Abstract
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 levodopa-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.
Highlights
Glutamatergic transmission is greatly involved in the pathophysiology of Parkinson’s disease (PD) and in levodopa (L-DOPA)-induced dyskinesias (LIDs; Calabresi et al, 2010)
Our results demonstrate that a single intrastriatal injection of a peptide (TAT2A) capable of reducing synaptic accumulation of GluN2A-containing N-methyl-D-aspartate receptors (NMDARs) leads to a dose-dependent decrease of abnormal involuntary movements (AIMs) in L-DOPA-treated dyskinetic rats
Systemic administration of targeting GluN2A/PSD-95 interaction (TAT2A) peptide to MPTP-treated monkey with established Levodopa-induced dyskinesias (LIDs) determined a dose-dependent reduction of dyskinetic behavior comparable to what was observed in the rat 6-OHDA model
Summary
Glutamatergic transmission is greatly involved in the pathophysiology of Parkinson’s disease (PD) and in levodopa (L-DOPA)-induced dyskinesias (LIDs; Calabresi et al, 2010). Prevention of the aberrant NMDAR GluN2A/GluN2B subunit ratio at striatal excitatory synapses by concomitant chronic administration of L-DOPA and TAT2A, a cell-permeable peptide (CPP) interfering with the interaction between GluN2A and the scaffolding protein postsynaptic density protein 95 (PSD-95), is sufficient to significantly reduce the onset of LIDs in parkinsonian rats (Gardoni et al, 2012). Such CPP approach appears as a promising putative anti-dyskinetic treatment in PD. In this work: (i) we evaluated NMDAR subunit composition at striatal synapses of parkinsonian and dyskinetic rats, monkeys and PD patients; and (ii) we explored the potential therapeutic effect of TAT2A administration to rats and monkeys with established and consolidated dyskinesia
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