Role of Serotonin Neurons in L-DOPA- and Graft-Induced Dyskinesia in a Rat Model of Parkinson's Disease

L-DOPA, the most effective drug to treat motor symptoms of Parkinson's disease, causes abnormal involuntary movements, limiting its use in advanced stages of the disease. An increasing body of evidence points to the serotonin system as a key player in the appearance of L-DOPA-induced dyskinesia (LID). In fact, exogenously administered L-DOPA can be taken up by serotonin neurons, converted to dopamine and released as a false transmitter, contributing to pulsatile stimulation of striatal dopamine receptors. Accordingly, destruction of serotonin fibers or silencing serotonin neurons by serotonin agonists could counteract LID in animal models. Recent clinical work has also shown that serotonin neurons are present in the caudate/putamen of patients grafted with embryonic ventral mesencephalic cells, producing intense serotonin hyperinnervation. These patients experience graft-induced dyskinesia (GID), a type of dyskinesia phenotypically similar to the one induced by L-DOPA but independent from its administration. Interestingly, the 5-HT1Areceptor agonist buspirone has been shown to suppress GID in these patients, suggesting that serotonin neurons might be involved in the etiology of GID as for LID. In this paper we will discuss the experimental and clinical evidence supporting the involvement of the serotonin system in both LID and GID.

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Foetal Cell Transplantation for Parkinson’s Disease: Focus on Graft-Induced Dyskinesia

Parkinson s Disease ◽

10.1155/2015/563820 ◽

2015 ◽

Vol 2015 ◽

pp. 1-6 ◽

Cited By ~ 4

Author(s):

Elisabetta Tronci ◽

Camino Fidalgo ◽

Manolo Carta

Keyword(s):

Parkinson’S Disease ◽

Parkinson's Disease ◽

Cell Transplantation ◽

Open Label ◽

Double Blind ◽

Clinical Investigations ◽

Serotonin Neurons ◽

Ventral Mesencephalic ◽

Preclinical And Clinical Studies ◽

Foetal Cell

Transplantation of dopamine- (DA-) rich foetal ventral mesencephalic cells emerged as a promising therapy for Parkinson’s disease (PD), as it allowed significant improvement of motor symptoms in several PD patients in open-label studies. However, double-blind clinical trials have been largely disappointing. The general agreement in the field is that the lack of standardization of tissue collection and preparation, together with the absence of postsurgical immunosuppression, played a key role in the failure of these studies. Moreover, a further complication that emerged in previous studies is the appearance of the so-called graft-induced dyskinesia (GID), in a subset of grafted patients, which resembles dyskinesia induced by L-DOPA but in the absence of medication. Preclinical evidence pointed to the serotonin neurons as possible players in the appearance of GID. In agreement, clinical investigations have shown that grafted tissue may contain a large number of serotonin neurons, in the order of half of the DA cells; moreover, the serotonin 5-HT1A receptor agonist buspirone has been found to produce significant dampening of GID in grafted patients. In this paper, we will review the recent preclinical and clinical studies focusing on cell transplantation for PD and on the mechanisms underlying GID.

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A szelektív monoaminoxidáz-B-gátlók helye a Parkinson-kór kezelési stratégiájában a marosvásárhelyi ideggyógyászati klinikák gyakorlatában

Orvosi Hetilap ◽

10.1556/650.2017.30914 ◽

2017 ◽

Vol 158 (51) ◽

pp. 2023-2028

Author(s):

József Attila Szász ◽

Viorelia Constantin ◽

Péter Alpár Fazakas ◽

Eszter Blényesi ◽

Levente Gábor Grieb ◽

...

Keyword(s):

Parkinson’S Disease ◽

Parkinson's Disease ◽

Monoamine Oxidase ◽

Dopamine Agonists ◽

Disease Duration ◽

Monoamine Oxidase Inhibitors ◽

Monoamine Oxidase B ◽

Advanced Stages ◽

Therapeutic Recommendations

Abstract: Introduction: Selective monoamine oxidase B inhibitors have an accurate place in therapeutical strategy of Parkinsons’s disease. In the early stages of the disease, especially in younger patients with milder symptoms, the introduction of levodopa substitution could be efficacious in delaying; in advanced stages they are mainly used to treat motor complications, as an adjunct to levodopa. Aim: The evaluation of therapeutical strategies used in the neurology clinics of Tirgu Mures County Emergency Clinical Hospital in order to define the role of monoamine oxidase B inhibitors. Method: This retrospective study includes all records of patients with Parkinson’s disease hospitalized between 1 January 2003 and 31 December 2016. From the 2194 reports we used data focusing on the therapeutic recommendations. Regarding disease duration, we divided the patients in two groups: less than or equal to 5 years and more than 5 years. Results: From the 1183 patients in first group, 243 received monoamine oxidase inhibitors: 12 as monotherapy, 52 together with dopamine agonists, in 61 cases combined with levodopa. In 118 cases monoamine oxidase inhibitors were combined with levodopa and dopamine agonists. From 582 cases whith Parkinson’s disease for more than 5 years, 195 received monoamine oxidase B inhibitors (selegiline: 10 cases, rasagiline: 185 cases). In 429 cases we did not find accurate data regarding disease duration (selegiline: 5 cases, rasagiline: 93 cases). Conclusion: The use of monoamine oxidase B inhibitors was similar to those found in literature. The treating physicians should utilise more confidently the available therapeutical combinations. Orv Hetil. 2017; 158(51): 2023–2028.

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Role of serotonin neurons in the induction of levodopa- and graft-induced dyskinesias in Parkinson's disease

Movement Disorders ◽

10.1002/mds.22792 ◽

2010 ◽

Vol 25 (S1) ◽

pp. S174-S179 ◽

Cited By ~ 55

Author(s):

Manolo Carta ◽

Thomas Carlsson ◽

Ana Muñoz ◽

Deniz Kirik ◽

Anders Björklund

Keyword(s):

Parkinson’S Disease ◽

Parkinson's Disease ◽

Serotonin Neurons

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Drug treatment of Parkinson's disease

Dialogues in Clinical Neuroscience ◽

10.31887/dcns.2004.6.3/akorczyn ◽

2004 ◽

Vol 6 (3) ◽

pp. 315-322 ◽

Cited By ~ 2

Keyword(s):

Parkinson’S Disease ◽

Parkinson's Disease ◽

Initial Therapy ◽

Dopaminergic Drugs ◽

Advanced Stages ◽

Receptor Blockers ◽

Extrapyramidal Effects ◽

Specific Symptoms

Parkinson's disease (PD) is a common neurodegenerative disease. While its cause remains elusive, much progress has been made regarding its treatment. Available drugs have a good symptomatic effect, but none has yet been shown to slow the progression of the disease in humans. The most efficacious drug is levodopa, but it remains unclear whether the symptomatic benefit is associated with neurotoxic effects and long-term deterioration. The long-term problem associated with levodopa is the appearance of dyskinesias, which is significantly delayed among patients treated with dopamine agonists as initial therapy. Less clear is the role of other drugs in PD, such as monoamine oxidase inhibitors (MAOIs), including selegiline and rasagiline, the putative N-meihyl-o-aspartaie (NMDA) receptor antagonists amantadine and memantine, and the muscarinic receptor blockers. All these may be used as initial therapy and delay the use of dopaminergic drugs, or can be added later to reduce specific symptoms (tremor or dyskinesias). Advanced PD is frequently associated with cognitive decline. To some extent, this can be helped by treatment with cholinesterase inhibitors such as rivastigmine. Similarly, hallucinations and delusions affect PD patients in the advanced stages of their disease. The use of classical neuroleptic drugs in these patients is contraindicated because of their extrapyramidal effects, but atypical drugs, and particularly clozapine, are very helpful. The big void in the therapy of PD lies in the more advanced stages. Several motor symptoms, like postural instability, dysphagia, and dysphonia, as well as dyskinesias, are poorly controlled by existing drugs. New therapies should also be developed against autonomic symptoms, particularly constipation.

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SEROTONIN-TO-DOPAMINE TRANSPORTER RATIOS IN THE STRIATUM OF PATIENTS WITH PARKINSON'S DISEASE: IMPACT ON LEVODOPA–INDUCED DYSKINESIAS

Journal of Neurology Neurosurgery & Psychiatry ◽

10.1136/jnnp-2015-312379.185 ◽

2015 ◽

Vol 86 (11) ◽

pp. e4.96-e4

Author(s):

Andreas-Antonios Roussakis ◽

Marios Politis ◽

David Towey ◽

Paola Piccini

Keyword(s):

Parkinson’S Disease ◽

Parkinson's Disease ◽

Dopamine Transporter ◽

Reference Tissue ◽

Binding Ratio ◽

Disease Impact ◽

And Gender ◽

Simplified Reference Tissue Model ◽

Patients Experience

BackgroundSerotonergic mechanisms play a key role in the development of the Levodopa-induced dyskinesias (LIDs) in patients with Parkinson's disease (PD). We hypothesised that an unfavourable serotonin-to-dopamine terminal ratio in the putamen would be most detrimental in dyskinetic patients. We investigated the role of serotonin-to-dopamine transporter binding ratios in the development of dyskinesias in Parkinson's disease patients.Methods/SubjectsTwenty-eight Parkinson's disease patients[17 with LIDs;11 stable] and 12 age and gender-matched healthy controls were studied with [11C]DASB PET and [123I]FP-CIT SPECT, Imaging. We have employed a simplified reference tissue model using cerebellar reference for the quantification of [11C]DASB, whereas a semi-quantification approach was used for [123I]FP-CIT. We estimated uptake values in the putamen.ResultsParkinson's disease patients showed decreases in [123I]FP-CIT binding (p<0.001) compared to controls, 51% in the stable and 62% in the LIDs group. PD patients showed decreases in [11C]DASB binding (p<0.01), but there were no differences between the stable (37% loss) and LIDs(31% loss) groups. PD patients with LIDs had 103% increased [11C]DASB-to-[123I]FP-CIT binding ratio, whereas in the PD stable group the ratio was increased by 76%, relative to HCs. Higher [11C]DASB-to-[123I]FP-CIT binding ratio correlated with longer disease duration for the 28 PD patients (r=0.52;p<0.01).ConclusionSERT-to-DAT ratio increases as PD progresses and patients experience LIDs.

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Role of biometals in pathogenesis treatment of Parkinson's disease (overview)

Medical alphabet ◽

10.33667/2078-5631-2020-1-21-27 ◽

2020 ◽

pp. 21-27

Author(s):

A. A. Pilipovich ◽

V. L. Golubev ◽

Al. B. Danilov ◽

R. R. Tyutina

Keyword(s):

Parkinson’S Disease ◽

Parkinson's Disease ◽

Trace Elements ◽

Neurodegenerative Diseases ◽

The Body ◽

Early Therapy ◽

Inorganic Substances ◽

Effects Of Radiation ◽

The One

The role of exogenous factors in the occurrence of neurodegenerative diseases has been shown in many works: on the effects of radiation, neurotoxicants, pesticides and other organic and inorganic substances. One of the interesting and promising areas for studying the pathogenesis of neurodegeneration is the analysis of the composition and ratio of trace elements in various tissues and organs of a person. The influence of trace elements on the development of neurodegenerative diseases, such as Parkinson's disease (PD), Alzheimer's disease (AD), Huntington's disease, amyotrophic lateral sclerosis, is given special attention, since such patients show multiple disorders in the homeostasis of the main endogenous brain biometals (calcium, magnesium, zinc, iron, manganese, copper, etc.). On the one hand, in a cell or its components, where metals play a key role in biological processes, a metal deficiency can occur, on the other hand, metals can accumulate in pathological proteins, causing cell dysfunction and death. Protein aggregation is a common feature of all neurodegenerative diseases. Specific changes in the concentration of biometals in various environments of the body can be considered as early biomarkers of neurodegenerations. And the identification of reliable biomarkers is considered a paramount task for the development of the direction of early therapy and prevention of the disease, in particular PD. A change in the distribution of metal, cell deficiency and sequestration in pathological proteins are abnormalities that must be addressed during neurodegeneration. Currently, approximately 800 compounds are used or tested for the treatment of PD, of which approximately 250 have the expected or established chelation properties of metals (CuII, CuI, FeII, FeIII, MnII, ZnII) that are involved in dyshomeostasis in PD. Today's knowledge of the pathogenesis of the most common neurodegenerations, such as AD and PD, is still not enough to develop clear recommendations for therapy with biometals and other trace elements, but work in this direction is actively ongoing.

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