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Glutathione and Neurodegenerative Disease

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It’s well known that our risk of developing chronic diseases increases as we age. The reasons behind this are incredibly complex, but one of the most widely accepted explanations is called the “free radical theory of aging” [1].  First conceived in 1956, it is one of the most thoroughly researched theories known and, although not fully proven, is the best theory so far. It provides conclusive evidence that oxidative stress is intimately involved in aging.

As our lifespan increases, we become more susceptible to chronic disease. Especially those brought on by oxidative stress, like neurodegenerative diseases [2] which insidiously affect our brain and cognition.

A compromised glutathione (GSH) system in the brain has a strong correlation with oxidative stress and has been shown to be implicated in neurodegenerative diseases such as Alzheimer’s disease, Parkinson’s disease, amyotrophic lateral sclerosis, progressive supranuclear palsy, Huntington’s disease and multiple sclerosis [3-5].

It is now possible to determine the concentration of glutathione (GSH) in living human brains using magnetic resonance spectroscopy (MRS), with multiple MRS studies showing depleted brain glutathione (GSH) levels in all the major neurodegenerative diseases [6-9].

Strategies to increase neuronal or brain glutathione (GSH) as a potential treatment have been proposed by many researchers. However, none of the therapeutic candidates have been successful so far [10-12], with the major impediment for most being a failure to cross the blood-brain barrier. As yet, there is no available evidence to suggest that orally administered gamma-glutamylcysteine (GGC) can reach the human brain, but there are several theories that indicate it may well do so. An animal study was able to demonstrate that intravenously administered gamma-glutamylcysteine (GGC) did cross the blood-brain barrier and increased glutathione (GSH) in the brain [31]. A MRS human clinical study is underway to determine if oral supplementation with gamma-glutamylcysteine (GGC) can increase brain glutathione (GSH) levels.

References

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  2. Lin, M.T. and M.F. Beal, Mitochondrial dysfunction and oxidative stress in neurodegenerative diseases. Nature, 2006. 443(7113): p. 787-795.
  3. Dringen, R. and J. Hirrlinger, Glutathione pathways in the brain. Biol Chem, 2003. 384(4): p. 505-16.
  4. Maher, P., The effects of stress and aging on glutathione metabolism. Ageing Research Reviews, 2005. 4(2): p. 288-314.
  5. Currais, A. and P. Maher, Functional Consequences of Age-Dependent Changes in Glutathione Status in the Brain. Antioxidants & Redox Signaling, 2013. 19(8): p. 813-822.
  6. Mueller, S.G., N. Schuff, and M.W. Weiner, Evaluation of treatment effects in Alzheimer’s and other neurodegenerative diseases by MRI and MRS. NMR in Biomedicine, 2006. 19(6): p. 655-668.
  7. Saharan, S. and P.K. Mandal, The Emerging Role of Glutathione in Alzheimer’s Disease. Journal of Alzheimer’s Disease, 2014. 40(3): p. 519-529.
  8. Mandal, P.K., et al., Brain glutathione levels–a novel biomarker for mild cognitive impairment and Alzheimer’s disease. Biol Psychiatry, 2015. 78(10): p. 702-10.
  9. Rae, C.D. and S.R. Williams, Glutathione in the human brain: Review of its roles and measurement by magnetic resonance spectroscopy. Anal Biochem, 2017. 529: p. 127-143.
  10. Aoyama, K., M. Watabe, and T. Nakaki, Regulation of Neuronal Glutathione Synthesis. Journal of Pharmacological Sciences, 2008. 108(3): p. 227-238.
  11. Aoyama, K. and T. Nakaki, Impaired Glutathione Synthesis in Neurodegeneration. International Journal of Molecular Sciences, 2013. 14(10): p. 21021-21044.
  12. Gu, F., V. Chauhan, and A. Chauhan, Glutathione redox imbalance in brain disorders. Curr Opin Clin Nutr Metab Care, 2015. 18(1): p. 89-95.
  13. Butterfield, D.A., C.B. Pocernich, and J. Drake, Elevated glutathione as a therapeutic strategy in Alzheimer’s disease. Drug Development Research, 2002. 56: p. 428-437.
  14. Liu, H., et al., Glutathione Metabolism during Aging and in Alzheimer Disease. Annals of the New York Academy of Sciences, 2004. 1019(1): p. 346-349.
  15. Viña, J., et al., Molecular bases of the treatment of Alzheimer’s disease with antioxidants: prevention of oxidative stress. Molecular Aspects of Medicine, 2004. 25(1-2): p. 117-123.
  16. Pocernich, C.B. and D.A. Butterfield, Elevation of glutathione as a therapeutic strategy in Alzheimer disease. Biochimica Et Biophysica Acta-Molecular Basis of Disease, 2012. 1822(5): p. 625-630.
  17. Cao, P., et al., Therapeutic approaches to modulating glutathione levels as a pharmacological strategy in Alzheimer’s disease. Curr Alzheimer Res, 2015. 12(4): p. 298-313.
  18. Nady, B., et al., Therapeutic Approaches to Modulating Glutathione Levels as a Pharmacological Strategy in Alzheimer`s Disease. Current Alzheimer Research, 2015. 12(4): p. 298-313.
  19. Zeevalk, G.D., R. Razmpour, and L.P. Bernard, Glutathione and Parkinson’s disease: Is this the elephant in the room? Biomedicine & Pharmacotherapy, 2008. 62(4): p. 236-249.
  20. Martin, H.L. and P. Teismann, Glutathione—a review on its role and significance in Parkinson’s disease. The FASEB Journal, 2009. 23(10): p. 3263-3272.
  21. Elokda, A., et al., Effects of exercise induced oxidative stress on glutathione levels in Parkinson’s disease on and off medication. J Neurol, 2010. 257(10): p. 1648-53.
  22. Sechi, G.P., Reduced glutathione and Parkinson’s disease. Mov Disord, 2010. 25(15): p. 2690-1.
  23. Martinez-Banaclocha, M.A., N-acetyl-cysteine in the treatment of Parkinson’s disease. What are we waiting for? Med Hypotheses, 2012. 79(1): p. 8-12.
  24. Dexter, D.T. and P. Jenner, Parkinson disease: from pathology to molecular disease mechanisms. Free Radical Biology and Medicine, 2013. 62: p. 132-144.
  25. Holmay, M.J., et al., N-Acetylcysteine boosts brain and blood glutathione in Gaucher and Parkinson diseases. Clin Neuropharmacol, 2013. 36(4): p. 103-6.
  26. Smeyne, M. and R.J. Smeyne, Glutathione metabolism and Parkinson’s disease. Free Radical Biology and Medicine, 2013. 62: p. 13-25.
  27. Mischley, L.K., et al., Glutathione as a Biomarker in Parkinson’s Disease: Associations with Aging and Disease Severity. Oxid Med Cell Longev, 2016. 2016: p. 9409363.
  28. Coles, L.D., et al., Repeated-Dose Oral N-Acetylcysteine in Parkinson’s Disease: Pharmacokinetics and Effect on Brain Glutathione and Oxidative Stress. The Journal of Clinical Pharmacology, 2018. 58(2): p. 158-167.
  29. Aoyama, K. and T. Nakaki, Glutathione in Cellular Redox Homeostasis: Association with the Excitatory Amino Acid Carrier 1 (EAAC1). Molecules, 2015. 20(5): p. 8742-58.
  30. Aoyama, K., M. Watabe, and T. Nakaki, Modulation of neuronal glutathione synthesis by EAAC1 and its interacting protein GTRAP3-18. Amino Acids, 2012. 42(1): p. 163-169.
  31. Le, T.M., et al., Gamma-glutamylcysteine ameliorates oxidative injury in neurons and astrocytes in vitro and increases brain glutathione in vivo. Neurotoxicology, 2011. 32(5): p. 518-25.

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