N‐acetylcysteine prevents loss of dopaminergic neurons in the EAAC1^−/− mouse

Abstract

Objective Dopaminergic neuronal death in Parkinson’s disease (PD) is accompanied by oxidative stress and preceded by glutathione depletion. The development of disease-modifying therapies for PD has been hindered by a paucity of animal models that mimic these features and demonstrate an age-related progression. The EAAC1−/− mouse may be useful in this regard, because EAAC1−/− mouse neurons have impaired neuronal cysteine uptake, resulting in reduced neuronal glutathione content and chronic oxidative stress. Here we aimed to (1) characterize the age-related changes in nigral dopaminergic neurons in the EAAC1−/− mouse, and (2) use the EAAC1−/− mouse to evaluate N-acetylcysteine, a membrane-permeable cysteine pro-drug, as a potential disease-modifying intervention for PD. Methods Wild-type mice, EAAC1−/− mice, and EAAC1−/− mice chronically treated with N-acetylcysteine were evaluated at serial time points for evidence of oxidative stress, dopaminergic cell death, and motor abnormalities. Results EAAC1−/− mice showed age-dependent loss of dopaminergic neurons in the substantia nigra pars compacta, with more than 40% of these neurons lost by age 12 months. This neuronal loss was accompanied by increased nitrotyrosine formation, nitrosylated α-synuclein, and microglial activation. These changes were substantially reduced in mice that received N-acetylcysteine. Interpretation These findings suggest that the EAAC1−/− mouse may be a useful model of the chronic neuronal oxidative stress that occurs in PD. The salutary effects of N-acetylcysteine in this mouse model provide an impetus for clinical evaluation of glutathione repletion in PD.

Neuronal Glutathione Content and Antioxidant Capacity can be Normalized In Situ by N-acetyl Cysteine Concentrations Attained in Human Cerebrospinal Fluid

“…Mice were either wild-type 3-6-month-old C57BL/6 strain (Jackson Laboratories, West Grove, PA, USA) or SLC1A1 -/-mice that had been back-crossed to the C57BL/6 strain. The SLCA1 -/-colony was maintained as homozygous with breeders back-crossed with C57BL/6 mice every 6 generations, to avoid genetic drift [6,18]. SLC1A1 is more commonly known as excitatory amino acid transporter 3 or excitatory amino acid carrier 1 (EAAC1), and will be termed EAAC1 throughout this report.…”

“…A causal role for oxidative stress and GSH depletion in PD is supported by both clinical and animal studies [1,[3][4][5]. In particular, factors that cause global impairments in neuronal GSH metabolism cause cytotoxicity preferentially in the neuronal populations most affected in PD [6][7][8].…”

Nanomicellar formulation of coenzyme Q10 (Ubisol-Q10) effectively blocks ongoing neurodegeneration in the mouse 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine model: potential use as an adjuvant treatment in Parkinson's disease

“…Glutathione (GSH) is considered the main regulator of redox balance in the cellular milieu due to its capacity for detoxifying noxious molecules (Byrd et al, 2004;Dringen, 2000;Dringen and Hirrlinger, 2003). Upregulation of GSH levels has been achieved using oral administration of N-acetyl-Lcysteine (NAC), which results in increased brain GSH level, brain synaptic mitochondrial complex I activity (Banaclocha, 2000), and also increased neuronal survival and behavioral read-outs in MPTP-induced parkinsonian degeneration in mice (Berman et al, 2011;Clark et al, 2010). NAC is currently approved for use in the United States, Europe, and Canada for the treatment of acetaminophen-induced hepatotoxicity (Prescott, 2005) and can be used for treatment of neurodegenerative diseases.…”

An increased need for dietary cysteine in support of glutathione synthesis may underlie the increased risk for mortality associated with low protein intake in the elderly

“…It is reasonable to suspect that an age-related decline in brain glutathione and Nrf2 could exacerbate their progression. Indeed, NAC has shown efficacy in rodent models of these disorders (Offen et al 1996;Martinez 2000;Chen et al 2007;Clark et al 2010;Berman et al 2011;Martinez-Banaclocha 2012;Smeyne and Smeyne 2013;Moreira et al 2007;Huang et al 2010;Pocernich and Butterfield 2012;Hsiao et al 2012;Farr et al 2003). NAC is also beneficial in a mouse model of ALS (Andreassen et al 2000).…”