, Kato Y (2015) Organic cation transporter Octn1-mediated uptake of food-derived antioxidant ergothioneine into infiltrating macrophages during intestinal inflammation in mice. Drug Metab Pharmacokinet 30:231–239

    Article  CAS  PubMed  Google Scholar 

  33. Wu LY, Cheah IK, Chong JR, Chai YL, Tan JY, Hilal S, Vrooman H, Chen CP, Halliwell B, Lai MKP (2021) Low plasma ergothioneine levels are associated with neurodegeneration and cerebrovascular disease in dementia. Free Radic Biol Med 177:201–211

    Article  CAS  PubMed  Google Scholar 

  34. Teruya T, Chen YJ, Kondoh H, Fukuji Y, Yanagida M (2021) Whole-blood metabolomics of dementia patients reveal classes of disease-linked metabolites. Proc Natl Acad Sci U S A 118

  35. Kameda M, Teruya T, Yanagida M, Kondoh H (2020) Frailty markers comprise blood metabolites involved in antioxidation, cognition, and mobility. Proc Natl Acad Sci U S A 117:9483–9489

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Kondoh H, Teruya T, Kameda M, Yanagida M (2022) Decline of ergothioneine in frailty and cognition impairment. FEBS Lett

  37. Ishimoto T, Kato Y (2022) Ergothioneine in the brain. FEBS Lett

  38. Watanabe N, Matsumoto S, Suzuki S, Fukaya T, Kato Y, Hashiya N (2020) Effect of Ergothioneine on the Cognitive Function Improvement in Healthy Volunteers and Mild Cognitive Impairment Subjects ―A Randomized, Double–blind, Parallel–group Comparison Study―. Jpn Pharmacol Ther 48:685–697

    CAS  Google Scholar 

  39. Yang NC, Lin HC, Wu JH, Ou HC, Chai YC, Tseng CY, Liao JW, Song TY (2012) Ergothioneine protects against neuronal injury induced by β-amyloid in mice. Food Chem Toxicol 50:3902–3911

    Article  CAS  PubMed  Google Scholar 

  40. Song TY, Chen CL, Liao JW, Ou HC, Tsai MS (2010) Ergothioneine protects against neuronal injury induced by cisplatin both in vitro and in vivo. Food Chem Toxicol 48:3492–3499

    Article  CAS  PubMed  Google Scholar 

  41. Toledo ARL, Monroy GR, Salazar FE, Lee JY, Jain S, Yadav H, Borlongan CV (2022) Gut-Brain Axis as a Pathological and Therapeutic Target for Neurodegenerative Disorders.Int J Mol Sci23

  42. Roe K (2022) An Alternative Explanation for Alzheimer’s Disease and Parkinson’s Disease Initiation from Specific Antibiotics, Gut Microbiota Dysbiosis and Neurotoxins. Neurochem Res 47:517–530

    Article  CAS  PubMed  Google Scholar 

  43. Matsuda Y, Ozawa N, Shinozaki T, Wakabayashi KI, Suzuki K, Kawano Y, Ohtsu I, Tatebayashi Y (2020) Ergothioneine, a metabolite of the gut bacterium Lactobacillus reuteri, protects against stress-induced sleep disturbances. Transl Psychiatry 10:170

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Liang CH, Huang PC, Mau JL, Chiang SS (2020) Effect of the King Oyster Culinary-Medicinal Mushroom Pleurotus eryngii (Agaricomycetes) Basidiocarps Powder to Ameliorate Memory and Learning Deficit in Ability in Aβ-Induced Alzheimer’s Disease C57BL/6J Mice Model. Int J Med Mushrooms 22:145–159

    Article  PubMed  Google Scholar 

  45. Song TY, Lin HC, Chen CL, Wu JH, Liao JW, Hu ML (2014) Ergothioneine and melatonin attenuate oxidative stress and protect against learning and memory deficits in C57BL/6J mice treated with D-galactose. Free Radic Res 48:1049–1060

    Article  CAS  PubMed  Google Scholar 

  46. Jang JH, Aruoma OI, Jen LS, Chung HY, Surh YJ (2004) Ergothioneine rescues PC12 cells from beta-amyloid-induced apoptotic death. Free Radic Biol Med 36:288–299

    Article  CAS  PubMed  Google Scholar 

  47. Jong NN, Nakanishi T, Liu JJ, Tamai I, McKeage MJ (2011) Oxaliplatin transport mediated by organic cation/carnitine transporters OCTN1 and OCTN2 in overexpressing human embryonic kidney 293 cells and rat dorsal root ganglion neurons. J Pharmacol Exp Ther 338:537–547

    Article  CAS  PubMed  Google Scholar 

  48. Cheah IK, Ng LT, Ng LF, Lam VY, Gruber J, Huang CYW, Goh FQ, Lim KHC, Halliwell B (2019) Inhibition of amyloid-induced toxicity by ergothioneine in a transgenic Caenorhabditis elegans model. FEBS Lett 593:2139–2150

    Article  CAS  PubMed  Google Scholar 

  49. Shitara Y, Nakamichi N, Norioka M, Shima H, Kato Y, Horie T (2013) Role of organic cation/carnitine transporter 1 in uptake of phenformin and inhibitory effect on complex I respiration in mitochondria. Toxicol Sci 132:32–42

    Article  CAS  PubMed  Google Scholar 

  50. Nakamichi N, Nakayama K, Ishimoto T, Masuo Y, Wakayama T, Sekiguchi H, Sutoh K, Usumi K, Iseki S, Kato Y (2016) Food-derived hydrophilic antioxidant ergothioneine is distributed to the brain and exerts antidepressant effect in mice. Brain Behav 6:e00477

    Article  PubMed  PubMed Central  Google Scholar 

  51. Ishimoto T, Masuo Y, Kato Y, Nakamichi N (2019) Ergothioneine-induced neuronal differentiation is mediated through activation of S6K1 and neurotrophin 4/5-TrkB signaling in murine neural stem cells. Cell Signal 53:269–280

    Article  CAS  PubMed  Google Scholar 

  52. Castrén E, Monteggia LM (2021) Brain-Derived Neurotrophic Factor Signaling in Depression and Antidepressant Action. Biol Psychiatry 90:128–136

    Article  PubMed  CAS  Google Scholar 

  53. K VA, Mohan AS, Chakravarty S (2020) Rapid acting antidepressants in the mTOR pathway: Current evidence. Brain Res Bull 163:170–177

    Article  CAS  Google Scholar 

  54. Nishiyama M, Nakamichi N, Yoshimura T, Masuo Y, Komori T, Ishimoto T, Matsuo JI, Kato Y (2020) Homostachydrine is a Xenobiotic Substrate of OCTN1/SLC22A4 and Potentially Sensitizes Pentylenetetrazole-Induced Seizures in Mice. Neurochem Res 45:2664–2678

    Article  CAS  PubMed  Google Scholar 

  55. Yang J, Yan B, Zhao B, Fan Y, He X, Yang L, Ma Q, Zheng J, Wang W, Bai L, Zhu F, Ma X (2020) Assessing the Causal Effects of Human Serum Metabolites on 5 Major Psychiatric Disorders. Schizophr Bull 46:804–813

    Article  PubMed  PubMed Central  Google Scholar 

  56. Nakamichi N, Kato Y (2017) Physiological Roles of Carnitine/Organic Cation Transporter OCTN1/SLC22A4 in Neural Cells. Biol Pharm Bull 40:1146–1152

    Article  CAS  PubMed  Google Scholar 

  57. Pochini L, Scalise M, Galluccio M, Indiveri C (2012) Regulation by physiological cations of acetylcholine transport mediated by human OCTN1 (SLC22A4). Implications in the non-neuronal cholinergic system. Life Sci 91:1013–1016

    Article  CAS  PubMed  Google Scholar 

  58. Gründemann D, Hartmann L, Flögel S (2021) The ergothioneine transporter (ETT): substrates and locations, an inventory. FEBS Lett

  59. Roda E, Priori EC, Ratto D, De Luca F, Di Iorio C, Angelone P, Locatelli CA, Desiderio A, Goppa L, Savino E, Bottone MG, Rossi P (2021) Neuroprotective Metabolites of Hericium erinaceus Promote Neuro-Healthy Aging.Int J Mol Sci22

  60. Moncaster JA, Walsh DT, Gentleman SM, Jen LS, Aruoma OI (2002) Ergothioneine treatment protects neurons against N-methyl-D-aspartate excitotoxicity in an in vivo rat retinal model. Neurosci Lett 328:55–59

    Article  CAS  PubMed  Google Scholar 

  61. Song TY, Yang NC, Chen CL, Thi TLV (2017) Protective Effects and Possible Mechanisms of Ergothioneine and Hispidin against Methylglyoxal-Induced Injuries in Rat Pheochromocytoma Cells. Oxid Med Cell Longev 2017:4824371

    PubMed  PubMed Central  Google Scholar 

  62. Koh SS, Ooi SC, Lui NM, Qiong C, Ho LT, Cheah IK, Halliwell B, Herr DR, Ong WY (2021) Effect of Ergothioneine on 7-Ketocholesterol-Induced Endothelial Injury. Neuromolecular Med 23:184–198

    Article  CAS  PubMed  Google Scholar 

  63. Futatsugi A, Masuo Y, Kawabata S, Nakamichi N, Kato Y (2016) L503F variant of carnitine/organic cation transporter 1 efficiently transports metformin and other biguanides. J Pharm Pharmacol 68:1160–1169

    Article  CAS  PubMed  Google Scholar 

  64. Toh DS, Koo SH, Limenta LM, Yee JY, Murray M, Lee EJ (2009) Genetic variations of the SLC22A4 gene in Chinese and Indian populations of Singapore. Drug Metab Pharmacokinet 24:475–481

    Article  CAS  PubMed  Google Scholar 

  65. Urban TJ, Yang C, Lagpacan LL, Brown C, Castro RA, Taylor TR, Huang CC, Stryke D, Johns SJ, Kawamoto M, Carlson EJ, Ferrin TE, Burchard EG, Giacomini KM (2007) Functional effects of protein sequence polymorphisms in the organic cation/ergothioneine transporter OCTN1 (SLC22A4). Pharmacogenet Genomics 17:773–782

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

We would like to thank Editage (www.editage.com) for English language editing.

Author information

Authors and Affiliations

Authors

Contributions

Conceptualization: Noritaka Nakamichi. Writing - original draft preparation: Noritaka Nakamichi. Writing, review, and editing: Noritaka Nakamichi, Sota Tsuzuku, Fumiya Shibagaki. Supervision: Noritaka Nakamichi.

Corresponding author

Correspondence to Noritaka Nakamichi.

Ethics declarations

Conflict of interest

The authors have no potential conflicts of interest.

Ethics approval

Not applicable.

Consent for publication

Not applicable.

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

Nakamichi, N., Tsuzuku, S. & Shibagaki, F. Ergothioneine and central nervous system diseases. Neurochem Res 47, 2513–2521 (2022). https://doi.org/10.1007/s11064-022-03665-2

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11064-022-03665-2

Keywords

Navigation