Targeting NR2A-containing NMDA receptors reduces L-DOPA-induced dyskinesias

doi:10.1016/j.neurobiolaging.2011.06.019

Neurobiology of Aging

Volume 33, Issue 9, September 2012, Pages 2138-2144

https://doi.org/10.1016/j.neurobiolaging.2011.06.019 Get rights and content

Abstract

Levodopa (L-DOPA)-induced dyskinesias represent the main side effect of the therapeutic strategy clinically used in Parkinson's disease (PD) treatment. The first beneficial “honeymoon” phase of L-DOPA therapy is followed by a phase of deterioration in which L-DOPA administration causes motor fluctuations in the drug efficacy (“on-off” state) and dyskinesias. Alterations of the composition and function of N-methyl-D-aspartate (NMDA) receptor represent one of the main causes for the striatal synaptic changes described in experimental model of dyskinesias. In the present study, the modulation of the composition of synaptic NMDA receptor by using a cell-permeable peptide targeting NR2A subunit during the development of dyskinesias led to a reduction of the percentage of parkinsonian rats developing dyskinetic movements.

Introduction

Levodopa (L-DOPA)-induced dyskinesias represent the main side effect of the therapeutic strategy clinically used in Parkinson's disease (PD) treatment (Calabresi et al., 2010). Although its discovery constitutes a major milestone in the modern neuropharmacology (Birkmayer and Hornykiewicz, 1961, Mercuri and Bernardi, 2005), the beneficial “honeymoon” phase of the treatment is followed by the appearance of motor fluctuations in the drug efficacy (“on-off” state) and dyskinesias (Calabresi et al., 2010, Cotzias et al., 1969).

Parkinsonian-like rats, obtained by unilateral injection of 6-hydroxydopamine (6-OHDA) into the medial forebrain bundle (MFB) (Schwarting and Huston, 1996), chronically treated with L-DOPA, experience a progressive shortening of the beneficial motor response to each drug dose developing abnormal involuntary movements (AIMs) (Cenci et al., 1998, Lee et al., 2003, Picconi et al., 2003). These effects are similar to the L-DOPA-induced fluctuations seen in PD patients, and develop AIMs (Cenci et al., 1998, Lee et al., 2003, Picconi et al., 2003). At a cellular level, PD rats lose their capability to display any form of striatal synaptic plasticity (Calabresi et al., 1992, Centonze et al., 1999) and after chronic L-DOPA treatment the development of AIMs involves an aberrant form of NMDA-dependent plasticity (Picconi et al., 2003). Accordingly, alteration of the molecular composition of NMDA receptor complex is considered the main responsible for the functional changes recently described in the striatum of experimental PD (Paillé et al., 2010, Picconi et al., 2004) as well as in animals developing AIMs (Gardoni et al., 2006, Hallett et al., 2005). These events are characterized by increased level of synaptic NR2A subunits and decreased level of synaptic NR2B subunits (Gardoni et al., 2006). We previously showed that intrastriatal treatment with a cell permeable peptide uncoupling NR2B subunit interaction with the postsynaptic density (PSD)-membrane-associated guanylate kinases (MAGUKs) proteins (TAT2B) was sufficient to increase NR2A/NR2B ratio at synaptic sites and to induce AIMs in parkinsonian rats that did not yet develop motor complications (Gardoni et al., 2006). All together, these results indicate that an alteration of synaptic NR2A/NR2B containing NMDA receptor may represent a major causal factor in the complex modifications taking place at corticostriatal glutamatergic synapses during dyskinesias (Gardoni et al., 2006).

Here we show that a concomitant systemic treatment with L-DOPA and TAT2A peptide, reducing the synaptic localization of the NR2A subunit (Bard et al., 2010, Gardoni et al., 2009, Lau and Zukin, 2007), is sufficient to decrease the percentage of parkinsonian rats developing AIMs.

Section snippets

Animals

Adult male Wistar rats (150–250 g) were used for the study. All experiments were approved by the Oregon Health & Science University (OHSU) Institutional Animal Care and Use Committee and by the Italian Health Ministry.

6-OHDA nigrostriatal lesion

Rats (n = 110) were unilaterally lesioned with 6-OHDA (12 μg/4 μL) injected into the medial forebrain bundle (MFB), as previously reported (Picconi et al., 2008). Fifteen days later, the rats were tested with 0.05 mg/kg subcutaneous injection of apomorphine, and the contralateral

Results

We used systemic injection of a cell-permeable TAT peptide fused to the last C-terminal 9 amino acids of the NR2A subunit of NMDA receptor (TAT2A) (Aarts et al., 2002, Gardoni et al., 2009, Lim et al., 2003) to obtain a chronic uncoupling of the PSD-MAGUKs/NR2A complex. Treatment with TAT2A(-SDV) peptide, lacking the relevant interaction domain with PSD-95, was performed as control. PD rats were treated for 3 weeks with L-DOPA plus TAT2A or with L-DOPA plus TAT2A(-SDV). After the behavioral

Discussion

Here we demonstrate that prevention of aberrant synaptic localization of NR2A-containing NMDA receptor is sufficient to determine a significant reduction of the onset of L-DOPA-induced dyskinesias in experimental parkinsonism in rats.

We previously showed that corticostriatal connections undergo adaptive changes after chronic L-DOPA therapy (Gardoni et al., 2006, Picconi et al., 2003). From a molecular point of view, L-DOPA-treated dyskinetic rats are characterized by increased levels of NR2A

Disclosure statement

Dr. Calabresi serves as an editorial board member of Lancet Neurology, the Journal of Neuroscience, Movement Disorders, and Synapse; receives research support from Bayer Schering, Biogen, Boehringer Ingelheim, Eisai, Novartis, Lundbeck, Sanofi-Aventis, Sigma-Tau, and UCB Pharma; and from Ricerca Corrente IRCCS, Ricerca Finalizzata IRCCS (European Community, Grants SYNSCAFF and REPLACES), the Italian Minister of Health and AIFA (Agenzia Italiana del Farmaco). All authors report no biomedical

Acknowledgements

We thank Dr. Vincenza Bagetta for her support in the behavioral experiments and in the critical revision of the manuscript. This work was supported by the European Community FP7-Thematic priority HEALTH contract number 222918 (REPLACES) (PC and MDL) and contract number 217902 (cPADS) (MDL), by the Ministry of Health Grants Progetto-Strategico (2007) (BP, MDL, and PC), Progetti-Finalizzati (2006–2008) (BP and PC), Progetto “Giovani-Ricercatori (2008)” (BP and FG) and Cariplo Foundation contract

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It is well established that dysregulated striatal overactivity by glutamate in LIDs is partly due to enhanced levels of NMDARs. In effect, elevated phosphorylation of NMDAR subunits, resulting from D1Rs activation after chronic L-Dopa treatment, causes overstimulation of the signaling pathways, including sequential phosphorylation of secondary messengers (Gardoni et al., 2006; Gardoni et al., 2012; Mellone et al., 2015; Mellone et al., 2019). Amantadine, a non-selective NMDA antagonist, causes an upregulation of brain-derived neurotrophic factor (BDNF) and tyrosine receptor kinase B (TrkB) expression, via the extracellular signal-regulated kinases (ERK) signaling cascade, able to block the phosphorylation of eEF2, which in turn silences BDNF translation (Autry et al., 2011).
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Regular paperTargeting NR2A-containing NMDA receptors reduces L-DOPA-induced dyskinesias

Abstract

Introduction

Section snippets

Animals

6-OHDA nigrostriatal lesion

Results

Discussion

Disclosure statement

Acknowledgements

Lancet Neurol

Neurobiol. Dis

Eur. J. Pharmacol

Neuropharmacology

Neurosci. Biobehav. Rev

Exp. Neurol

Neuropharmacology

Trends Pharmacol. Sci

Neurobiol. Dis

Prog. Neurobiol

Treatment of ischemic brain damage by perturbing NMDA receptor- PSD-95 protein interactions

Science

Dynamic and specific interaction between synaptic NR2-NMDA receptor and PDZ proteins

Proc. Natl. Acad. Sci. U. S. A.

Regular paper
Targeting NR2A-containing NMDA receptors reduces L-DOPA-induced dyskinesias