title: 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.
  
  
  CONCLUSIONS
  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.
authors: Department of Neurology, University of California, San Francisco, San Francisco Veterans Affairs Medical Center, USA.
authors: Ari E
authors: AE
authors: Berman
authors: Wai Yee
authors: WY
authors: Chan
authors: Angela M
authors: AM
authors: Brennan
authors: Reno C
authors: RC
authors: Reyes
authors: Brittany L
authors: BL
authors: Adler
authors: Sang Won
authors: SW
authors: Suh
authors: Tiina M
authors: TM
authors: Kauppinen
authors: Ylva
authors: Y
authors: Edling
authors: Raymond A
authors: RA
authors: Swanson
mesh_terms: D000111:Acetylcysteine / Q000494:pharmacology*; D000367:Age Factors; D000368:Aged; D000704:Analysis of Variance; D000818:Animals; D015153:Blotting, Western; D002452:Cell Count; D016923:Cell Death / Q000187:drug effects; D004195:Disease Models, Animal; D004298:Dopamine / Q000378:metabolism*; D050580:Excitatory Amino Acid Transporter 3 / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D007150:Immunohistochemistry; D051379:Mice; D018345:Mice, Knockout; D017628:Microglia / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D009043:Motor Activity / Q000187:drug effects; D009474:Neurons / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D018384:Oxidative Stress / Q000187:drug effects; D010300:Parkinson Disease / Q000378:metabolism* / Q000473:pathology; D013378:Substantia Nigra / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D014446:Tyrosine 3-Monooxygenase / Q000378:metabolism
chemical_list: D050580:Excitatory Amino Acid Transporter 3; D014446:Tyrosine 3-Monooxygenase; D004298:Dopamine; D000111:Acetylcysteine