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L-DOPA induced dyskinesia

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https://www.readbyqxmd.com/read/29305656/serotonergic-targets-for-the-treatment-of-l-dopa-induced-dyskinesia
#1
REVIEW
Kathryn Lanza, Christopher Bishop
Dopamine (DA) replacement therapy with L-3,4-dihydroxyphenylalanine (L-DOPA) continues to be the gold-standard treatment for Parkinson's disease (PD). Despite clear symptomatic benefit, long-term L-DOPA use often results in the development of L-DOPA-induced dyskinesia (LID), significantly reducing quality of life and increasing costs for PD patients and their caregivers. Accumulated research has demonstrated that several pre- and post-synaptic mechanisms contribute to LID development and expression. In particular, raphe-striatal hyperinnervation and unregulated DA release from 5-HT terminals is postulated to play a central role in LID manifestation...
January 5, 2018: Journal of Neural Transmission
https://www.readbyqxmd.com/read/29287112/mitochondrial-dna-depletion-by-ethidium-bromide-decreases-neuronal-mitochondrial-creatine-kinase-implications-for-striatal-energy-metabolism
#2
Emily Booth Warren, Aidan Edward Aicher, Joshua Patrick Fessel, Christine Konradi
Mitochondrial DNA (mtDNA), the discrete genome which encodes subunits of the mitochondrial respiratory chain, is present at highly variable copy numbers across cell types. Though severe mtDNA depletion dramatically reduces mitochondrial function, the impact of tissue-specific mtDNA reduction remains debated. Previously, our lab identified reduced mtDNA quantity in the putamen of Parkinson's Disease (PD) patients who had developed L-DOPA Induced Dyskinesia (LID), compared to PD patients who had not developed LID and healthy subjects...
2017: PloS One
https://www.readbyqxmd.com/read/29247391/trazodone-alleviates-both-dyskinesia-and-psychosis-in-the-parkinsonian-marmoset-model-of-parkinson-s-disease
#3
Adjia Hamadjida, Stephen G Nuara, Jim C Gourdon, Philippe Huot
Trazodone is a clinically available anti-depressant that exhibits affinity for serotonin 1A and 2A receptors, as well as for alpha-adrenoceptors, suggesting that it may be useful to treat L-3,4-dihydroxyphenylalanine (L-DOPA)-induced dyskinesia and psychosis that are encountered in advanced Parkinson's disease (PD). Here, we investigated the anti-dyskinetic and anti-psychotic effects of trazodone in the parkinsonian non-human primate. 6 common marmosets were rendered parkinsonian by administration of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)...
December 15, 2017: Journal of Neural Transmission
https://www.readbyqxmd.com/read/29242978/animal-models-of-l-dopa-induced-dyskinesia-the-6-ohda-lesioned-rat-and-mouse
#4
REVIEW
Elisabetta Tronci, Veronica Francardo
Appearance of L-DOPA-induced dyskinesia (LID) represents a major limitation in the pharmacological therapy with the dopamine precursor L-DOPA. Indeed, the vast majority of parkinsonian patients develop dyskinesia within 9-10 years of L-DOPA oral administration. This makes the discovery of new therapeutic strategies an important need. In the last decades, several animal models of Parkinson's disease (PD) have been developed, to both study mechanisms underlying PD pathology and treatment-induced side effects (i...
December 14, 2017: Journal of Neural Transmission
https://www.readbyqxmd.com/read/29241709/regulation-of-pleiotrophin-and-fyn-in-the-striatum-of-rats-undergoing-l-dopa-induced-dyskinesia
#5
Gimena Gomez, Mariano D Saborido, María A Bernardi, Oscar S Gershanik, Irene R Taravini, Juan E Ferrario
L-DOPA is the gold standard pharmacological therapy for symptomatic treatment of Parkinson's disease (PD), however, its long-term use is associated with the emergence of L-DOPA-induced dyskinesia (LID). Understanding the underlying molecular mechanisms of LID is crucial for the development of newer and more effective therapeutic approaches. In previous publications, we have shown that Pleiotrophin (PTN), a developmentally regulated trophic factor, is up-regulated by L-DOPA in the striatum of dopamine denervated rats...
December 11, 2017: Neuroscience Letters
https://www.readbyqxmd.com/read/29233065/understanding-the-role-of-glycogen-synthase-kinase-3-in-l-dopa-induced-dyskinesia-in-parkinson-s-disease
#6
Hojin Choi, Seong-Ho Koh
Levodopa (L-DOPA) is the most commonly used drug for Parkinson's disease (PD), but its long-term use is associated with various complications, including L-DOPA-induced dyskinesia (LID). Many studies have suggested that L-DOPA neurotoxicity and LID are associated with glycogen synthase kinase-3 (GSK-3) activation. Areas covered: LID is caused by striatal dopamine (DA) denervation in PD and pulsatile L-DOPA treatment. These factors lead to dysregulated DA transmission, abnormal intracellular signaling and transcription factors in striatal neurons, and altered gene expression and plasticity at corticostriatal synapses...
December 15, 2017: Expert Opinion on Drug Metabolism & Toxicology
https://www.readbyqxmd.com/read/29226687/validation-of-a-new-scoring-scale-for-behavioral-assessment-of-l-dopa-induced-dyskinesia-in-the-rat-a-new-tool-for-early-decision-making-in-drug-development
#7
Simon Loiodice, Anne-Sophie Denibaud, Wendy Deffains, Magali Alix, Pierre Montagne, Marine Seffals, Christophe Drieu La Rochelle
The 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-treated non-human primate (NHP) has been described as the most translatable model for experimental reproduction of L-dopa-induced dyskinesia (LID). However, from a drug discovery perspective, the risk associated with investment in this type of model is high due to the time and cost. The 6-hydroxydopamine (6-OHDA) rat dyskinesia model is recommended for testing compounds but relies on onerous, and non-standard behavioral rating scales. We sought to develop a simplified and sensitive method aiming at assessing LID in the rat...
December 11, 2017: ACS Chemical Neuroscience
https://www.readbyqxmd.com/read/29219207/motor-complications-in-parkinson-s-disease-striatal-molecular-and-electrophysiological-mechanisms-of-dyskinesias
#8
REVIEW
Barbara Picconi, Ledia F Hernández, Jose A Obeso, Paolo Calabresi
Long-term levodopa (l-dopa) treatment in patients with Parkinson´s disease (PD) is associated with the development of motor complications (ie, motor fluctuations and dyskinesias). The principal etiopathogenic factors are the degree of nigro-striatal dopaminergic loss and the duration and dose of l-dopa treatment. In this review article we concentrate on analysis of the mechanisms underlying l-dopa-induced dyskinesias, a phenomenon that causes disability in a proportion of patients and that has not benefited from major therapeutic advances...
December 8, 2017: Movement Disorders: Official Journal of the Movement Disorder Society
https://www.readbyqxmd.com/read/29209553/antidyskinetic-treatment-with-mtep-affects-multiple-molecular-pathways-in-the-parkinsonian-striatum
#9
Jing-Ya Lin, Zhen-Guo Liu, Cheng-Long Xie, Lu Song, Ai-Juan Yan
Parkinson's disease is characterized by dopaminergic neuron loss and dopamine (DA) depletion in the striatum. Standard treatment is still focused on the restoration of dopamine with exogenous L-Dopa, which however causes L-Dopa-induced dyskinesia (LID). Several studies have shown that antagonism of the metabotropic glutamate receptor 5 alleviates LID, but the underlying mechanisms have remained unclear. We set out to determine where this alleviation may depend on restoring the equilibrium between the two main striatofugal pathways...
2017: Parkinson's Disease
https://www.readbyqxmd.com/read/29197517/dpi-289-a-novel-mixed-delta-opioid-agonist-mu-opioid-antagonist-dama-has-l-dopa-sparing-potential-in-parkinson-s-disease
#10
Tom H Johnston, Eboo Versi, Patrick A Howson, Paula Ravenscroft, Susan H Fox, Michael P Hill, Bruce E Reidenberg, Ronald Corey, Jonathan M Brotchie
L-DOPA-induced dyskinesia (LID) remains a significant problem in the management of Parkinson's disease (PD). In rodent and macaque models of PD, delta opioid receptor agonists have anti-parkinsonian actions while mu opioid antagonists can reduce the expression of LID. DPI-289 is a novel molecule with a unique combination of opioid receptor DAMA actions: delta agonist (Ki: 0.73 nM); mu antagonist (Ki: 12 nM). We demonstrated that DPI-289 has oral bioavailability and established its pharmacokinetic profile in both rat and primate...
November 29, 2017: Neuropharmacology
https://www.readbyqxmd.com/read/29178365/levodopa-a-new-look-at-an-old-friend
#11
REVIEW
C Warren Olanow, Fabrizio Stocchi
Levodopa is the most effective antiparkinsonian agent, but chronic treatment is associated with the development of motor complications in the majority of patients with PD. Recent scientific and clinical advances are improving this situation. Long-term, double-blind studies demonstrate that dose is an important risk factor for the development of both motor fluctuations and dyskinesia, and suggest that it is best to use low doses of l-dopa when possible. Inhaled l-dopa and sublingual apomorphine are now being developed as rescue therapies that permit rapid and predictable reversal of off periods...
November 27, 2017: Movement Disorders: Official Journal of the Movement Disorder Society
https://www.readbyqxmd.com/read/29126856/nlx-112-a-highly-selective-5-ht1a-receptor-agonist-effects-on-body-temperature-and-plasma-corticosterone-levels-in-rats
#12
A Newman-Tancredi, R Depoortère, E Carilla-Durand, J P Tarayre, M Kleven, W Koek, L Bardin, M A Varney
NLX-112 (a.k.a. F13640 or befiradol), exhibits nanomolar affinity, exceptional selectivity and high agonist efficacy at 5-hydroxytryptamine 5-HT1A receptors. It possesses marked activity in a variety of animal models of depression, pain and L-DOPA-induced dyskinesia. However, its influence on translational biomarkers of central 5-HT1A receptor activation has not been previously described. Here, we report on the activity, in rats, of NLX-112 to increase plasma corticosterone levels and produce hypothermia, two responses which are also elicited by 5-HT1A receptor agonists in humans...
November 7, 2017: Pharmacology, Biochemistry, and Behavior
https://www.readbyqxmd.com/read/29125979/synaptic-plasticity-may-underlie-l-dopa-induced-dyskinesia
#13
REVIEW
Anders Borgkvist, Ori J Lieberman, David Sulzer
l-DOPA provides highly effective treatment for Parkinson's disease, but l-DOPA induced dyskinesia (LID) is a very debilitating response that eventually is presented by a majority of patients. A central issue in understanding the basis of LID is whether it is due to a response to chronic l-DOPA over years of therapy, and/or due to synaptic changes that follow the loss of dopaminergic neurotransmission and then triggered by acute l-DOPA administration. We review recent work that suggests that specific synaptic changes in the D1 dopamine receptor-expressing direct pathway striatal projection neurons due to loss of dopamine in Parkinson's disease are responsible for LID...
November 7, 2017: Current Opinion in Neurobiology
https://www.readbyqxmd.com/read/29115484/lipoic-acid-alleviates-l%C3%A2-dopa%C3%A2-induced-dyskinesia-in-6%C3%A2-ohda-parkinsonian-rats-via-anti%C3%A2-oxidative-stress
#14
Su-Fang Zhang, Cheng-Long Xie, Jing-Ya Lin, Mei-Hua Wang, Xi-Jin Wang, Zhen-Guo Liu
Levodopa (L‑DOPA) is the gold standard for symptomatic treatment of Parkinson's disease (PD); however, long‑term therapy is associated with the emergence of L‑DOPA‑induced dyskinesia (LID). Nigral dopaminergic cell loss determines the degree of drug exposure and time required for the initial onset of LID. Accumulating evidence indicates that α‑lipoic acid (ALA) decreases this nigral dopaminergic cell loss. However, until now, the precise mechanisms of ALA have only been partially understood in LID...
November 6, 2017: Molecular Medicine Reports
https://www.readbyqxmd.com/read/29100803/the-effects-of-cysteamine-in-a-mouse-model-of-levodopa-induced-dyskinesias
#15
Linda S David, Martine Saint-Pierre, Jérôme Lamontagne-Proulx, Francesca Cicchetti
Levo-dopa (L-DOPA) has shown significant and long-lasting efficacy in the treatment of motor features characteristic of Parkinson's disease (PD). However, the effects tend to wear off at a time typically when side-effects, such as L-DOPA induced dyskinesias (LIDs), start to emerge and for which the treatment options are very limited. In recent years, we have reported on the neuroprotective and neurorestorative properties of the compounds cystamine/cysteamine in ameliorating several aspects of PD. Building on these observations, we set out to further evaluate the benefits of cysteamine on LIDs...
October 31, 2017: Neuroscience Letters
https://www.readbyqxmd.com/read/29097596/ck2-oppositely-modulates-l-dopa-induced-dyskinesia-via-striatal-projection-neurons-expressing-d1-or-d2-receptors
#16
Marisol Cortés, Lauren Malave, Julia Castello, Marc Flajolet, M Angela Cenci, Eitan Friedman, Heike Rebholz
We have previously shown that casein kinase 2 (CK2) negatively regulates dopamine D1- and adenosine A2a receptor signaling in the striatum. Ablation of CK2 in D1-receptor-positive striatal neurons caused enhanced locomotion and exploration at baseline, whereas CK2 ablation in D2 receptor-positive neurons caused increased locomotion after treatment with A2a antagonist, caffeine. Since both, D1 and A2a receptors, play major roles in the cellular responses to L-DOPA in the striatum, these findings prompted us to examine the impact of CK2 ablation on the effects of L-DOPA treatment in the unilateral 6-OHDA lesioned mouse model of Parkinson's disease...
November 2, 2017: Journal of Neuroscience: the Official Journal of the Society for Neuroscience
https://www.readbyqxmd.com/read/29093677/levodopa-benserazide-loaded-microspheres-alleviate-l-dopa-induced-dyskinesia-through-preventing-the-over-expression-of-d1r-shp-2-erk1-2-signaling-pathway-in-a-rat-model-of-parkinson-s-disease
#17
Ying Wan, Na Wu, Lu Song, Xijin Wang, Zhenguo Liu, Weien Yuan, Jing Gan
Background: The long-term intermittent Levodopa (L-dopa) stimulation contributes to an aberrant activation of D1 receptor (D1R) mediated extracellular signal-regulated kinases1/2 (ERK1/2) in the striatal medium spiny neurons, resulting in the occurrence of L-dopa induced dyskinesia (LID). Recently, a novel signaling pathway, D1R/Shp-2/ERK1/2, was proposed to be required for the occurrence of LID. Here we designed the study in which two different methods of L-dopa delivery [continuous dopamine stimulation (CDS) vs...
2017: Frontiers in Aging Neuroscience
https://www.readbyqxmd.com/read/29055799/altered-mglur5-binding-potential-and-glutamine-concentration-in-the-6-ohda-rat-model-of-acute-parkinson-s-disease-and-levodopa-induced-dyskinesia
#18
Melissa Crabbé, Anke Van der Perren, Akila Weerasekera, Uwe Himmelreich, Veerle Baekelandt, Koen Van Laere, Cindy Casteels
Several lines of evidence point to alterations in glutamatergic signaling in Parkinson's disease (PD) and levodopa-induced dyskinesia (LID), involving the metabotropic glutamate receptor type 5 (mGluR5). Using small-animal positron emission tomography (PET) with [(18)F]FPEB and proton magnetic resonance spectroscopy, we investigated cerebral changes in the mGluR5 and glutamate/glutamine availability in vivo in PD rats and following onset of LIDs. In parallel, behavioral tests were performed. Comparing PD to control rats, mGluR5 binding potential was decreased in a cluster comprising the bilateral caudate-putamen (CP), ipsilateral motor cortex and somatosensory cortex, and the contralateral somatosensory cortex and parietal association cortex, with the most pronounced reduction in the ipsilateral CP...
September 21, 2017: Neurobiology of Aging
https://www.readbyqxmd.com/read/29046640/antiparkinsonian-efficacy-of-guanosine-in-rodent-models-of-movement-disorder
#19
Caio M Massari, Marc López-Cano, Fabiana Núñez, Víctor Fernández-Dueñas, Carla I Tasca, Francisco Ciruela
Guanosine (GUO) is a guanine-based purine nucleoside with important trophic functions and promising neuroprotective properties. Although the neuroprotective effects of GUO have been corroborated in cellular models of Parkinson's disease (PD), its efficacy as an antiparkinsonian agent has not been fully explored in PD animal models. Accordingly, we evaluated the effectiveness of GUO in reversing motor impairments in several rodent movement disorder models, including catalepsy, tremor, and hemiparkinsonism. Our results showed that orally administered GUO antagonized reserpine-mediated catalepsy, reduced reserpine-induced tremulous jaw movements, and potentiated the number of contralateral rotations induced by L-3,4-dihydroxyphenylalanine in unilaterally 6-hydroxidopamine-lesioned rats...
2017: Frontiers in Pharmacology
https://www.readbyqxmd.com/read/29039022/metformin-inhibits-the-development-of-l-dopa-induced-dyskinesia-in-a-murine-model-of-parkinson-s-disease
#20
Young-Kyoung Ryu, Hye-Yeon Park, Jun Go, Dong-Hee Choi, Yong-Hoon Kim, Jung Hwan Hwang, Jung-Ran Noh, Tae Geol Lee, Chul-Ho Lee, Kyoung-Shim Kim
Metformin is a medication that is widely prescribed for the management of type 2 diabetes. In addition to its anti-diabetic uses, metformin has been proposed as a therapeutically effective drug candidate in various central nervous system disorders, including Parkinson's disease (PD). PD is characterized by severe movement defects and is commonly treated with the dopamine (DA) precursor 3,4-dihydroxyphenyl-l-alanine (L-DOPA). However, prolonged use of L-DOPA can lead to the development of L-DOPA-induced dyskinesia (LID)...
October 16, 2017: Molecular Neurobiology
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