Article

N-Acetylcysteine Prevents Loss of Dopaminergic Neurons in the EAAC1(-/-) Mouse

Department of Neurology, University of California, San Francisco, San Francisco Veterans Affairs Medical Center, USA.
Annals of Neurology (Impact Factor: 11.91). 03/2011; 69(3):509-20. DOI: 10.1002/ana.22162
Source: PubMed

ABSTRACT 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.
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.
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.
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.

0 Bookmarks
 · 
121 Views
  • [Show abstract] [Hide abstract]
    ABSTRACT: The selective detection of cysteine and homocysteine over glutathione and other amino acids was demonstrated with an 8-MeS-BODIPY probe, by mimicking the native chemical ligation approach, which allowed the selective and ratiometric fluorescence sensing of cysteine over other biothiols at physiologically relevant concentrations and in different organs of zebrafish.
    The Analyst 11/2014; 140(2). DOI:10.1039/C4AN01791A · 3.91 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: New insights into the molecular dynamics of the EAAT transport cycle are reviewed.•Modes of action and properties of novel generations of EAAT modulators are outlined.•Recently identified physiological functions of EAATs are presented.
    Current Opinion in Pharmacology 11/2014; DOI:10.1016/j.coph.2014.10.008 · 4.23 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Metabonomics aims to measure the global, dynamic metabolic response of living system to biological stimuli. This approach requires to get a fingerprint analysis of body fluids (urine, plasma, etc.) using various spectroscopic methods, like 1H-NMR or mass spectrometry. Therefore, statistical datamining of spectra is necessary to extract the useful metabolic information. Metabonomics, by monitoring all influencing factors without making any assumption about their respective involvement, can detect properties about new toxicants and some putative related mechanisms of so-induced disruptive events. Metabonomics was used to investigate the toxicity of a plant, Hypochoeris radicata (HR), involved in a neurological horse disease, called Australian stringhalt. First described in 1848, this peripheral neuropathy induced by this plant, only observed in horse, leads to abnormal characteristic movements of hindlimbs and a laryngeal paresis. This affection was chosen as a toxicological model to apply metabonomics on a complex matrix to reveal unknown toxic principles without having any pathophysiological information. Without clinical trouble observed, the urinary fingerprinting of HR-treated mice allowed to reveal the main involved metabolite, scyllo-inositol, which is also found as a biomarker in liver and brain. In order to know whether scyllo-inositol is really a HR intoxication marker, brains of HR-treated mice were analyzed by magnetic resonance imaging, and confirmed the presence of abnormal concentrations of scyllo-inositol. Besides, we carried out behavioural tests demonstrating the HR infraclinical impact. Metabonomics provides a powerful approach to explore retrospectively the markers of a disease risk and to provide some indications of a pathophysiological situation. Several doses of the xenobiotics have to be tested to improve chemometric analysis of biological NMR spectra. Interestingly, this technology is being developed in the pharmaceutical industry for drug screening and for new candidate medicine selection. If genetic and individual effects on the metabolic status can be attenuated in laboratory animals, the challenge is from now on detection of subtle disruptions within the huge adaptable and complex biochemical system of the sick horses.
    16th North American Regional International society for the study of xenobiotics Meeting;

Full-text (2 Sources)

Download
12 Downloads
Available from
Jul 17, 2014