A mGluR5 antagonist under clinical development improves L-DOPA-induced dyskinesia in parkinsonian rats and monkeys

Rylander, Daniella; Iderberg, Hanna; Li, Qin; Dekundy, Andrzej; Zhang, Jinlan; Li, Hao; Baishen, Ren; Danysz, Wojciech; Bézard, Erwan; Cenci, M. Angela

doi:10.1016/j.nbd.2010.05.001

Cited by 144 publications

(106 citation statements)

References 66 publications

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“…Instead, our combined results indicate that reduced glutamatergic neurotransmission via mGluR5 may underlie the lowered development of AIMs in p11KO and D1R-p11cKO mice. This is consistent with preclinical studies showing that antagonism of mGluR5 counteracts AIMs in both rodent and monkey models of parkinsonism (21). Our observation that evoked glutamate release is reduced in p11KO mice provides additional support for a blunted glutamatergic neurotransmission in these mice.…”

Section: Discussionsupporting

confidence: 90%

p11 modulates L-DOPA therapeutic effects and dyskinesia via distinct cell types in experimental Parkinsonism

Schintu

Zhang

Alvarsson

et al. 2016

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

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The reduced movement repertoire of Parkinson's disease (PD) is mainly due to degeneration of nigrostriatal dopamine neurons. Restoration of dopamine transmission by levodopa (L-DOPA) relieves motor symptoms of PD but often causes disabling dyskinesias. Subchronic L-DOPA increases levels of adaptor protein p11 (S100A10) in dopaminoceptive neurons of the striatum. Using experimental mouse models of Parkinsonism, we report here that global p11 knockout (KO) mice develop fewer jaw tremors in response to tacrine. Following L-DOPA, global p11KO mice show reduced therapeutic responses on rotational motor sensitization, but also develop less dyskinetic side effects. Studies using conditional p11KO mice reveal that distinct cell populations mediate these therapeutic and side effects. Selective deletion of p11 in cholinergic acetyltransferase (ChAT) neurons reduces tacrine-induced tremor. Mice lacking p11 in dopamine D2R-containing neurons have a reduced response to L-DOPA on the therapeutic parameters, but develop dyskinetic side effects. In contrast, mice lacking p11 in dopamine D1R-containing neurons exhibit tremor and rotational responses toward L-DOPA, but develop less dyskinesia. Moreover, coadministration of rapamycin with L-DOPA counteracts L-DOPA-induced dyskinesias in wild-type mice, but not in mice lacking p11 in D1R-containing neurons. 6-OHDA lesioning causes an increase of evoked striatal glutamate release in wild type, but not in global p11KO mice, indicating that altered glutamate neurotransmission could contribute to the reduced L-DOPA responsivity. These data demonstrate that p11 located in ChAT or D2R-containing neurons is involved in regulating therapeutic actions in experimental PD, whereas p11 in D1R-containing neurons underlies the development of L-DOPA-induced dyskinesias. S100A10 | dopamine | 6-hydroxydopamine | tremor | tacrine

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Section: Discussionsupporting

confidence: 90%

p11 modulates L-DOPA therapeutic effects and dyskinesia via distinct cell types in experimental Parkinsonism

Schintu

Zhang

Alvarsson

et al. 2016

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

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“…The improved Horsley-Clarke stereotactic technique was used as previously described to inject, at 2 rostrocaudal levels of the motor striatum (anterior commissural, -1 mm and -5 mm), 100 μl shPSD (n = 4) or GFP (mock; n = 3) LV (25,37,85). Starting at 4 weeks after surgery, animals were repeatedly assayed 2 days apart for behavioral responses to 100% of the tailored oral dose of l-DOPA, alone or in combination with amantadine (20 mg/kg orally) (44). The monkeys' behavior was first recorded in the Off state for 60 minutes in an observation cage (1.1 m × 1.5 m × 1.1 m).…”

Section: Monkey Experimentsmentioning

confidence: 99%

PSD-95 expression controls l-DOPA dyskinesia through dopamine D1 receptor trafficking

Porras¹,

Berthet²,

Dehay³

et al. 2012

J. Clin. Invest.

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117

132

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l-DOPA-induced dyskinesia (LID), a detrimental consequence of dopamine replacement therapy for Parkinson's disease, is associated with an alteration in dopamine D1 receptor (D1R) and glutamate receptor interactions. We hypothesized that the synaptic scaffolding protein PSD-95 plays a pivotal role in this process, as it interacts with D1R, regulates its trafficking and function, and is overexpressed in LID. Here, we demonstrate in rat and macaque models that disrupting the interaction between D1R and PSD-95 in the striatum reduces LID development and severity. Single quantum dot imaging revealed that this benefit was achieved primarily by destabilizing D1R localization, via increased lateral diffusion followed by increased internalization and diminished surface expression. These findings indicate that altering D1R trafficking via synapse-associated scaffolding proteins may be useful in the treatment of dyskinesia in Parkinson's patients. IntroductionIn the striatum, dopamine (DA) terminals from the substantia nigra pars compacta (SNc) converge with glutamatergic signals from the cortex on dendritic spines of striatal medium spiny projecting GABAergic neurons (1, 2). The degeneration of the nigrostriatal pathway in Parkinson's disease (PD) induces complex modifications in both DA and glutamate signaling, leading to significant morphological and functional modifications in the striatal neuronal circuitry (3-5). Chronic DA replacement therapy with l-3,4-dihydroxyphenylalanine (l-DOPA) superimposes upon these DA depletion-induced changes, resulting in debilitating motor complications known as l-DOPAinduced dyskinesia (LID) (6-8). At the molecular level, the subcellular organization of and functional interactions between glutamate and DA receptors within the striatum are crucial both in the pathogenesis of PD (9) and in the development of LID (10, 11). LID has indeed been associated with plastic changes in postsynaptic neuronal targets in the striatum, including elevated extracellular levels of glutamate (12) and DA (13) and abnormal trafficking of DA D1 receptor (D1R) (14, 15) and of NMDA and AMPA glutamate receptor subunits (5,10,16,17). Such exaggerated DA and glutamate receptor expression at the plasma membrane results in abnormal activation of key signaling kinases (18)(19)(20)(21)(22). All these changes point to dysfunctional interactions between DA and glutamate neurotransmission in LID (5,23,24), although the molecular mechanisms remain elusive, despite recent progress (14, 25).The membrane-associated guanylate kinase (MAGUK) proteins, such as postsynaptic density 95 (PSD-95), organize ionotropic glutamate receptors and their associated signaling proteins, regulating the strength of synaptic activity. Interestingly, PSD-95 might also interact with DA D1R (26), thereby potentially regulating DA

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“…However, nAChRs with a novel pharmacological profile were ascribed to serotonin terminals based on transmitter release studies from synaptosomes (Reuben and Clarke, 2000). The relationship between nAChRs and serotonergic terminals warrants clarification in view of recent evidence for the sprouting of these afferents in L-DOPA-induced dyskinesia (Rylander et al, 2010).…”

Section: Nicotinic Acetylcholine Receptor Subtypes In the Striatummentioning

confidence: 99%

α6β2* and α4β2* Nicotinic Acetylcholine Receptors As Drug Targets for Parkinson's Disease

Quik

Wonnacott²

2011

Pharmacol Rev

177

185

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A mGluR5 antagonist under clinical development improves L-DOPA-induced dyskinesia in parkinsonian rats and monkeys

Cited by 144 publications

References 66 publications

p11 modulates L-DOPA therapeutic effects and dyskinesia via distinct cell types in experimental Parkinsonism

p11 modulates L-DOPA therapeutic effects and dyskinesia via distinct cell types in experimental Parkinsonism

PSD-95 expression controls l-DOPA dyskinesia through dopamine D1 receptor trafficking

α6β2* and α4β2* Nicotinic Acetylcholine Receptors As Drug Targets for Parkinson's Disease

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