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

"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
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
1989

Pileblad et al 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 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 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 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 Proved that GSH- deficient mice were more susceptible to the introduction of MPTP.

2010

Clark et al 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 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."

Related pages
See also: Deficiencies as PD cause/Glutathione