Landmark 129 · Discovery
Glutathione loss in the nigra
Brains from people with Parkinson's had about 40% less glutathione, the cell's main antioxidant, in the area that loses dopamine cells.
In short
Post-mortem brains showed about 40% less of the cell's main antioxidant, glutathione, in the Parkinson's nigra and nowhere else, early evidence that oxidative stress is part of the disease.
- What it is
- Discovery
- Outcome
- Still being studied
- When
- 1994
- Approach
- Help cells clean up
- Research lane
- Oxidative stress
- Trial registry
- NCT02424708
- Last checked
- 19 Oct 2026
The research record
This is the project's file for this landmark, as written and checked. Sources are listed at the end; anything not yet confirmed is marked "Not yet verified".
Who
J. Sian, D. T. Dexter, A. J. Lees, S. Daniel, Y. Agid, F. Javoy-Agid, P. Jenner and C. D. Marsden (Ann Neurol 1994;36:348–355). First author's affiliation: Parkinson's Disease Society Experimental Research Laboratories, King's College London. Funders are not stated in the abstract.
What happened
The team measured reduced (GSH) and oxidised (GSSG) glutathione in several brain regions from people who died with Parkinson's, progressive supranuclear palsy, multiple system atrophy or Huntington's disease, and from controls. In Parkinson's, nigral GSH was about 40% lower than in controls. GSSG rose slightly, not significantly. No other region changed. Nigral GSH was not significantly reduced in multiple system atrophy or progressive supranuclear palsy despite similar cell loss, so cell death alone and drug treatment did not explain it.
Why it moved us toward a cure
It gave a measurable target for antioxidant therapy, alongside the energy defect of landmark 11, in the neurons first lost in landmark 1. Glutathione-raising approaches followed, including intranasal glutathione: a 30-person Phase I/IIa safety study (Mischley 2015) and then a 45-person Phase IIb (NCT02424708, Bastyr University, with Michael J. Fox Foundation support), in which neither dose was better than placebo (Mischley 2017). Those trials looked at symptoms; a disease-modification trial has not been run.
Outcome
Open. Antioxidants have not been shown to slow Parkinson's, and the oxidative-stress branch is pruned. The nigral glutathione drop stays a marker of the disease process, with no replication or causal test checked here.
Sources
- Sian et al., Ann Neurol 1994;36:348–355, DOI 10.1002/ana.410360305, PMID 8080242 (abstract via Europe PMC)
- Mischley et al., Phase I/IIa, PMID 26230671; Mischley et al., Phase IIb, J Parkinsons Dis 2017, PMID 28436395
- ClinicalTrials.gov NCT02424708
- Not yet verified: the number of brains per group (not in the abstract; full text not read).
How it connects
Built on
- builds on Dopamine is missing from the Parkinson's brain · 1960
- builds on Complex I deficiency in the Parkinson's brain · 1989
Led to
- builds on Molecular hydrogen trials · 2013
- builds on N-acetylcysteine (Monti) · 2014
- tests Intranasal glutathione, Phase IIb · 2015
- builds on EPI-589 Phase 2a · 2016