Progressive Parkinsonism by acute dysfunction of excitatory amino acid transporters in the rat substantia nigra

Neurobiol Dis. 2014 May:65:69-81. doi: 10.1016/j.nbd.2014.01.011. Epub 2014 Jan 27.


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.

Keywords: Animal model; Excitotoxicity; Glutamate transporters; Neurodegeneration; Neuroprotection; Oxidative stress; PDC (l-trans-pyrrolidine-2,4-dicarboxylate); Parkinson's disease.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acetylcysteine / therapeutic use
  • Action Potentials / drug effects
  • Animals
  • Dicarboxylic Acids / toxicity
  • Disease Models, Animal
  • Exploratory Behavior / physiology
  • Forelimb / physiopathology
  • Free Radical Scavengers / therapeutic use
  • Functional Laterality
  • Glutamate Decarboxylase / metabolism
  • Glutamate Plasma Membrane Transport Proteins / metabolism*
  • In Vitro Techniques
  • Male
  • Motor Activity / drug effects
  • Neuroglia / pathology
  • Neurotransmitter Uptake Inhibitors / toxicity
  • Parkinsonian Disorders / chemically induced
  • Parkinsonian Disorders / drug therapy
  • Parkinsonian Disorders / metabolism*
  • Parkinsonian Disorders / pathology*
  • Pyrrolidines / toxicity
  • Rats
  • Rats, Wistar
  • Substantia Nigra / drug effects
  • Substantia Nigra / metabolism*
  • Thiobarbituric Acid Reactive Substances / metabolism
  • Tyrosine 3-Monooxygenase / genetics
  • Tyrosine 3-Monooxygenase / metabolism


  • Dicarboxylic Acids
  • Free Radical Scavengers
  • Glutamate Plasma Membrane Transport Proteins
  • Neurotransmitter Uptake Inhibitors
  • Pyrrolidines
  • Thiobarbituric Acid Reactive Substances
  • pyrrolidine-2,4-dicarboxylic acid
  • Tyrosine 3-Monooxygenase
  • Glutamate Decarboxylase
  • glutamate decarboxylase 1
  • Acetylcysteine