Cerebellar stimulation prevents Levodopa-induced dyskinesia in mice and normalizes activity in a motor network.
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ABSTRACT:
SUBMITTER: Coutant B
PROVIDER: S-EPMC9184492 | biostudies-literature | 2022 Jun
REPOSITORIES: biostudies-literature
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Cerebellar stimulation prevents Levodopa-induced dyskinesia in mice and normalizes activity in a motor network.
Coutant Bérénice B Frontera Jimena Laura JL Perrin Elodie E Combes Adèle A Tarpin Thibault T Menardy Fabien F Mailhes-Hamon Caroline C Perez Sylvie S Degos Bertrand B Venance Laurent L Léna Clément C Popa Daniela D
Nature communications 20220609 1
Chronic Levodopa therapy, the gold-standard treatment for Parkinson's Disease (PD), leads to the emergence of involuntary movements, called levodopa-induced dyskinesia (LID). Cerebellar stimulation has been shown to decrease LID severity in PD patients. Here, in order to determine how cerebellar stimulation induces LID alleviation, we performed daily short trains of optogenetic stimulations of Purkinje cells (PC) in freely moving LID mice. We demonstrated that these stimulations are sufficient t ...[more]
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Project description:OBJECTIVE:The precise pathogenesis or neural correlates underlying levodopa-induced dyskinesia (LID) remains poorly understood. There is growing evidence of the involvement of the cerebellum in Parkinson's disease (PD). The present study evaluated the role of motor cerebellar connectivity in determining vulnerability to LID. METHODS:We enrolled 25 de novo patients with PD who developed LID within 5 years of levodopa treatment, 26 propensity score-matched PD patients who had not developed LID, and 24 age- and sex-matched healthy controls. We performed a comparative analysis of resting-state functional connectivity (FC) between the motor cerebellum and whole brain between the groups. RESULTS:The patients with PD had increased FC bewteen the motor cerebellum and posterior cortical and cerebellar regions, while no gray matter regions had decreased FC with the motor cerebellum compared to the control participant. The patients with PD who were vulnerable to the development of LID had a significantly higher FC between the motor cerebellum lobule VIIIb and the left inferior frontal gyrus than those who were resistant to LID development. The connectivity of the motor cerebellum and left inferior frontal gyrus was negatively correlated with the latency from PD onset to the occurrence of LID. INTERPRETATION:Increased FC between the motor cerebellum and left inferior frontal gyrus in de novo patients with PD could be an important determinant of vulnerability to LID.
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Project description:BackgroundLevodopa-induced dyskinesias are an often debilitating side effect of levodopa therapy in Parkinson's disease. Although up to 90% of individuals with PD develop this side effect, uniformly effective and well-tolerated antidyskinetic treatment remains a significant unmet need. The pathognomonic loss of striatal dopamine in PD results in dysregulation and disinhibition of striatal CaV1.3 calcium channels, leading to synaptopathology that appears to be involved in levodopa-induced dyskinesias. Although there are clinically available drugs that can inhibit CaV1.3 channels, they are not adequately potent and have only partial and transient impact on levodopa-induced dyskinesias.MethodsTo provide unequivocal target validation, free of pharmacological limitations, we developed a CaV1.3 shRNA to provide high-potency, target-selective, mRNA-level silencing of striatal CaV1.3 channels and examined its ability to impact levodopa-induced dyskinesias in severely parkinsonian rats.ResultsWe demonstrate that vector-mediated silencing of striatal CaV1.3 expression in severely parkinsonian rats prior to the introduction of levodopa can uniformly and completely prevent induction of levodopa-induced dyskinesias, and this antidyskinetic benefit persists long term and with high-dose levodopa. In addition, this approach is capable of ameliorating preexisting severe levodopa-induced dyskinesias. Importantly, motoric responses to low-dose levodopa remained intact in the presence of striatal CaV1.3 silencing, indicating preservation of levodopa benefit without dyskinesia liability.DiscussionThe current data provide some of the most profound antidyskinetic benefit reported to date and suggest that genetic silencing of striatal CaV1.3 channels has the potential to transform treatment of individuals with PD by allowing maintenance of motor benefit of levodopa in the absence of the debilitating levodopa-induced dyskinesia side effect. © 2019 The Authors. Movement Disorders published by Wiley Periodicals, Inc. on behalf of International Parkinson and Movement Disorder Society.
| S-EPMC6563183 | biostudies-literature
Project description:ObjectiveTo compare the efficacy of subthalamic nucleus (STN) and globus pallidus internus (GPi) deep brain stimulation (DBS) on reducing levodopa-induced dyskinesia (LID) in Parkinson's disease, and to explore the potential underlying mechanisms.MethodsWe retrospectively assessed clinical outcomes in 43 patients with preoperative LID who underwent DBS targeting the STN (20/43) or GPi (23/43). The primary clinical outcome was the change from baseline in the Unified Dyskinesia Rating Scale (UDysRS) and secondary outcomes included changes in the total daily levodopa equivalent dose, the drug-off Unified Parkinson Disease Rating Scale Part Ⅲ at the last follow-up (median, 18 months), adverse effects, and programming settings. Correlation analysis was used to find potential associated factors that could be used to predict the efficacy of DBS for dyskinesia management.ResultsCompared to baseline, both the STN group and the GPi group showed significant improvement in LID with 60.73 ± 40.29% (mean ± standard deviation) and 93.78 ± 14.15% improvement, respectively, according to the UDysRS score. Furthermore, GPi-DBS provided greater clinical benefit in the improvement of dyskinesia (P < 0.05) compared to the STN. Compared to the GPi group, the levodopa equivalent dose reduction was greater in the STN group at the last follow-up (43.81% vs. 13.29%, P < 0.05). For the correlation analysis, the improvement in the UDysRS outcomes were significantly associated with a reduction in levodopa equivalent dose in the STN group (r = 0.543, P = 0.013), but not in the GPi group (r = -0.056, P = 0.801).InterpretationBoth STN and GPi-DBS have a beneficial effect on LID but GPi-DBS provided greater anti-dyskinetic effects. Dyskinesia suppression for STN-DBS may depend on the reduction of levodopa equivalent dose. Unlike the STN, GPi-DBS might exert a direct and independent anti-dyskinesia effect.
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Project description:Action selection relies on the coordinated activity of striatal direct and indirect pathway medium spiny neurons (dMSNs and iMSNs, respectively). Loss of dopamine in Parkinson's disease is thought to disrupt this balance. While dopamine replacement with levodopa may restore normal function, the development of involuntary movements (levodopa-induced dyskinesia [LID]) limits therapy. How chronic dopamine loss and replacement with levodopa modulate the firing of identified MSNs in behaving animals is unknown. Using optogenetically labeled striatal single-unit recordings, we assess circuit dysfunction in parkinsonism and LID. Counter to current models, we found that following dopamine depletion, iMSN firing was elevated only during periods of immobility, while dMSN firing was dramatically and persistently reduced. Most notably, we identified a subpopulation of dMSNs with abnormally high levodopa-evoked firing rates, which correlated specifically with dyskinesia. These findings provide key insights into the circuit mechanisms underlying parkinsonism and LID, with implications for developing targeted therapies.
| S-EPMC6407866 | biostudies-literature
Project description:Dopamine replacement by levodopa is the most widely used therapy for Parkinson's disease (PD), however patients often develop side effects, known as levodopa-induced dyskinesia (LID), that usually need therapeutic intervention. There are no suitable therapeutic options for LID, except for the use of the NMDA receptor antagonist amantadine, which has limited efficacy. The NMDA receptor is indeed the most plausible target to manage LID in PD and recently the kinase Fyn- one of its key regulators- became a new putative molecular target involved in LID. The aim of this work was to reduce Fyn expression to alleviate LID in a mouse model of PD. We performed intra-striatal delivery of a designed micro-RNA against Fyn (miRNA-Fyn) in 6-OHDA-lesioned mice treated with levodopa. The miRNA-Fyn was delivered either before or after levodopa exposure to assess its ability to prevent or revert dyskinesia. Pre-administration of miRNA-Fyn reduced LID with a concomitant reduction of FosB-ΔFosB protein levels -a marker of LID- as well as decreased phosphorylation of the NR2B-NMDA subunit, which is a main target of Fyn. On the other hand, post L-DOPA delivery of miRNA-Fyn was less effective to revert already established dyskinesia, suggesting that early blocking of Fyn activity might be a more efficient therapeutic approach. Together, our results provide proof of concept about Fyn as a plausible therapeutic target to manage LID, and validate RNA silencing as a potential approach to locally reduce striatal Fyn, rising new perspectives for RNA therapy interventions in PD.Significance StatementLevodopa induced dyskinesia (LID) is an incapacitant side effect of treatment in Parkinson's disease (PD). LID is a therapeutic challenge, lacking an effective pharmacological treatment, except for the use of inhibitors of the NMDA receptor, which have limited efficacy and may trigger untoward side effects. The kinase Fyn is a key regulator of NMDA function and a potential therapeutic target to control LID. Here, we show that RNA interference therapy to reduce the amount of Fyn mRNA in the adult brain is effective to prevent LID in a mouse model of PD, setting the grounds for future biomedical interventions to manage LID in PD.
| S-EPMC8281260 | biostudies-literature
Project description:Levodopa-induced dyskinesia gradually emerges during long-term dopamine therapy, causing major disability in patients with Parkinson disease. Using pharmacodynamic functional MRI, we have previously shown that the intake of levodopa triggers an excessive activation of the pre-supplementary motor area in Parkinson disease patients with peak-of-dose dyskinesia. In this pre-registered, interventional study, we tested whether the abnormal responsiveness of the pre-supplementary motor area to levodopa may constitute a 'stimulation target' for treating dyskinesia. A gender-balanced group of 17 Parkinson disease patients with peak-of-dose dyskinesia received 30 min of robot-assisted repetitive transcranial magnetic stimulation, after they had paused their anti-Parkinson medication. Real-repetitive transcranial magnetic stimulation at 100% or sham-repetitive transcranial magnetic stimulation at 30% of individual resting corticomotor threshold of left first dorsal interosseous muscle was applied on separate days in counterbalanced order. Following repetitive transcranial magnetic stimulation, patients took 200 mg of oral levodopa and underwent functional MRI to map brain activity, while they performed the same go/no-go task as in our previous study. Blinded video assessment revealed that real-repetitive transcranial magnetic stimulation delayed the onset of dyskinesia and reduced its severity relative to sham-repetitive transcranial magnetic stimulation. Individual improvement in dyskinesia severity scaled linearly with the modulatory effect of real-repetitive transcranial magnetic stimulation on task-related activation in the pre-supplementary motor area. Stimulation-induced delay in dyskinesia onset correlated positively with the induced electrical field strength in the pre-supplementary motor area. Our results provide converging evidence that the levodopa-triggered increase in pre-supplementary motor area activity plays a causal role in the pathophysiology of peak-of-dose dyskinesia and constitutes a promising cortical target for brain stimulation therapy.
| S-EPMC7667528 | biostudies-literature
Project description:Levodopa-induced dyskinesia (LID) is a persistent behavioral sensitization that develops after repeated levodopa (L-DOPA) exposure in Parkinson disease (PD) patients. we used reduced representation bisulfite sequencing to determine the methylation status of cytosines genome wide at base pair resolution following a parkinsonian-like lesion and LID development. Due to the enrichment of RRBS, we focused our analysis to cytosines in a CpG context and observed extensive locus-specific changes in DNA methylation, including a preponderance of demethylation, in the dorsal striatum following the development of dyskinetic behaviors in our animal model system. Changes in DNA methylation were concentrated in putative regulatory regions of many genes known to be aberrantly transcribed following L-DOPA exposure and enriched for genes relevant to mechanisms of synaptic plasticity. In the areas of the genome exhibiting the highest levels of effect, the magnitudes of change to methylation were strongly correlated with dyskinetic behaviors.
2016-06-16 | GSE83385 | GEO
Project description:A disruption in the slow wave activity (SWA) mediated synaptic downscaling process features Parkinson's disease (PD) patients presenting levodopa-induced dyskinesia (LID). To corroborate the role of SWA in LID development, 15 PD patients with LID, who underwent a polysomnography before LID's appearance, were included. Slow wave sleep epochs were extracted, combined and segmented into early and late sleep. SWA power was calculated. A linear regression model established that the SWA overnight decrease could predict the time to the emergence of LID. Our finding supports the link between SWA-mediated synaptic downscaling and the development of LID. If confirmed, it could pave the way to the study of possible sleep targeted therapies able to protect PD patients from LID development.
| S-EPMC10509191 | biostudies-literature
Project description:Levodopa-induced dyskinesia (LID) is a persistent behavioral sensitization that develops after repeated levodopa (L-DOPA) exposure in Parkinson disease (PD) patients. we used reduced representation bisulfite sequencing to determine the methylation status of cytosines genome wide at base pair resolution following a parkinsonian-like lesion and LID development. Due to the enrichment of RRBS, we focused our analysis to cytosines in a CpG context and observed extensive locus-specific changes in DNA methylation, including a preponderance of demethylation, in the dorsal striatum following the development of dyskinetic behaviors in our animal model system. Changes in DNA methylation were concentrated in putative regulatory regions of many genes known to be aberrantly transcribed following L-DOPA exposure and enriched for genes relevant to mechanisms of synaptic plasticity. In the areas of the genome exhibiting the highest levels of effect, the magnitudes of change to methylation were strongly correlated with dyskinetic behaviors. Rats were given a unilateral dopaminergic lesion to the left medial forebrain bundle with 6-OHDA to destroy at least 90% of TH positive axons. Animals were allowed to recover for 3 weeks and then given daily injections of L-DOPA (6 mg/kg) for seven days to establish stable dyskinesia. Animals were sacked 3 hrs following the final L-DOPA injection and the dorsal striatum was immediately dissected and flash frozen. Striatal tissue samples were processed for nucleic acid isolation using the AllPrep DNA/RNA Mini Kit (Qiagen) following the manufacturer's instructions. One μg of gDNA sample was used for library construction. Bisulfite converted DNA libraries were produced and adaptor ligated, and single-end reads were sequenced on an Illumina HiSeq-2500 following library QC. Bisulfite conversion efficiency was greater that 98% for all of the samples and we obtained an average of 68 million reads per library. Quality control on raw reads was performed with FastQC (version 0.10.1, http://www.bioinformatics.bbsrc.ac.uk/projects/fastqc), and adaptor trimming and removal of trimmed reads shorter than 20 bp was performed with Trim Galore (version 0.3.7, http://www.bioinformatics.babraham.ac.uk/projects/trim_galore). Trimmed reads were mapped to the UCSC Rattus norvegicus rn5 genome with the methylation-aware mapper bismark (version 0.13.0). Samtools (version 0.1.19â??96b5f2294a) was used to sort SAM files produced by bismark and de-duplicate reads. SAM files were analyzed using MethylKit (version 0.9.2) in R (Akalin et al., 2012). Reads were filtered based on coverage, with a cutoff of at least ten reads per site, and normalized for each samples coverage before analysis. The genome was tiled at 250 bp and regions were counted if they contained at least 2 identified CpGs per tile. Differential methylation was defined as a sliding linear model correct p-value of <0.01 and, for highly dynamic regions, included at least a 5% change.
2016-06-16 | E-GEOD-83385 | biostudies-arrayexpress
Project description:Dyskinesia is a serious complication of Parkinson's disease during levodopa (L-DOPA) treatment. The pathophysiology of L-DOPA-induced dyskinesia (LID) is complex and not fully illuminated. At present, treatment of dyskinesia is quite limited. Recent studies demonstrated neuroinflammation plays an important role in development of LID. Thus, inhibition of neuroinflammation might open a new avenue for LID treatment. Resveratrol (RES) is the most well-known polyphenolic stilbenoid and verified to possess a large variety of biological activities. DA neurotoxicity was assessed via behavior test and DA neuronal quantification. The movement disorders of dyskinesia were detected by the abnormal involuntary movements scores analysis. Effects of RES on glial cells-elicited neuroinflammation were also explored. Data showed that RES attenuated dyskinesia induced by L-DOPA without affecting L-DOPA's anti-parkinsonian effects. Furthermore, RES generated neuroprotection against long term treatment of L-DOPA-induced DA neuronal damage. Meanwhile, RES reduced protein expression of dyskinesia molecular markers, ΔFOS B and ERK, in the striatum. Also, there was a strong negative correlation between DA system damage and ΔFOS B level in the striatum. In addition, RES inhibited microglia and astroglia activation in substantia nigra and subsequent inflammatory responses in the striatum during L-DOPA treatment. RES alleviates dyskinesia induced by L-DOPA and these beneficial effects are closely associated with protection against DA neuronal damage and inhibition of glial cells-mediated neuroinflammatory reactions.
| S-EPMC8267475 | biostudies-literature