Repeated‐Dose Oral N‐Acetylcysteine in Parkinson's Disease: Pharmacokinetics and Effect on Brain Glutathione and Oxidative Stress

Abstract

Parkinson's disease (PD) is associated with oxidative stress and decreased nigral glutathione (GSH), suggesting that therapies that boost GSH may have a disease-modifying effect. Intravenous administration of a high dose of N-acetylcysteine (NAC), a well-known antioxidant and GSH precursor, increases blood and brain GSH in individuals with PD and with Gaucher disease and in healthy controls. To characterize the pharmacokinetics of repeated high oral doses of NAC and their effect on brain and blood oxidative stress measures, we conducted a 4-week open-label prospective study of oral NAC in individuals with PD (n = 5) and in healthy controls (n = 3). Brain GSH was measured in the occipital cortex using H-MRS at 3 and 7 tesla before and after 28 days of 6000 mg NAC/day. Blood was collected prior to dosing and at predetermined collection times before and after the last dose to assess NAC, cysteine, GSH, catalase, malondialdehyde (MDA) and 4-hydroxynonenal (4-HNE) concentrations and the reduced-to-oxidized GSH ratio (GSH/ glutathione disulfide [GSSG]). Symptomatic adverse events were reported by 3 of the 5 subjects with PD. NAC plasma concentration-time profiles were described by a first-order absorption, 1-compartment pharmacokinetic model. Although peripheral antioxidant measures (catalase and GSH/GSSG) increased significantly relative to baseline, indicators of oxidative damage, that is, measures of lipid peroxidation (4-HNE and MDA) were unchanged. There were no significant increases in brain GSH, which may be related to low oral NAC bioavailability and small fractional GSH/GSSG blood responses. Additional studies are needed to further characterize side effects and explore the differential effects of NAC on measures of antioxidant defense and oxidative damage.

Disease Modification in Parkinson's Disease: Current Approaches, Challenges, and Future Considerations

“…A number of treatments have been directed at this finding, including peripheral GSH infusions (not proven to cross the blood–brain barrier). In a recent study, supplementation with N‐acetylcysteine, a GSH precursor, significantly increased peripheral antioxidant measures (catalase and GSH/Glutathione disulfide (GSSG)), but failed to increase brain GSH (using proton magnetic resonance spectroscopy at 3 and 7 tesla), possibly related to low oral N‐acetylcysteine (NAC) bioavailability . EPI‐589 (also known as [R]‐troloxamide quinone in amyotrophic lateral sclerosis research), a drug claimed to catalytically increase GSH in cells, is being evaluated in a phase 2a safety and biomarker study in mitochondrial genetic subtypes as well as sporadic PD (NCT02462603).…”

N‐Acetyl Cysteine Is Associated With Dopaminergic Improvement in Parkinson's Disease

“…NAC with oral supplementation between infusions. One study using only oral NAC (6,000 mg/day) revealed no increase in glutathione levels in the brain as measured by MRS, whereas the same group showed an increase in brain glutathione levels in a study of patients with PD receiving i.v. NAC .…”

“…NAC . An early pharmacokinetic study showed that oral NAC resulted in about 1/10 of the amount of NAC in the serum compared with being given i.v., and increasing the oral dose substantially may not lead to higher serum concentrations …”

Brain Magnetic Resonance Imaging (MRI) as a Potential Biomarker for Parkinson’s Disease (PD)

“…Our interest in GSH led to additional 1 H-MRS work, where we utilized 8 mL occipital ROIs to measure GSH concentrations in two pharmacodynamic studies of the GSH precursor N-acetylcysteine (NAC): (1) a single (i.v.) dose study; and (2) a repeated oral dose trial [116,117]. The i.v.…”

“…Our 4 week daily oral NAC dose study in PD and control subjects showed blood antioxidant parameter increases (though 10-fold lower than the increases seen in the i.v. study), and trends, but not statistically significant, brain GSH increases [117]. The goal of the oral NAC study was to help determine dosing for a longer oral NAC clinical trial planned by colleagues at the University of California at San Francisco.…”