Phase IIb Study of Intranasal Glutathione in Parkinson’s Disease

Abstract

Background: Reduced glutathione (GSH) is an endogenously synthesized tripeptide depleted early in the course of Parkinson’s disease (PD) and GSH augmentation has been proposed as a therapeutic strategy in PD.Objective: This Phase IIb study was designed to evaluate whether a Phase III study of intranasal GSH, (in)GSH, for symptomatic relief is warranted and to determine the most appropriate trial design for a disease-modification study.Methods: This was a double-blind, placebo-controlled trial of 45 individuals with Hoehn & Yahr Stage 1–3 PD. Participants were randomized to receive intranasal placebo (saline), 100 mg GSH, or 200 mg GSH thrice daily for three months, and were observed over a one-month washout period.Results: All cohorts improved over the intervention period, including placebo. The high-dose group demonstrated improvement in total Unified PD Rating Scale (UPDRS) (–4.6 (4.7), P = 0.0025) and UPDRS motor subscore (–2.2 (3.8), P = 0.0485) over baseline, although neither treatment group was superior to placebo. One participant in the high-dose GSH cohort developed cardiomyopathy.Conclusions: Although predicted improvements in PD total and motor scores were observed, these data do not suggest (in)GSH is superior to placebo after a three month intervention. The symptomatic effects are sufficient to warrant a delayed-start or wash-out design study for disease-modification trials. Whether long-term use of (in)GSH leads to clinical improvements that are sustained and significantly different than placebo will require appropriately-powered longer-duration studies in larger cohorts. The improvement in the placebo arm was more robust than has been observed in previous PD studies and warrants further investigation.

Subcellular Localization of Glutathione Peroxidase, Change in Glutathione System during Ageing and Effects on Cardiometabolic Risks and Associated Diseases

“…In the central nervous system (CNS), GSH functions include maintenance of neurotransmitters, membrane protection, detoxification, metabolic regulation, and modulation of signal transduction. The depletion of GSH in the brain is implicated in both Parkinson's disease and neuronal damage after stroke [7].…”

“…Intracellular GSH homeostasis is regulated not only by de novo synthesis but also by several factors, including its use and recycling in cells [3]. A disruption of GSH homeostasis could induce oxidative stress and lead to neurodegenerative diseases, including amyotrophic lateral sclerosis, Parkinson's disease, Alzheimer's disease, and dementia, with impaired motor and cognitive functions [7]. There is also increasing evidence that deregulation of GSH synthesis contributes to the pathogenesis of diseases such as diabetes mellitus, pulmonary and hepatic fibrosis, alcoholic liver disease, cholestatic liver injury, endotoxemia, and drug-resistant tumors cells [10].…”

“…The GSH redox cycle is a major source of protection against mild oxidative stress with the GPx, antioxidant enzyme that oxidizes GSH to GSSG to protect cells against the proliferation of reactive oxygen species (ROS) or reactive nitrogen species (RNS), sparing them from oxidative damage, while catalase is becoming increasingly important in protecting against severe oxidative stress [3, 6, 10]. The Glutathione system with synthesis routes and pentose phosphates: the enzymes that catalyze the reactions are (1) GPxs, (2) superoxide dismutase, (3) NADPH oxidase and mitochondrial respiratory complexes, (4) glutathione reductase, (5) gluco-6-phosphate dehydrogenase, (6) γ-glutamyl transpeptidase, (7) γ-glutamyl cyclotransferase, (8) γ-glutamylcysteine synthetase, (9) glutathione synthetase, (10) variation in the erythrocyte GSH system without nuclear capacity to restore homeostasis may be an early biomarker of chronic oxidative stress that could be a first step in the development of cardiometabolic complications. If the cells are overwhelmed by the intensity of the oxidative stress, they die by necrosis or apoptosis [13].…”

Brain Redox Imaging Using In Vivo Electron Paramagnetic Resonance Imaging and Nitroxide Imaging Probes

“…GSH is an important antioxidant that can protect cells under oxidative stress. The maintenance of GSH levels is important to prevent neuronal disorders such as AD and Parkinson's disease [51,52]. The reduction reaction of nitroxides in vivo depends on the concentration of ascorbic acid, and this reaction is catalyzed, depending on GSH levels in vivo [19,53].…”

Preventing and Slowing the Progression of Parkinson's: A Clinical Conversation with Laurie Mischley, ND, MPH, PhD, and Robert Rountree, MD

“…21,22 However, in the second study, the placebo response was so robust that we had to conclude that intranasal glutathione was not superior to placebo. 23 I am actively working on a good study design to try and tease out this placebo response. In a third study, we used an MRI machine to measure baseline brain glutathione.…”