期刊
FRONTIERS IN CELLULAR NEUROSCIENCE
卷 9, 期 -, 页码 -出版社
FRONTIERS MEDIA SA
DOI: 10.3389/fncel.2015.00245
关键词
NMDA receptor; Parkinson's disease; levodopa-induced dyskinesias; 6-OHDA rat model; MPTP monkey model; patients; cell-permeable peptides; striatum
资金
- European Community EP7-Thematic priority HEALTH [222918]
- Cariplo Foundation [0661-2010, 0660-2014]
- Progetto di Ricerca di Interesse Nazionale [PRIN2010AHHP5H]
- Progetto Giovani Ricercatori Minister Sanita
- Investissements d'avenir [ANR-10-IAIHU-06]
Levodopa-induced dyskinesias (LIDs) are major complications in the pharmacological management of Parkinson's disease (PD). Abnormal glutamatergic transmission in the striatum is considered a key factor in the development of LIDs. This work aims at: (i) characterizing N-methyl-D-aspartate (NMDA) receptor GluN2A/GluN2B subunit ratio as a common synaptic trait in rat and primate models of LIDs as well as in dyskinetic PD patients; and (ii) validating the potential therapeutic effect of a cell-permeable peptide (CPP) interfering with GluN2A synaptic localization on the dyskinetic behavior of these experimental models of LIDs. Here we demonstrate an altered ratio of synaptic GluN2A/GluN2B-containing NMDA receptors in the striatum of leyodopa-treated dyskinetic rats and monkeys as well as in post-mortem tissue from dyskinetic PD patients. The modulation of synaptic NMDA receptor composition by a cell permeable peptide interfering with GluN2A subunit interaction with the scaffolding protein postsynaptic density protein 95 (PSD-95) leads to a reduction in the dyskinetic motor behavior in the two animal models of LIDs. Our results indicate that targeting synaptic NMDA receptor subunit composition may represent an intriguing therapeutic approach aimed at ameliorating levodopa motor side effects.
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