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Dyskinesia in Parkinson's Disease: New Mechanisms and Molecular Targets

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A special issue of Cells (ISSN 2073-4409). This special issue belongs to the section "Cells of the Nervous System".

Deadline for manuscript submissions: closed (10 March 2023) | Viewed by 15186

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Special Issue Editors

Prof. Dr. Manolo Carta

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Guest Editor

Department of Biomedical Sciences, Section of Physiology, Cagliari University, Cagliari, Italy
Interests: Parkinson’s disease; dyskinesia; dopamine; serotonin; neurosteroids

Prof. Dr. Barbara Picconi

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Guest Editor

Department of Human Science and Promotion of Quality of Life, Telematic University San Raffaele, Rome, Italy
Interests: Parkinson’s disease; dyskinesia; electrophysiology; synaptic plasticity

Special Issue Information

Dear Colleagues,

L-DOPA still represents the most effective medication for alleviating motor symptoms of Parkinson’s disease. However, as the disease progresses and neuronal degeneration gets worse, the efficacy of L-DOPA is progressively reduced and motor complications, particularly L-DOPA-induced dyskinesia (LID), appear, complicating disease management.

A great contribution to the understanding of the mechanisms underlying LID has been achieved by the introduction of validated animal models of dyskinesia, mainly rodents and non-human primates. In this Special Issue, we will focus on peak-dose dyskinesia, the most troublesome type of dyskinesia, which can be reliably mimicked in such animal models.

This work aims at providing an updated overview on the mechanisms, circuits, and therapeutic approaches in dyskinesia by collecting a series of contributions from recognized international experts in this field working on either clinical or preclinical aspects.

Prof. Dr. Manolo Carta
Prof. Dr. Barbara Picconi
Guest Editors

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Keywords

Parkinson’s disease
L-DOPA-induced dyskinesia
basal ganglia circuits
motor impairments
striatal synaptic alterations

Published Papers (5 papers)

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Research

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16 pages, 5870 KiB

Open AccessArticle

Ropinirole Cotreatment Prevents Perivascular Glial Recruitment in a Rat Model of L-DOPA-Induced Dyskinesia

by Osama F. Elabi, Elena Espa, Katrine Skovgård, Silvia Fanni and Maria Angela Cenci

Cells 2023, 12(14), 1859; https://doi.org/10.3390/cells12141859 - 14 Jul 2023

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Abstract

Dopamine replacement therapy for Parkinson’s disease is achieved using L-DOPA or dopamine D2/3 agonists, such as ropinirole. Here, we compare the effects of L-DOPA and ropinirole, alone or in combination, on patterns of glial and microvascular reactivity in the striatum. Rats with unilateral 6-hydroxydopamine lesions were treated with therapeutic-like doses of L-DOPA (6 mg/kg), an equipotent L-DOPA-ropinirole combination (L-DOPA 3 mg/kg plus ropinirole 0.5 mg/kg), or ropinirole alone. Immunohistochemistry was used to examine the reactivity of microglia (ionized calcium-binding adapter molecule 1, IBA-1) and astroglia (glial fibrillary acidic protein, GFAP), as well as blood vessel density (rat endothelial cell antigen 1, RECA-1) and albumin extravasation. L-DOPA monotreatment and L-DOPA–ropinirole cotreatment induced moderate-severe dyskinesia, whereas ropinirole alone had negligible dyskinetic effects. Despite similar dyskinesia severity, striking differences in perivascular microglia and astroglial reactivity were found between animals treated with L-DOPA vs. L-DOPA–ropinirole. The former exhibited a marked upregulation of perivascular IBA-1 cells (in part CD68-positive) and IBA-1–RECA-1 contact points, along with an increased microvessel density and strong perivascular GFAP expression. None of these markers were significantly upregulated in animals treated with L-DOPA–ropinirole or ropinirole alone. In summary, although ropinirole cotreatment does not prevent L-DOPA-induced dyskinesia, it protects from maladaptive gliovascular changes otherwise associated with this disorder, with potential long-term benefits to striatal tissue homeostasis. Full article

(This article belongs to the Special Issue Dyskinesia in Parkinson's Disease: New Mechanisms and Molecular Targets)

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19 pages, 3572 KiB

Open AccessArticle

Intermittent Theta Burst Stimulation Improves Motor and Behavioral Dysfunction through Modulation of NMDA Receptor Subunit Composition in Experimental Model of Parkinson’s Disease

by Milica Zeljkovic Jovanovic, Jelena Stanojevic, Ivana Stevanovic, Andjela Stekic, Samuel J. Bolland, Nebojsa Jasnic, Milica Ninkovic, Marina Zaric Kontic, Tihomir V. Ilic, Jennifer Rodger, Nadezda Nedeljkovic and Milorad Dragic

Cells 2023, 12(11), 1525; https://doi.org/10.3390/cells12111525 - 01 Jun 2023

Cited by 3 | Viewed by 1943

Abstract

Parkinson’s disease (PD) is the second most common neurodegenerative disorder characterized by the progressive degeneration of the dopaminergic system, leading to a variety of motor and nonmotor symptoms. The currently available symptomatic therapy loses efficacy over time, indicating the need for new therapeutic approaches. Repetitive transcranial magnetic stimulation (rTMS) has emerged as one of the potential candidates for PD therapy. Intermittent theta burst stimulation (iTBS), an excitatory protocol of rTMS, has been shown to be beneficial in several animal models of neurodegeneration, including PD. The aim of this study was to investigate the effects of prolonged iTBS on motor performance and behavior and the possible association with changes in the NMDAR subunit composition in the 6-hydroxydopamine (6-OHDA)-induced experimental model of PD. Two-month-old male Wistar rats were divided into four groups: controls, 6-OHDA rats, 6-OHDA + iTBS protocol (two times/day/three weeks) and the sham group. The therapeutic effect of iTBS was evaluated by examining motor coordination, balance, spontaneous forelimb use, exploratory behavior, anxiety-like, depressive/anhedonic-like behavior and short-term memory, histopathological changes and changes at the molecular level. We demonstrated the positive effects of iTBS at both motor and behavioral levels. In addition, the beneficial effects were reflected in reduced degeneration of dopaminergic neurons and a subsequent increase in the level of DA in the caudoputamen. Finally, iTBS altered protein expression and NMDAR subunit composition, suggesting a sustained effect. Applied early in the disease course, the iTBS protocol may be a promising candidate for early-stage PD therapy, affecting motor and nonmotor deficits. Full article

(This article belongs to the Special Issue Dyskinesia in Parkinson's Disease: New Mechanisms and Molecular Targets)

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13 pages, 11949 KiB

Open AccessArticle

Broad Serotonergic Actions of Vortioxetine as a Promising Avenue for the Treatment of L-DOPA-Induced Dyskinesia

by Carla Budrow, Kayla Elder, Michael Coyle, Ashley Centner, Natalie Lipari, Sophie Cohen, John Glinski, N’Senga Kinzonzi, Emily Wheelis, Grace McManus, Fredric Manfredsson and Christopher Bishop

Cells 2023, 12(6), 837; https://doi.org/10.3390/cells12060837 - 08 Mar 2023

Cited by 2 | Viewed by 1966

Abstract

Parkinson’s Disease (PD) is a neurodegenerative disorder characterized by motor symptoms that result from loss of nigrostriatal dopamine (DA) cells. While L-DOPA provides symptom alleviation, its chronic use often results in the development of L-DOPA-induced dyskinesia (LID). Evidence suggests that neuroplasticity within the serotonin (5-HT) system contributes to LID onset, persistence, and severity. This has been supported by research showing 5-HT compounds targeting 5-HT_1A/1B receptors and/or the 5-HT transporter (SERT) can reduce LID. Recently, vortioxetine, a multimodal 5-HT compound developed for depression, demonstrated acute anti-dyskinetic effects. However, the durability and underlying pharmacology of vortioxetine’s anti-dyskinetic actions have yet to be delineated. To address these gaps, we used hemiparkinsonian rats in Experiment 1, examining the effects of sub-chronic vortioxetine on established LID and motor performance. In Experiment 2, we applied the 5-HT_1A antagonist WAY-100635 or 5-HT_1B antagonist SB-224289 in conjunction with L-DOPA and vortioxetine to determine the contributions of each receptor to vortioxetine’s effects. The results revealed that vortioxetine consistently and dose-dependently attenuated LID while independently, 5-HT_1A and 5-HT_1B receptors each partially reversed vortioxetine’s effects. Such findings further support the promise of pharmacological strategies, such as vortioxetine, and indicate that broad 5-HT actions may provide durable responses without significant side effects. Full article

(This article belongs to the Special Issue Dyskinesia in Parkinson's Disease: New Mechanisms and Molecular Targets)

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10 pages, 1361 KiB

Open AccessArticle

AV-101, a Pro-Drug Antagonist at the NMDA Receptor Glycine Site, Reduces L-Dopa Induced Dyskinesias in MPTP Monkeys

by Mélanie Bourque, Laurent Grégoire, Waseema Patel, David Dickens, Ralph Snodgrass and Thérèse Di Paolo

Cells 2022, 11(22), 3530; https://doi.org/10.3390/cells11223530 - 08 Nov 2022

Cited by 4 | Viewed by 2401

Abstract

N-methyl-D-aspartate (NMDA) receptors have been implicated in L-Dopa-induced dyskinesias (LID) in Parkinson’s disease patients, but the use of antagonists that directly inhibit this receptor is associated with severe side effects. L-4-chlorokynurenine (4-Cl-KYN or AV-101) is a pro-drug of 7-chlorokynurenic acid (7-Cl-KYNA), a potent and specific antagonist of the glycine (GlyB) co-agonist site of NMDA receptors. The 7-Cl-KYNA has limited ability to cross the blood–brain barrier, whereas AV-101 readily accesses the brain. We investigated if AV-101 reduces LID in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-lesioned monkeys while maintaining the antiparkinsonian activity of L-Dopa. A first pilot study using three dyskinetic MPTP monkeys showed that acute AV-101 treatment (250 and 450 mg/kg) reduced LID and maintained the antiparkinsonian activity of L-Dopa. The main study using six additional dyskinetic MPTP monkeys showed that repeated AV-101 treatment (250 mg/kg, b.i.d. for 4 consecutive days) maintained their L-Dopa antiparkinsonian response. We measured significantly less LID when AV-101 was combined with L-Dopa treatment. AV-101 alone or with L-Dopa had no non-motor adverse effects in MPTP monkeys. Our study showed antidyskinetic activity of AV-101 in MPTP monkeys was comparable to amantadine tested previously in our laboratory in this model. We observed no adverse effects with AV-101, which is an improvement over amantadine, with its known side effects. Full article

(This article belongs to the Special Issue Dyskinesia in Parkinson's Disease: New Mechanisms and Molecular Targets)

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Review

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26 pages, 2161 KiB

Open AccessReview

Levodopa-Induced Dyskinesia in Parkinson’s Disease: Pathogenesis and Emerging Treatment Strategies

by Destany K. Kwon, Mohit Kwatra, Jing Wang and Han Seok Ko

Cells 2022, 11(23), 3736; https://doi.org/10.3390/cells11233736 - 23 Nov 2022

Cited by 24 | Viewed by 7095

Abstract

The most commonly used treatment for Parkinson’s disease (PD) is levodopa, prescribed in conjunction with carbidopa. Virtually all patients with PD undergo dopamine replacement therapy using levodopa during the course of the disease’s progression. However, despite the fact that levodopa is the “gold standard” in PD treatments and has the ability to significantly alleviate PD symptoms, it comes with side effects in advanced PD. Levodopa replacement therapy remains the current clinical treatment of choice for Parkinson’s patients, but approximately 80% of the treated PD patients develop levodopa-induced dyskinesia (LID) in the advanced stages of the disease. A better understanding of the pathological mechanisms of LID and possible means of improvement would significantly improve the outcome of PD patients, reduce the complexity of medication use, and lower adverse effects, thus, improving the quality of life of patients and prolonging their life cycle. This review assesses the recent advancements in understanding the underlying mechanisms of LID and the therapeutic management options available after the emergence of LID in patients. We summarized the pathogenesis and the new treatments for LID-related PD and concluded that targeting pathways other than the dopaminergic pathway to treat LID has become a new possibility, and, currently, amantadine, drugs targeting 5-hydroxytryptamine receptors, and surgery for PD can target the Parkinson’s symptoms caused by LID. Full article

(This article belongs to the Special Issue Dyskinesia in Parkinson's Disease: New Mechanisms and Molecular Targets)

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