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Progress and Prospects in Parkinson's Research/Therapy/Neuroprotection/Glutathione (GSH)

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This is only a small sample of a considerable body of evidence pointing to the neuroprotective qualities of glutathione and its use as the basis of a novel form of PD therapy.

Background

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Glutathione (GSH) is an antioxidant, preventing damage to important cellular components caused by |reactive oxygen species such as free radicals and peroxides. All human cells have the capability of synthesising GSH but the principal source has been shown to be the liver.

Research

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1989

Pileblad et al [1] tested the effect of GSH depletion on rats. Their finding was:-

One may suggest an important role for GSH in catecholaminergic neurons: protecting against the oxidation of endogenous catechols.


1996

Seaton et al [2] tested whether in animal models treatment with thioctic acid would reverse the symptoms induced by GSH deficiency. The project proved conclusively that this was not the case.

Wüllner et al [3] studied whether GSH depletion could lead to cell death.

Our data show that glutathione depletion can result in cell death if the nigrostriatal system is metabolically compromised.


2000

Schulz et al [4] reviewed the evidence for a disturbance of glutathione homeostasis that may either lead to or result from oxidative stress in neurodegenerative disorders.

An important role for glutathione was proposed for the pathogenesis of Parkinson's disease, because a decrease in total glutathione concentrations in the substantia nigra has been observed in preclinical stages, at a time at which other biochemical changes are not yet detectable.

Klivenyi et al [5] Proved that GSH- deficient mice were more susceptible to the introduction of MPTP.

2010

Clark et al [6] hypothesized that since levels of glutathione are lower in the substantia nigra early in Parkinson's disease this may contribute to mitochondrial dysfunction and oxidative stress. Oxidative stress may in turn increase the accumulation of toxic forms of α-synuclein (SNCA).

They experimented to find out if supplementation with n-acetylcysteine (NAC), a source of cysteine – the limiting amino acid in glutathione synthesis, would protect against α-synuclein toxicity. In transgenic mice. Their conclusion:-

Overall, these results indicate that oral NAC supplementation decreases SNCA levels in brain and partially protects against loss of dopaminergic terminals associated with overexpression of α-synuclein in this model.


2011

Garrido et al [7] evaluated the possibilities of using glutathione to treat PD.

Over-expression of either of the two subunits of glutamate-cysteine ligase induced aberrant glutathiolation of cellular proteins and significant degeneration of dopaminergic neurons. Thus, while glutathione depletion was demonstrated to be a selective trigger for dopaminergic neuron degeneration, a glutathione replacement approach as a potential treatment option for Parkinson's patients must be considered with great care. In conclusion, our data demonstrate that survival of nigral dopaminergic neurons crucially depends on a tight regulation of their glutathione levels and that the depleted glutathione content detected in the brains of Parkinson's disease patients can be a causative insult for neuronal degeneration.

Further Reading

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2011

Zhou, Wenbo; Bercury, Kathryn Jessica Cummiskey, Jessica; Nancy Luong, Nancy; Lebin, Jacob and Freed, Curt R. Full Text J. Biol. Chem. 286 (17): 14941–14951.

Phenylbutyrate Up-regulates the DJ-1 Protein and Protects Neurons in Cell Culture and in Animal Models of Parkinson Disease.

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3083206/?tool=pmcentrez


2012

Kim, Kiyoung; Kim, Song-Hee; Kim, Jaekwang; Kim, Heuijong and J Yim, Jeongbin. Full Text Biol. Chem. 287(9): 6628–6641.

Glutathione S-Transferase Omega 1 Activity Is Sufficient to Suppress Neurodegeneration in a Drosophila Model of Parkinson Disease

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3307323/?tool=pmcentrez


Volodymyr, I Full Text J. Amino Acids. 2012: 736837.

Glutathione Homeostasis and Functions: Potential Targets for Medical Interventions.

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3303626/?tool=pmcentrez

Today

Literature search:

Use the following links to query the PubMed, PubMed Central and Google Scholar databases using the Search terms:- Parkinson's_Disease Glutathione.
This will list the latest papers on this topic. You are invited to update this page to reflect such recent results, pointing out their significance.
Pubmed (abstracts)
Pubmed_Central (Full_Text)
Google_Scholar


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Therapy > Neuroprotection

Sub Pages:

Neuroprotective agents
Substances with possible neuroprotective properties:
Caffeine,--Celastrol,--Co-Enzyme Q10,--Creatine,--DHA,--Exendin-4 (EX-4),--GDNF,--Glutathione (GSH),--GM1,--Isradipine,--Melatonin,--Minocycline,--Nicotine,--NSAIDs,--Phenylbutyrate,--Phytic Acid,--Probucol,--Quinoxaline,--Rasagiline,--Riboflavin,--Statins,--Tolcapone,--Urate & Uric Acid,--Vitamin D,--Vitamin E,--

See also: Deficiencies as PD cause/Glutathione


References

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<references>

  1. ↑ Pileblad, E.; Magnusson, T. and Fornstedt, B.(1989) Abstract J. Neurochem. 52 (3):978-980. Reduction of brain glutathione by L-buthionine sulfoximine potentiates the dopamine-depleting action of 6-hydroxydopamine in rat striatum. http://www.ncbi.nlm.nih.gov/pubmed/2493072
  2. ↑ Seaton, T. A.; Jenner, P. and Marsden, C. D. (1996) Abstract J, Neural. Transm. 103 (3):315 - 329. Thioctic acid does not restore glutathione levels or protect against the potentiation of 6-hydroxydopamine toxicity induced by glutathione depletion in rat brain. http://www.ncbi.nlm.nih.gov/pubmed/8739843
  3. ↑ Wüllner U.; Löschmann, P. A.; Schulz JB.; Schmid A.; Dringen, R.; Eblen, F,; Turski, L. and Klockgether, T. (1996) Abstract Neuroreport. 7 (4):921 - 923. Glutathione depletion potentiates MPTP and MPP+ toxicity in nigral dopaminergic neurones. http://www.ncbi.nlm.nih.gov/pubmed/8724674
  4. ↑ Schulz J. B.; Lindenau, J.; Seyfried, J. and Dichgans, J.(2000) Abstract Eur. J. Biochem. 267(16):4904 - 4011. Glutathione, oxidative stress and neurodegeneration. http://www.ncbi.nlm.nih.gov/pubmed/10931172
  5. ↑ Klivenyi, P.; Andreassen, O. A.: Ferrante R. J.; Dedeoglu, A.; Mueller G.; Lancelot E.; Bogdanov, M.; Andersen, J. K.: Jiang, D. and Beal, M. F (2000)Abstract J. Neurosci. 20 (1):1-7. Mice deficient in cellular glutathione peroxidase show increased vulnerability to malonate, 3-nitropropionic acid, and 1-methyl-4-phenyl-1,2,5,6-tetrahydropyridine. http://www.ncbi.nlm.nih.gov/pubmed/10627575
  6. ↑ Clark, Joanne; Clore, Elizabeth L.; Zheng, Kangni; Adame, Anthony; Masliah, Eliezer and Simon, David K. (2010) Full Text PLoS One. 2010; 5(8): e12333 Oral N-Acetyl-Cysteine Attenuates Loss of Dopaminergic Terminals in α-Synuclein Overexpressing Mice http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2925900/?tool=pmcentrez
  7. ↑ Garrido, M.; Tereshchenko, Y. Zhevtsova, Z.; Taschenberger, G.; Bähr, M. and Kügler, S.(2011)Abstract Acta Neuropathol. (4):475 - 485. Glutathione depletion and overproduction both initiate degeneration of nigral dopaminergic neurons.http://www.ncbi.nlm.nih.gov/pubmed/21191602
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