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

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• 作者：Maxime Assous^a ; Laurence Had-Aissouni^a ; Paolo Gubellini^a ; Christophe Melon^a ; Imane Nafia^b ; Pascal Salin^a ; Lydia Kerkerian-Le-Goff^a ; ¹ ; ² ; ^{lydia.kerkerian-le-goff@univ-amu.fr" class="auth_mail} ; Philippe Kachidian^a ; ¹ ; ^{philippe.kachidian@univ-amu.fr" class="auth_mail}
• 关键词：Animal model ; Excitotoxicity ; Glutamate transporters ; Neurodegeneration ; Neuroprotection ; Oxidative stress ; Parkinson's disease ; PDC (l-trans-pyrrolidine-2 ; 4-dicarboxylate)
• 刊名：Neurobiology of Disease
• 出版年：May, 2014
• 年：2014
• 卷：65
• 期：Complete
• 页码：69-81
• 全文大小：2084 K

文摘

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.