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: 9.98). 03/2011; 69(3):509-20. DOI: 10.1002/ana.22162
Source: PubMed


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.

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Available from: Tiina Kauppinen, Jul 17, 2014
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    • "Indeed, in EAAT3 deficient mice, the dopaminergic neurons of the substantia nigra pars compacta, a neuronal population highly susceptible to oxidative stress, show decreased levels of neuronal glutathione, increased evidence for oxidative stress and decreased neuronal survival during aging [24]. Treatment of these mice with the cysteine analogue N-acetylcysteine (NAC), which is taken up by cells in an EAAT3 independent manner, rescues the phenotype supporting the idea that EAAT3 activity is important for cellular cysteine homeostasis [4], [25]. "
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    • "PDC being a substrate inhibitor of neuronal and glial EAATs, the question of which EAAT mediates PDC-triggered neurodegeneration arises. Although the contribution of glial EAATs cannot be excluded, a role of EAAC1 can be suggested since SNc DA neurons in EAAC1 −/− mice undergo age-related neurodegeneration associated with reduced GSH levels and increased oxidative stress (Berman et al., 2011). "
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    ABSTRACT: Parkinson's disease (PD) is characterized by the progressive degeneration of substantia nigra (SN) dopamine neurons, involving a multifactorial cascade of pathogenic events. Here we explored the hypothesis that dysfunction of excitatory amino acid transporters (EAATs) might be involved. Acutely-induced dysfunction of EAATs in the rat SN, by single unilateral injection of their substrate inhibitor L-trans-pyrrolidine-2,4-dicarboxylate (PDC), triggers a neurodegenerative process mimicking several PD features. Dopamine neurons are selectively affected, consistent with their sustained excitation by PDC measured by slice electrophysiology. The anti-oxidant N-acetylcysteine and the NMDA receptor antagonists ifenprodil and memantine provide neuroprotection. Besides oxidative stress and NMDA receptor-mediated excitotoxicity, glutathione depletion and neuroinflammation characterize the primary insult. Most interestingly, the degeneration progresses overtime with unilateral to bilateral and caudo-rostral evolution. Transient adaptive changes in dopamine function markers in SN and striatum accompany cell loss and axonal dystrophy, respectively. Motor deficits appear when neuron loss exceeds 50% in the most affected SN and striatal dopamine tone is dramatically reduced. These findings outline a functional link between EAAT dysfunction and several PD pathogenic mechanisms/pathological hallmarks, and provide a novel acutely-triggered model of progressive parkinsonism.
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    • "Natural antioxidant phytocompound curcumin showed neuroprotective capacity in the 6-OHDA model of PD [86], [87] and also attenuated aggregation of α-synuclein in cell model of PD [88], [89]. The simpler anti-oxidant N-acetylcysteine prevents loss of DA neurons in the EAAC1-/- mouse [90]. Oral N-acetylcysteine reduced loss of dopaminergic terminals in α-synuclein overexpressing mice model [91]. "
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