Progressive Parkinsonism by acute dysfunction of excitatory amino acid transporters in the rat substantia nigra.
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.
Aix-Marseille Université, CNRS, IBDML, UMR7288, 13009, Case 907, Parc Scientifique de Luminy, 13009 Marseille, France.
Maxime
M
Assous
Aix-Marseille Université, CNRS, IBDML, UMR7288, 13009, Case 907, Parc Scientifique de Luminy, 13009 Marseille, France.
Laurence
L
Had-Aissouni
Aix-Marseille Université, CNRS, IBDML, UMR7288, 13009, Case 907, Parc Scientifique de Luminy, 13009 Marseille, France.
Paolo
P
Gubellini
Aix-Marseille Université, CNRS, IBDML, UMR7288, 13009, Case 907, Parc Scientifique de Luminy, 13009 Marseille, France.
Christophe
C
Melon
Fluofarma, 2 Rue Robert Escarpit, 33607, Pessac, France.
Imane
I
Nafia
Aix-Marseille Université, CNRS, IBDML, UMR7288, 13009, Case 907, Parc Scientifique de Luminy, 13009 Marseille, France.
Pascal
P
Salin
Aix-Marseille Université, CNRS, IBDML, UMR7288, 13009, Case 907, Parc Scientifique de Luminy, 13009 Marseille, France. Electronic address: lydia.kerkerian-le-goff@univ-amu.fr.
Lydia
L
Kerkerian-Le-Goff
Aix-Marseille Université, CNRS, IBDML, UMR7288, 13009, Case 907, Parc Scientifique de Luminy, 13009 Marseille, France. Electronic address: philippe.kachidian@univ-amu.fr.
Philippe
P
Kachidian
D000111:Acetylcysteine / Q000627:therapeutic use; D000200:Action Potentials / Q000187:drug effects; D000818:Animals; D003998:Dicarboxylic Acids / Q000633:toxicity; D004195:Disease Models, Animal; D005106:Exploratory Behavior / Q000502:physiology; D005552:Forelimb / Q000503:physiopathology; D016166:Free Radical Scavengers / Q000627:therapeutic use; D007839:Functional Laterality; D005968:Glutamate Decarboxylase / Q000378:metabolism; D050491:Glutamate Plasma Membrane Transport Proteins / Q000378:metabolism*; D066298:In Vitro Techniques; D008297:Male; D009043:Motor Activity / Q000187:drug effects; D009457:Neuroglia / Q000473:pathology; D014179:Neurotransmitter Uptake Inhibitors / Q000633:toxicity; D020734:Parkinsonian Disorders / Q000139:chemically induced / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology*; D011759:Pyrrolidines / Q000633:toxicity; D051381:Rats; D017208:Rats, Wistar; D013378:Substantia Nigra / Q000187:drug effects / Q000378:metabolism*; D017392:Thiobarbituric Acid Reactive Substances / Q000378:metabolism; D014446:Tyrosine 3-Monooxygenase / Q000235:genetics / Q000378:metabolism
D003998:Dicarboxylic Acids; D016166:Free Radical Scavengers; D050491:Glutamate Plasma Membrane Transport Proteins; D014179:Neurotransmitter Uptake Inhibitors; D011759:Pyrrolidines; D017392:Thiobarbituric Acid Reactive Substances; C083486:pyrrolidine-2,4-dicarboxylic acid; D014446:Tyrosine 3-Monooxygenase; D005968:Glutamate Decarboxylase; C402565:glutamate decarboxylase 1; D000111:Acetylcysteine
Animal model; Excitotoxicity; Glutamate transporters; Neurodegeneration; Neuroprotection; Oxidative stress; PDC (l-trans-pyrrolidine-2,4-dicarboxylate); Parkinson's disease