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

Assous, Maxime, Had-Aissouni, Laurence, Gubellini, Paolo, Melon, Christophe, Nafia, Imane, Salin, Pascal, Kerkerian-Le-Goff, Lydia and Kachidian, Philippe 2014. Progressive Parkinsonism by acute dysfunction of excitatory amino acid transporters in the rat substantia nigra. Neurobiology of Disease 65 , pp. 69-81. 10.1016/j.nbd.2014.01.011

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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.

Item Type: Article
Date Type: Publication
Status: Published
Schools: Biosciences
Publisher: Elsevier
ISSN: 0969-9961
Date of Acceptance: 14 January 2014
Last Modified: 15 Mar 2023 17:00

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