Abstract
Glutathione (GSH) is depleted early in the course of Parkinson’s disease (PD), and deficiency has been shown to perpetuate oxidative stress, mitochondrial dysfunction, impaired autophagy, and cell death. GSH repletion has been proposed as a therapeutic intervention. The objective of this study was to evaluate whether intranasally administered reduced GSH, (in)GSH, is capable of augmenting central nervous system GSH concentrations, as determined by magnetic resonance spectroscopy in 15 participants with mid-stage PD. After baseline GSH measurement, 200 mg (in)GSH was self-administered inside the scanner without repositioning, then serial GSH levels were obtained over ~1 h. Statistical significance was determined by one-way repeated measures analysis of variance. Overall, (in)GSH increased brain GSH relative to baseline (P<0.001). There was no increase in GSH 8 min after administration, although it was significantly higher than baseline at all of the remaining time points (P<0.01). This study is the first to demonstrate that intranasal administration of GSH elevates brain GSH levels. This increase persists at least 1 h in subjects with PD. Further dose–response and steady-state administration studies will be required to optimize the dosing schedule for future trials to evaluate therapeutic efficacy.
Highlights
Glutathione (GSH) deficiency is one of the earliest biochemical perturbations in Parkinson’s disease (PD),[1,2] leading to the hypothesis that GSH supplementation may have therapeutic value in alleviating PD symptoms or modifying progression.[3]
The current study addressed these limitations by testing a noninvasive nasal GSH repletion strategy, and measuring central nervous system (CNS) uptake via proton magnetic resonance spectroscopy (1H-MRS)
Baseline GSH levels were undetectable, and one post-dose spectrum from one subject was omitted owing to poor data quality. This is the first study to demonstrate an increase in CNS GSH levels with a noninvasive GSH augmentation strategy
Summary
Glutathione (GSH) deficiency is one of the earliest biochemical perturbations in Parkinson’s disease (PD),[1,2] leading to the hypothesis that GSH supplementation may have therapeutic value in alleviating PD symptoms or modifying progression.[3]. Two major factors have limited progress toward investigating the utility of GSH supplementation as a therapeutic strategy in PD. GSH bioavailability is very low following oral administration. Alternative repletion strategies have focused on oral administration of GSH precursors (e.g., cysteine and glycine supplementation9), and intravenous administration of GSH,[10] which promising, is invasive and inconvenient, and unlikely to be a practical solution. The inability to quantify central nervous system (CNS) GSH concentrations in vivo has substantially hindered therapeutic trials targeting CNS augmentation. The current study addressed these limitations by testing a noninvasive nasal GSH repletion strategy, and measuring CNS uptake via proton magnetic resonance spectroscopy (1H-MRS)
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