N-acetylcysteine prevents loss of dopaminergic neurons in the EAAC1-/- mouse

Ann Neurol. 2011 Mar;69(3):509-20. doi: 10.1002/ana.22162. Epub 2010 Nov 23.


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.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Acetylcysteine / pharmacology*
  • Age Factors
  • Aged
  • Analysis of Variance
  • Animals
  • Blotting, Western
  • Cell Count
  • Cell Death / drug effects
  • Disease Models, Animal
  • Dopamine / metabolism*
  • Excitatory Amino Acid Transporter 3 / genetics
  • Excitatory Amino Acid Transporter 3 / metabolism*
  • Humans
  • Immunohistochemistry
  • Mice
  • Mice, Knockout
  • Microglia / drug effects
  • Microglia / metabolism
  • Microglia / pathology
  • Motor Activity / drug effects
  • Neurons / drug effects*
  • Neurons / metabolism
  • Neurons / pathology
  • Oxidative Stress / drug effects
  • Parkinson Disease / metabolism*
  • Parkinson Disease / pathology
  • Substantia Nigra / drug effects*
  • Substantia Nigra / metabolism
  • Substantia Nigra / pathology
  • Tyrosine 3-Monooxygenase / metabolism


  • Excitatory Amino Acid Transporter 3
  • Tyrosine 3-Monooxygenase
  • Dopamine
  • Acetylcysteine