Alterations of striatal NMDA receptor subunits associated with the development of dyskinesia in the MPTP-lesioned primate model of Parkinson's disease

Hallett, Peter; Dunah, Anthone W.; Ravenscroft, Paula; Zhou, Shaobo; Bézard, Erwan; Crossman, Alan R.; Brotchie, Jonathan M.; Standaert, David G.

doi:10.1016/j.neuropharm.2004.11.008

Cited by 176 publications

(128 citation statements)

References 42 publications

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“…The subcellular organization as well as the functional interactions of glutamate receptors (GluRs) within the striatum appears to be crucial in the pathogenesis of PD as well as in the development of L-DOPA-induced dyskinesia (Hallett et al, 2005). NMDA receptor antagonists exert a beneficial effect in experimental models of PD (Nash et al, 2000;Loschmann et al, 2004), and they are also effective in blocking the development of L-DOPA-induced dyskinesias (Hadj Tahar et al, 2004;Wessell et al, 2004).…”

Section: Introductionmentioning

confidence: 99%

A Critical Interaction between NR2B and MAGUK in l-DOPA Induced Dyskinesia

Gardoni¹,

Picconi²,

Ghiglieri³

et al. 2006

J. Neurosci.

243

192

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Abnormal function of NMDA receptor has been suggested to be correlated with the pathogenesis of Parkinson's disease (PD) as well as with the development of L-3,4-dihydroxyphenylalanine (L-DOPA)-induced dyskinesia. Here we show that NMDA receptor NR2 subunits display specific alterations of their subcellular distribution in striata from unilateral 6-hydroxydopamine-lesioned, L-DOPA-treated dyskinetic, and L-DOPA-treated nondyskinetic rats. Dyskinetic animals have significantly higher levels of NR2A subunit in the postsynaptic compartment than all other experimental groups, whereas NR2B subunit shows a significant reduction in both dopaminedenervated and dyskinetic rats. These events are paralleled by profound modifications of NMDA receptor NR2B subunit association with interacting elements, i.e., members of the membrane-associated guanylate kinase (MAGUK) protein family postsynaptic density-95, synapse-associated protein-97 and synapse-associated protein-102. Treatment of nondyskinetic animals with a synthetic peptide (TAT2B) able to affect NR2B binding to MAGUK proteins as well as synaptic localization of this subunit in nondyskinetic rats was sufficient to induce a shift of treated rats toward a dyskinetic motor behavior. These data indicate abnormal NR2B redistribution between synaptic and extrasynaptic membranes as an important molecular disturbance of the glutamatergic synapse involved in L-DOPA-induced dyskinesia.

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Section: Introductionmentioning

confidence: 99%

A Critical Interaction between NR2B and MAGUK in l-DOPA Induced Dyskinesia

Gardoni¹,

Picconi²,

Ghiglieri³

et al. 2006

J. Neurosci.

243

192

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“…Excitotoxicity has been implicated in the pathophysiology of various human brain disorders, including Alzheimer disease [9,10], Parkinson disease [11], Huntington disease [12], schizophrenia [13], and bipolar disorder [14][15][16]. Studies have demonstrated increased concentrations of glutamate and reduced levels of NMDA receptor (NR) subunits in the brain of some of these patients.…”

Section: Introductionmentioning

confidence: 99%

Chronic NMDA Administration Increases Neuroinflammatory Markers in Rat Frontal Cortex: Cross-Talk Between Excitotoxicity and Neuroinflammation

et al. 2008

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Chronic N-Methyl-D-aspartate (NMDA) administration, a model of excitotoxicity, and chronic intracerebroventricular lipopolysaccharide infusion, a model of neuroinflammation, are reported to upregulate arachidonic acid incorporation and turnover in rat brain phospholipids as well as enzymes involved in arachidonic acid metabolism. This suggests cross-talk between signaling pathways of excitotoxicity and of neuroinflammation, involving arachidonic acid. To test whether chronic NMDA administrations to rats can upregulate brain markers of neuroinflammation, NMDA (25 mg/kg i.p.) or vehicle (1 ml saline/kg i.p.) was administered daily to adult male rats for 21 days. Protein and mRNA levels of cytokines and other inflammatory markers were measured in the frontal cortex using immunoblot and real-time PCR. Compared with chronic vehicle, chronic NMDA significantly increased protein and mRNA levels of interleukin-1beta, tumor necrosis factor alpha, glial fibrillary acidic protein and inducible nitric oxide synthase. Chronic NMDA receptor overactivation results in increased levels of neuroinflammatory markers in the rat frontal cortex, consistent with cross-talk between excitotoxicity and neuroinflammation. As both processes have been reported in a number of human brain diseases, NMDA receptor inhibitors might be of use in treating neuroinflammation in these diseases.

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“…Despite these drawbacks, L-DOPA is still the mainstay of PD treatment for its unsurpassed antiparkinsonian efficacy. Studies in animal models of PD suggest that dyskinesias are associated with enhanced G protein-mediated signaling at dopamine receptors (17-23) potentially leading to changes in gene expression and uncontrolled neuronal excitability (21,(24)(25)(26)(27)(28). Therefore, PD therapy strategies that moderate G protein signaling and neuronal excitability while maintaining normal movement may be an ideal way to eliminate DA receptor-associated dyskinesias.…”

mentioning

confidence: 99%

“…Therefore, PD therapy strategies that moderate G protein signaling and neuronal excitability while maintaining normal movement may be an ideal way to eliminate DA receptor-associated dyskinesias. To moderate this uncontrolled signaling or neuronal excitability, several approaches have been explored such as reducing D1R surface expression (29, 30), dampening overactive intracellular signaling (20,23,31,32), and inhibiting A2A (33, 34), mGluR5 (35-37) or NMDA receptors (24,25,(38)(39)(40). Although these targets have clinical potential, several drugs to these targets have either failed clinical trials or have the potential to affect other key CNS physiological processes.…”

mentioning

confidence: 99%

Targeting β-arrestin2 in the treatment ofl-DOPA–induced dyskinesia in Parkinson’s disease

Urs¹,

Bido

Peterson³

et al. 2015

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

105

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Parkinson's disease (PD) is characterized by severe locomotor deficits and is commonly treated with the dopamine (DA) precursor L-3,4-dihydroxyphenylalanine (L-DOPA), but its prolonged use causes dyskinesias referred to as L-DOPA-induced dyskinesias (LIDs). Recent studies in animal models of PD have suggested that dyskinesias are associated with the overactivation of G proteinmediated signaling through DA receptors. β-Arrestins desensitize G protein signaling at DA receptors (D1R and D2R) in addition to activating their own G protein-independent signaling events, which have been shown to mediate locomotion. Therefore, targeting β-arrestins in PD L-DOPA therapy might prove to be a desirable approach. Here we show in a bilateral DA-depletion mouse model of Parkinson's symptoms that genetic deletion of β-arrestin2 significantly limits the beneficial locomotor effects while markedly enhancing the dyskinesia-like effects of acute or chronic L-DOPA treatment. Viral rescue or overexpression of β-arrestin2 in knockout or control mice either reverses or protects against LIDs and its key biochemical markers. In other more conventional animal models of DA neuron loss and PD, such as 6-hydroxydopamine-treated mice or rats and 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-treated nonhuman primates, β-arrestin2 overexpression significantly reduced dyskinesias while maintaining the therapeutic effect of L-DOPA. Considerable efforts are being spent in the pharmaceutical industry to identify therapeutic approaches to block LIDs in patients with PD. Our results point to a potential therapeutic approach, whereby development of either a genetic or pharmacological intervention to enhance β-arrestin2-or limit G protein-dependent D1/D2R signaling could represent a more mechanistically informed strategy.is a major catecholamine neurotransmitter that is released by midbrain DA neurons. DA activates G protein-coupled receptors (GPCRs), which belong to the dopamine D1 (D1R and D5R) or D2 (D2R, D3R, and D4R) class of DA receptors that are known to signal via G protein-dependent mechanisms (1, 2). However, recent studies have shown that in addition to G protein-mediated signaling, many GPCRs, including DA receptors, signal through beta-arrestin 1 and 2 (βarr1 and βarr2)-dependent mechanisms (3, 4). The two isoforms of β-arrestin, β-arrestin1 (βarr1) and β-arrestin2 (βarr2) are widely coexpressed in the brain (5, 6). β-Arrestins were originally appreciated for their ability to desensitize (i.e., turn off) GPCR signaling in a GPCR kinase (GRK)-dependent manner (7,8). Binding of β-arrestin to the GPCR sterically hinders G protein binding and in most instances initiates receptor endocytosis via interactions with adaptor protein complex-2 (AP-2) and clathrin (9-11). It is now appreciated that β-arrestins regulate physiology and behaviors independently of G protein signaling through their ability to scaffold multiple intracellular signaling molecules such as kinases and phosphatases (3,4,12,13). Studies from our laboratory have shown that through ...

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Alterations of striatal NMDA receptor subunits associated with the development of dyskinesia in the MPTP-lesioned primate model of Parkinson's disease

Cited by 176 publications

References 42 publications

A Critical Interaction between NR2B and MAGUK in l-DOPA Induced Dyskinesia

A Critical Interaction between NR2B and MAGUK in l-DOPA Induced Dyskinesia

Chronic NMDA Administration Increases Neuroinflammatory Markers in Rat Frontal Cortex: Cross-Talk Between Excitotoxicity and Neuroinflammation

Targeting β-arrestin2 in the treatment ofl-DOPA–induced dyskinesia in Parkinson’s disease

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