Eltoprazine counteracts l-DOPA-induced dyskinesias in Parkinson’s disease: a dose-finding study

Svenningsson, Per; Rosenblad, Carl; Arvidsson, Karolina af Edholm; Wictorin, Klas; Keywood, Charlotte; Shankar, Bavani; Lowe, David; Björklund, Anders; Widner, Håkan

doi:10.1093/brain/awu409

Cited by 143 publications

(70 citation statements)

References 34 publications

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“…Our observation that evoked glutamate release is reduced in p11KO mice provides additional support for a blunted glutamatergic neurotransmission in these mice. Because both 5-HT 1A/B R agonists and mGluR5 antagonists have shown antidyskinetic properties in PD patients with LIDs (22,23), it will be important to further delineate the pathways whereby p11 influences serotonergic and glutamatergic mechanisms underlying LIDs.…”

Section: Discussionmentioning

confidence: 99%

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: Discussionmentioning

confidence: 99%

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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“…Indeed, silencing of serotonin neuron activity by 5-HT1 receptor agonists has been shown to produce near-complete suppression of LID in experimental models of PD [1,4,7,9,12,22]. Most interestingly, eltoprazine was recently shown to produce significant reduction of LID in dyskinetic patients [11]. However, although in the Svenningsson study no exacerbation of the PD motor disability was found after eltoprazine administration, several preclinical and clinical studies reported a reduction of the therapeutic effects of l-DOPA and induction of serotonin syndrome after 5-HT1 receptor activation [6,7,14], raising concerns for clinical feasibility of this approach to counteract dyskinesia.…”

Section: Discussionmentioning

confidence: 99%

“…Conversely, in a situation of advanced PD stage, when most of DA neurons have degenerated, DA is released via serotonergic neurons in a pulsatile, non-physiological manner, leading to abnormal stimulation of the supersensitive post-synaptic striatal DA receptors, and development of dyskinesia [1,[3][4][5]. Accordingly, the use of serotonin 5-HT1 receptor agonists to dampen serotonergic neuron activity, and in turn DA release, is effective in reducing LID in both pre-clinical and clinical studies [4][5][6][7][8][9][10][11]. http However, administration of 5-HT1 receptor agonists to dyskinetic animals and patients is associated with worsening of PD symptoms [7,[12][13][14].…”

Section: Introductionmentioning

confidence: 99%

Effect of selective and non-selective serotonin receptor activation on l-DOPA-induced therapeutic efficacy and dyskinesia in parkinsonian rats

Tronci

Fidalgo

Stancampiano

et al. 2015

Behavioural Brain Research

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“…12,28 In humans, a recent clinical and PET imaging study from our group showed that buspirone, a 5-HT1a partial agonist, when administered acutely prior to levodopa in patients with PD with LIDs, is able to normalize levodopa-derived levels of synaptic dopamine and to alleviate dyskinesias. 12 Similarly, a recent phase I/IIa clinical trial in patients with PD 29 confirmed antidyskinetic effects of the 5-HT1a/5-HT1b partial agonist eltoprazine following the promising results of the same drug in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-treated macaques. 12 Taken together, these studies suggest that the development of LIDs is dependent on compromised dopaminergic function and on aberrant serotonergic function in the striatum.…”

mentioning

confidence: 90%

Serotonin-to-dopamine transporter ratios in Parkinson disease

et al. 2016

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Objective: To investigate whether a serotonin-to-dopamine terminal ratio is related to the appearance of dyskinesias in patients with Parkinson disease (PD).Methods: Twenty-eight patients with idiopathic PD (17 with levodopa-induced dyskinesias [LIDs], 11 without dyskinesias) and 12 age-matched healthy controls were studied with PET and 5[11 C]-3-amino-4-(2-dimethylaminomethylphenyl-sulfanyl)-benzonitrile ( 11 C-DASB) and with SPECT and [ 123 I]N-w-fluoropropyl-2b-carbomethoxy-3b-(4-iodophenyl)nortropane ( 123 I-ioflupane), which are in vivo specific markers of the serotonin and dopamine transporters' availability, respectively. We have employed a simplified reference tissue model for the quantification of 11 C-DASB, whereas a semiquantification approach was used for 123 I-ioflupane data. We calculated 11 C-DASB binding to 123 I-ioflupane uptake ratios for the caudate and the putamen.Results: Patients with PD showed striatal decreases in 11 C-DASB binding potential (p , 0.01) and in 123 I-ioflupane mean uptake (p , 0.001) compared to controls. The mean 11 C-DASB binding to 123 I-ioflupane uptake ratio in the putamen was 0.779 (increased by 75.8% of the controls' mean) for the nondyskinetic group and 0.901 (increased by 103.4% of the controls' mean) for the patients with dyskinesias. There was a statistically significant difference (p , 0.001) in 11 C-DASB binding to 123 I-ioflupane uptake ratio in the putamen between the group of patients with and without dyskinesias. Higher 11 C-DASB to 123 I-ioflupane binding ratios correlated with longer disease duration for the 28 patients with PD (r 5 0.52; p , 0.01).Conclusions: Serotonin-to-dopamine transporter binding ratio increases as PD progresses and patients experience LIDs. Our findings suggest that, when the dopaminergic innervation in the striatum is critically low, the serotonergic system plays an important role in development of LIDs. Studies in the animal model of Parkinson disease (PD)1 as well as in humans 2-4 have indicated that degeneration of dopaminergic presynaptic terminals in the striatum is critical in the development of L-dopa-induced dyskinesias (LIDs). Due to the progressive degeneration, striatal dopaminergic terminals lose their dopamine storage capacity and the ability to maintain a stable dopamine release rate in the synapse. 5 Serotonergic terminals have been found capable of converting exogenous levodopa into dopamine, store it in synaptic vesicles, and release it in an activity-dependent manner. [6][7][8][9] The above studies propose that serotonergic terminals in the degenerating striatum are responsible for mishandling exogenous levodopa and exacerbating dyskinesia in the animal model 10-12 and PD.13 Accordingly, the presence of dyskinesia could be a reflection of serotonergic over

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Eltoprazine counteracts l-DOPA-induced dyskinesias in Parkinson’s disease: a dose-finding study

Cited by 143 publications

References 34 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

Effect of selective and non-selective serotonin receptor activation on l-DOPA-induced therapeutic efficacy and dyskinesia in parkinsonian rats

Serotonin-to-dopamine transporter ratios in Parkinson disease

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