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| 2. |
- Kuter, Katarzyna Z., et al.
(författare)
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The role of glia in Parkinson's disease : Emerging concepts and therapeutic applications
- 2020
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Ingår i: Recent Advances in Parkinson's Disease. - : Elsevier. - 0079-6123 .- 1875-7855. - 9780444642608 ; 252, s. 131-168
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Bokkapitel (refereegranskat)abstract
- Originally believed to primarily affect neurons, Parkinson's disease (PD) has recently been recognized to also affect the functions and integrity of microglia and astroglia, two cell categories of fundamental importance to brain tissue homeostasis, defense, and repair. Both a loss of glial supportive-defensive functions and a toxic gain of glial functions are implicated in the neurodegenerative process. Moreover, the chronic treatment with L-DOPA may cause maladaptive glial plasticity favoring a development of therapy complications. This chapter focuses on the pathophysiology of PD from a glial point of view, presenting this rapidly growing field from the first discoveries made to the most recent developments. We report and compare histopathological and molecular findings from experimental models of PD and human studies. We moreover discuss the important role played by astrocytes in compensatory adaptations taking place during presymptomatic disease stages. We finally describe examples of potential therapeutic applications stemming from an increased understanding of the important roles of glia in PD.
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| 3. |
- Cenci, M. Angela, et al.
(författare)
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Cells, pathways, and models in dyskinesia research
- 2024
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Ingår i: Current Opinion in Neurobiology. - : Elsevier BV. - 0959-4388 .- 1873-6882. ; 84
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Forskningsöversikt (refereegranskat)abstract
- L-DOPA-induced dyskinesia (LID) is the most common form of hyperkinetic movement disorder resulting from altered information processing in the cortico-basal ganglia network. We here review recent advances clarifying the altered interplay between striatal output pathways in this movement disorder. We also review studies revealing structural and synaptic changes to the striatal microcircuitry and altered cortico-striatal activity dynamics in LID. We furthermore highlight the recent progress made in understanding the involvement of cerebellar and brain stem nuclei. These recent developments illustrate that dyskinesia research continues to provide key insights into cellular and circuit-level plasticity within the cortico-basal ganglia network and its interconnected brain regions.
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| 4. |
- Cenci, M. Angela, et al.
(författare)
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Dyskinesia matters
- 2020
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Ingår i: Movement Disorders. - : Wiley. - 0885-3185 .- 1531-8257. ; 35:3, s. 392-396
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Tidskriftsartikel (refereegranskat)abstract
- Levodopa-induced dyskinesia (LID) represents a significant source of discomfort for people with Parkinson's disease (PD). It negatively affects quality of life, it is associated with both motor and nonmotor fluctuations, and it brings an increased risk of disability, balance problems, and falls. Although the prevalence of severe LID appears to be lower than in previous eras (likely owing to a more conservative use of oral levodopa), we have not yet found a way to prevent the development of this complication. Advanced surgical therapies, such as deep brain stimulation, ameliorate LID, but only a minority of PD patients qualify for these interventions. Although some have argued that PD patients would rather be ON with dyskinesia than OFF, the deeper truth is that patients would very much prefer to be ON without dyskinesia. As researchers and clinicians, we should aspire to make that goal a reality. To this end, translational research on LID is to be encouraged and persistently pursued.
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| 5. |
- Cenci, M. Angela, et al.
(författare)
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Non-dopaminergic approaches to the treatment of motor complications in Parkinson's disease
- 2022
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Ingår i: Neuropharmacology. - : Elsevier BV. - 0028-3908. ; 210
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Forskningsöversikt (refereegranskat)abstract
- Dopamine replacement therapy with L-DOPA is the most efficacious symptomatic treatment for Parkinson's disease, but its utility is limited by a development of motor fluctuations and abnormal involuntary movements (dyskinesia) in the majority of patients. These complications are attributed to the combined effects of dopaminergic degeneration and non-physiological reinstatement of dopamine transmission by the standard oral medications. There is substantial evidence that this altered state of dopamine transmission causes pathophysiological changes to a variety of non-dopaminergic neurotransmitter systems in the brain. This evidence has prompted an interest in developing drugs that target non-dopaminergic receptors for the purpose of improving L-DOPA-induced dyskinesia and/or motor fluctuations. We here review all the most important categories of non-dopaminergic targets that have been investigated so far, but with a particular focus on modulators of glutamatergic and serotonergic transmission, which continue to inspire significant efforts towards clinical translation. In particular, we discuss both the experimental rationale and the clinical experience thus far gained from studying 5-HT1A and 5-HT1B receptor agonists, NMDA and AMPA receptor antagonists, mGluR5 negative allosteric modulators, mGluR4 positive allosteric modulators, and adenosine A2a receptor antagonists. We also review compounds with complex pharmacological properties that are already used clinically or about to enter an advanced phase of clinical development (amantadine, safinamide, zonisamide, pridopidine, mesdopetam). We conclude with an outlook on possible directions to address unmet needs and improve the chance of successful translation in this therapeutic area.
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| 6. |
- Cenci, M. Angela, et al.
(författare)
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Toxin-Based Rodent Models of Parkinson’s Disease
- 2021
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Ingår i: Neuromethods. - New York, NY : Springer US. - 1940-6045 .- 0893-2336. - 9781071609125 - 9781071609118 ; 160, s. 3-19
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Bokkapitel (refereegranskat)abstract
- A major pathological hallmark of Parkinson’s disease (PD) is a severe degeneration of dopamine (DA)-producing neurons in the substantia nigra pars compacta (SNc) projecting to the motor part of the striatum. Therefore, there is a long-standing interest in using animal models with severe nigrostriatal degeneration for experimental research. Pathophysiological and behavioral features of PD are best studied in mammalian species endowed with well-developed corticobasal ganglia thalamocortical loops, such as rodents. Different toxins can be used to generate nigrostriatal damage, including 6-hydroxydopamine (6-OHDA), 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), paraquat, and rotenone. Models based on 6-OHDA lesions provide the main advantage of a severe and reproducible DA lesions. Models based on MPTP provide easy and versatile tools to rapidly evaluate potential neuroprotective treatments. Models based on paraquat and rotenone are appealing for their relevance to some well-known environmental risk factors of the human PD, although they yield only partial dopaminergic degeneration and entail a considerable risk of nonspecific toxicity. The main general limitation of neurotoxin-based models is that they do not replicate some characterizing features of PD pathology, such as the formation of Lewy body–like proteinaceous aggregates or the anatomical pattern of neurodegeneration, which also affects nondopaminergic brain regions.
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| 7. |
- Clemensson, Erik K.H., et al.
(författare)
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Tracking Rats in Operant Conditioning Chambers Using a Versatile Homemade Video Camera and DeepLabCut
- 2020
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Ingår i: Journal of visualized experiments : JoVE. - : MyJove Corporation. - 1940-087X. ; :160
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Tidskriftsartikel (refereegranskat)abstract
- Operant conditioning chambers are used to perform a wide range of behavioral tests in the field of neuroscience. The recorded data is typically based on the triggering of lever and nose-poke sensors present inside the chambers. While this provides a detailed view of when and how animals perform certain responses, it cannot be used to evaluate behaviors that do not trigger any sensors. As such, assessing how animals position themselves and move inside the chamber is rarely possible. To obtain this information, researchers generally have to record and analyze videos. Manufacturers of operant conditioning chambers can typically supply their customers with high-quality camera setups. However, these can be very costly and do not necessarily fit chambers from other manufacturers or other behavioral test setups. The current protocol describes how to build an inexpensive and versatile video camera using hobby electronics components. It further describes how to use the image analysis software package DeepLabCut to track the status of a strong light signal, as well as the position of a rat, in videos gathered from an operant conditioning chamber. The former is a great aid when selecting short segments of interest in videos that cover entire test sessions, and the latter enables analysis of parameters that cannot be obtained from the data logs produced by the operant chambers.
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| 8. |
- Espa, Elena, et al.
(författare)
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Dopamine Agonist Cotreatment Alters Neuroplasticity and Pharmacology of Levodopa-Induced Dyskinesia
- 2023
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Ingår i: Movement Disorders. - : Wiley. - 0885-3185 .- 1531-8257. ; 38:3, s. 410-422
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Current models of levodopa (L-dopa)-induced dyskinesia (LID) are obtained by treating dopamine-depleted animals with L-dopa. However, patients with LID receive combination therapies that often include dopamine agonists.OBJECTIVE: Using 6-hydroxydopamine-lesioned rats as a model, we aimed to establish whether an adjunct treatment with the D2/3 agonist ropinirole impacts on patterns of LID-related neuroplasticity and drug responses.METHODS: Different regimens of L-dopa monotreatment and L-dopa-ropinirole cotreatment were compared using measures of hypokinesia and dyskinesia. Striatal expression of ∆FosB and angiogenesis markers were studied immunohistochemically. Antidyskinetic effects of different drug categories were investigated in parallel groups of rats receiving either L-dopa monotreatment or L-dopa combined with ropinirole.RESULTS: We defined chronic regimens of L-dopa monotreatment and L-dopa-ropinirole cotreatment inducing overall similar abnormal involuntary movement scores. Compared with the monotreatment group, animals receiving the L-dopa-ropinirole combination exhibited an overall lower striatal expression of ∆FosB with a distinctive compartmental distribution. The expression of angiogenesis markers and blood-brain barrier hyperpermeability was markedly reduced after L-dopa-ropinirole cotreatment compared with L-dopa monotreatment. Moreover, significant group differences were detected upon examining the response to candidate antidyskinetic drugs. In particular, compounds modulating D1 receptor signaling had a stronger effect in the L-dopa-only group, whereas both amantadine and the selective NMDA antagonist MK801 produced a markedly larger antidyskinetic effect in L-dopa-ropinirole cotreated animals.CONCLUSIONS: Cotreatment with ropinirole altered LID-related neuroplasticity and pharmacological response profiles. The impact of adjuvant dopamine agonist treatment should be taken into consideration when investigating LID mechanisms and candidate interventions in both clinical and experimental settings. © 2023 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.
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| 9. |
- Fieblinger, Tim, et al.
(författare)
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Non‐Apoptotic Caspase‐3 Activation Mediates Early Synaptic Dysfunction of Indirect Pathway Neurons in the Parkinsonian Striatum
- 2022
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Ingår i: International Journal of Molecular Sciences. - : MDPI AG. - 1661-6596 .- 1422-0067. ; 23:10
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Tidskriftsartikel (refereegranskat)abstract
- Non‐apoptotic caspase‐3 activation is critically involved in dendritic spine loss and synaptic dysfunction in Alzheimer’s disease. It is, however, not known whether caspase‐3 plays similar roles in other pathologies. Using a mouse model of clinically manifest Parkinson’s disease, we provide the first evidence that caspase‐3 is transiently activated in the striatum shortly after the degeneration of nigrostriatal dopaminergic projections. This caspase‐3 activation concurs with a rapid loss of dendritic spines and deficits in synaptic long‐term depression (LTD) in striatal projection neurons forming the indirect pathway. Interestingly, systemic treatment with a caspase inhibitor prevents both the spine pruning and the deficit of indirect pathway LTD without interfering with the ongoing dopaminergic degeneration. Taken together, our data identify transient and non‐apoptotic caspase activation as a critical event in the early plastic changes of indirect pathway neurons following dopamine denervation.
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| 10. |
- Grigoriou, Sotirios, et al.
(författare)
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Comparison of dyskinesia profiles after L-DOPA dose challenges with or without dopamine agonist coadministration
- 2023
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Ingår i: Neuropharmacology. - 0028-3908. ; 237
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Tidskriftsartikel (refereegranskat)abstract
- Many patients with Parkinson's disease (PD) experiencing L-DOPA-induced dyskinesia (LID) receive adjunct treatment with dopamine agonists, whose functional impact on LID is unknown. We set out to compare temporal and topographic profiles of abnormal involuntary movements (AIMs) after L-DOPA dose challenges including or not the dopamine agonist ropinirole. Twenty-five patients with PD and a history of dyskinesias were sequentially administered either L-DOPA alone (150% of usual morning dose) or an equipotent combination of L-DOPA and ropinirole in random order. Involuntary movements were assessed by two blinded raters prior and every 30 min after drug dosing using the Clinical Dyskinesia Rating Scale (CDRS). A sensor-recording smartphone was secured to the patients' abdomen during the test sessions. The two raters’ CDRS scores were highly reliable and concordant with models of hyperkinesia presence and severity trained on accelerometer data. The dyskinesia time curves differed between treatments as the L-DOPA-ropinirole combination resulted in lower peak severity but longer duration of the AIMs compared with L-DOPA alone. At the peak of the AIMs curve (60–120 min), L-DOPA induced a significantly higher total hyperkinesia score, whereas in the end phase (240–270 min), both hyperkinesia and dystonia tended to be more severe after the L-DOPA-ropinirole combination (though reaching statistical significance only for the item, arm dystonia). Our results pave the way for the introduction of a combined L-DOPA-ropinirole challenge test in the early clinical evaluation of antidyskinetic treatments. Furthermore, we propose a machine-learning method to predict CDRS hyperkinesia severity using accelerometer data.
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