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L-DOPA induced dyskinesia

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https://www.readbyqxmd.com/read/28424060/effects-of-a-combination-treatment-of-kd5040-and-l-dopa-in-a-mouse-model-of-parkinson-s-disease
#1
Sora Ahn, Taek-Jin Song, Seong-Uk Park, Songhee Jeon, Jongpil Kim, Joo-Young Oh, Jaehwan Jang, Sanhwa Hong, Min-A Song, Hye-Seoung Shin, Young-Rim Jung, Hi-Joon Park
BACKGROUND: Although the dopamine precursor L-3, 4-dihydroxyphenylalanine ( l -dopa) remains the gold standard pharmacological therapy for patients with Parkinson's disease (PD), long-term treatment with this drug has been known to result in several adverse effects, including l -dopa-induced dyskinesia (LID). Recently, our group reported that KD5040, a modified herbal remedy, had neuroprotective effects in both in vitro and in vivo models of PD. Thus, the present study investigated whether KD5040 would have synergistic effects with l -dopa and antidyskinetic effects caused by l -dopa as well...
April 19, 2017: BMC Complementary and Alternative Medicine
https://www.readbyqxmd.com/read/28391443/non-human-primate-models-of-pd-to-test-novel-therapies
#2
REVIEW
Marc Morissette, Thérèse Di Paolo
Non-human primate (NHP) models of Parkinson disease show many similarities with the human disease. They are very useful to test novel pharmacotherapies as reviewed here. The various NHP models of this disease are described with their characteristics including the macaque, the marmoset, and the squirrel monkey models. Lesion-induced and genetic models are described. There is no drug to slow, delay, stop, or cure Parkinson disease; available treatments are symptomatic. The dopamine precursor, L-3,4-dihydroxyphenylalanine (L-Dopa) still remains the gold standard symptomatic treatment of Parkinson...
April 8, 2017: Journal of Neural Transmission
https://www.readbyqxmd.com/read/28379218/further-pharmacological-characterization-of-eltoprazine-focus-on-its-anxiolytic-anorexic-and-adverse%C3%A2-effect-potential
#3
Andreas Gravius, Andrzej Dekundy, Anita Vanaga, Lutz Franke, Wojciech Danysz
Eltoprazine, a drug that had previously been developed for aggression, has recently been investigated for L-DOPA-induced dyskinesia in animal models of Parkinson´s disease (PD) and in dyskinetic PD patients. Much less is known about effects of eltoprazine in other therapeutic indications. Indeed, the pharmacological profile of eltoprazine might suggest its effects on anxiety and food intake, but also adverse effect potential, which is the focus of the present study. Given for 2 weeks either as infusion or as twice-daily treatment, eltoprazine produced a decrease in food intake and body weight at doses leading to 200-500 nM plasma concentrations...
2017: Acta Neurobiologiae Experimentalis
https://www.readbyqxmd.com/read/28377741/adenosine-a2a-receptor-gene-knockout-prevents-l-3-4-dihydroxyphenylalanine-induced-dyskinesia-by-downregulation-of-striatal-gad67-in-6-ohda-lesioned-parkinson-s-mice
#4
Su-Bing Yin, Xiao-Guang Zhang, Shuang Chen, Wen-Ting Yang, Xia-Wei Zheng, Guo-Qing Zheng
l-3,4-Dihydroxyphenylalanine (l-DOPA) remains the primary pharmacological agent for the symptomatic treatment of Parkinson's disease (PD). However, the development of l-DOPA-induced dyskinesia (LID) limits the long-term use of l-DOPA for PD patients. Some data have reported that adenosine A2A receptor (A2AR) antagonists prevented LID in animal model of PD. However, the mechanism in which adenosine A2AR blockade alleviates the symptoms of LID has not been fully clarified. Here, we determined to knock out (KO) the gene of A2AR and explored the possible underlying mechanisms implicated in development of LID in a mouse model of PD...
2017: Frontiers in Neurology
https://www.readbyqxmd.com/read/28363801/continuous-cerebroventricular-administration-of-dopamine-a-new-treatment-for-severe-dyskinesia-in-parkinson-s-disease
#5
C Laloux, F Gouel, C Lachaud, K Timmerman, B Do Van, A Jonneaux, M Petrault, G Garcon, N Rouaix, C Moreau, R Bordet, J A Duce, J C Devedjian, D Devos
In Parkinson's disease (PD) depletion of dopamine in the nigro-striatal pathway is a main pathological hallmark that requires continuous and focal restoration. Current predominant treatment with intermittent oral administration of its precursor, Levodopa (l-dopa), remains the gold standard but pharmacological drawbacks trigger motor fluctuations and dyskinesia. Continuous intracerebroventricular (i.c.v.) administration of dopamine previously failed as a therapy because of an inability to resolve the accelerated dopamine oxidation and tachyphylaxia...
March 29, 2017: Neurobiology of Disease
https://www.readbyqxmd.com/read/28342749/characterizing-the-differential-roles-of-striatal-5-ht1a-auto-and-hetero-receptors-in-the-reduction-of-l-dopa-induced-dyskinesia
#6
Samantha M Meadows, Nicole E Chambers, Melissa M Conti, Sharon C Bossert, Crystal Tasber, Eitan Sheena, Mark Varney, Adrian Newman-Tancredi, Christopher Bishop
l-DOPA remains the benchmark treatment for Parkinson's disease (PD) motor symptoms, but chronic use leads to l-DOPA-induced dyskinesia (LID). The serotonin (5-HT) system has been established as a key modulator of LID and 5-HT1A receptors (5-HT1AR) stimulation has been shown to convey anti-dyskinetic effects. However, 5-HT1AR agonists often compromise clinical efficacy or display intrinsic side effects and their site(s) of actions remain debatable. Recently, highly selective G-protein biased 5-HT1AR agonists, F13714 and F15599, were shown to potently target 5-HT1A auto- or hetero-receptors, respectively...
March 23, 2017: Experimental Neurology
https://www.readbyqxmd.com/read/28337120/antidyskinetic-effects-of-mek-inhibitor-are-associated-with-multiple-neurochemical-alterations-in-the-striatum-of-hemiparkinsonian-rats
#7
Guiqin Chen, Shuke Nie, Chao Han, Kai Ma, Yan Xu, Zhentao Zhang, Stella M Papa, Xuebing Cao
L-DOPA-induced dyskinesia (LID) represents one of the major problems of the long-term therapy of patients with Parkinson's disease (PD). Although, the pathophysiologic mechanisms underlying LID are not completely understood, activation of the extracellular signal regulated kinase (ERK) is recognized to play a key role. ERK is phosphorylated by mitogen-activated protein kinase kinase (MEK), and thus MEK inhibitor can prevent ERK activation. Here the effect of the MEK inhibitor PD98059 on LID and the associated molecular changes were examined...
2017: Frontiers in Neuroscience
https://www.readbyqxmd.com/read/28315782/human-comt-over-expression-confers-a-heightened-susceptibility-to-dyskinesia-in-mice
#8
Oscar Solís, Jose-Rubén García-Montes, Patricia Garcia-Sanz, Antonio S Herranz, Maria-José Asensio, Gina Kang, Noboru Hiroi, Rosario Moratalla
Catechol-O-methyltransferase (COMT) degrades dopamine and its precursor l-DOPA and plays a critical role in regulating synaptic dopamine actions. We investigated the effects of heightened levels of COMT on dopamine-regulated motor behaviors and molecular alterations in a mouse model of dyskinesia. Transgenic mice overexpressing human COMT (TG) and their wildtype (WT) littermates received unilateral 6-OHDA lesions in the dorsal striatum and were treated chronically with l-DOPA for two weeks. l-DOPA-induced dyskinesia was exacerbated in TG mice without altering l-DOPA motor efficacy as determined by contralateral rotations or motor coordination...
June 2017: Neurobiology of Disease
https://www.readbyqxmd.com/read/28286180/dysregulation-of-bet-proteins-in-levodopa-induced-dyskinesia
#9
David A Figge, David G Standaert
Levodopa (L-DOPA) remains the most effective pharmacological treatment for Parkinson Disease (PD) but its use is limited by the development of debilitating drug-related side effects, particularly L-DOPA induced dyskinesia (LID). LID is a consequence of long-term L-DOPA use, and in model systems is characterized by a "priming effect", whereby initial administrations of L-DOPA trigger a sensitized biochemical and transcriptional response upon subsequent dopaminergic stimulation. Preliminary studies into the mechanisms underlying this cellular memory have indicated an important role for epigenetic change but many of the downstream mechanisms remain unknown...
June 2017: Neurobiology of Disease
https://www.readbyqxmd.com/read/28284817/differential-effects-of-gaseous-versus-injectable-anesthetics-on-changes-in-regional-cerebral-blood-flow-and-metabolism-induced-by-l-dopa-in-a-rat-model-of-parkinson-s-disease
#10
Zisis Bimpisidis, Carl M Öberg, Natallia Maslava, M Angela Cenci, Cornelia Lundblad
Preclinical imaging of brain activity requires the use of anesthesia. In this study, we have compared the effects of two widely used anesthetics, inhaled isoflurane and ketamine/xylazine cocktail, on cerebral blood flow and metabolism in a rat model of Parkinson's disease and l-DOPA-induced dyskinesia. Specific tracers were used to estimate regional cerebral blood flow (rCBF - [(14)C]-iodoantipyrine) and regional cerebral metabolic rate (rCMR - [(14)C]-2-deoxyglucose) with a highly sensitive autoradiographic method...
March 8, 2017: Experimental Neurology
https://www.readbyqxmd.com/read/28256089/striatal-activation-by-optogenetics-induces-dyskinesias-in-the-6-hydroxydopamine-rat-model-of-parkinson-disease
#11
Ledia F Hernández, Ivan Castela, Irene Ruiz-DeDiego, Jose A Obeso, Rosario Moratalla
BACKGROUND: Long-term levodopa (l-dopa) treatment is associated with the development of l-dopa-induced dyskinesias in the majority of patients with Parkinson disease (PD). The etiopathogonesis and mechanisms underlying l-dopa-induced dyskinesias are not well understood. METHODS: We used striatal optogenetic stimulation to induce dyskinesias in a hemiparkinsonian model of PD in rats. Striatal dopamine depletion was induced unilaterally by 6-hydroxydopamine injection into the medial forebrain bundle...
April 2017: Movement Disorders: Official Journal of the Movement Disorder Society
https://www.readbyqxmd.com/read/28256010/striatal-d1-medium-spiny-neuron-activation-induces-dyskinesias-in-parkinsonian-mice
#12
Xiomara A Perez, Danhui Zhang, Tanuja Bordia, Maryka Quik
BACKGROUND: Dyskinesias are a disabling motor complication that arises with prolonged l-dopa treatment. Studies using D1 receptor drugs and genetically modified mice suggest that medium spiny neurons expressing D1 receptors play a primary role in l-dopa-induced dyskinesias. However, the specific role of these neurons in dyskinesias is not fully understood. METHODS: We used optogenetics, which allows for precise modulation of select neurons in vivo, to investigate whether striatal D1-expressing medium spiny neuron activity regulates abnormal involuntary movements or dyskinesia in parkinsonian mice...
April 2017: Movement Disorders: Official Journal of the Movement Disorder Society
https://www.readbyqxmd.com/read/28244186/cerebrospinal-fluid-levels-of-catecholamines-and-its-metabolites-in-parkinson-s-disease-effect-of-l-dopa-treatment-and-changes-in-levodopa-induced-dyskinesia
#13
Andreas Dammann Andersen, Morten Blaabjerg, Michael Binzer, Akram Kamal, Helle Thagesen, Troels Wesenberg Kjaer, Egon Stenager, Jan Bert Paul Gramsbergen
Levodopa (l-DOPA, l-3,4-dihydroxyphenylalanine) is the most effective drug in the symptomatic treatment of Parkinson's disease (PD), but chronic use initiates a maladaptive process leading to l-DOPA-induced dyskinesia (LID). Risk factors for early onset LID include younger age, more severe disease at baseline and higher daily l-DOPA dose, but biomarkers to predict the risk of motor complications are not yet available. Here, we investigated whether CSF levels of catecholamines and its metabolites are altered in PD patients with LID [PD-LID, n = 8)] as compared to non-dyskinetic PD patients receiving l-DOPA (PD-L, n = 6), or not receiving l-DOPA (PD-N, n = 7) as well as non-PD controls (n = 16)...
February 28, 2017: Journal of Neurochemistry
https://www.readbyqxmd.com/read/28239340/dopamine-induced-changes-in-g%C3%AE-olf-protein-levels-in-striatonigral-and-striatopallidal-medium-spiny-neurons-underlie-the-genesis-of-l-dopa-induced-dyskinesia-in-parkinsonian-mice
#14
Ryoma Morigaki, Shinya Okita, Satoshi Goto
The dopamine precursor, l-3,4-dihydroxyphenylalanine (l-DOPA), exerts powerful therapeutic effects but eventually generates l-DOPA-induced dyskinesia (LID) in patients with Parkinson's disease (PD). LID has a close link with deregulation of striatal dopamine/cAMP signaling, which is integrated by medium spiny neurons (MSNs). Olfactory type G-protein α subunit (Gαolf), a stimulatory GTP-binding protein encoded by the GNAL gene, is highly concentrated in the striatum, where it positively couples with dopamine D1 (D1R) receptor and adenosine A2A receptor (A2AR) to increase intracellular cAMP levels in MSNs...
2017: Frontiers in Cellular Neuroscience
https://www.readbyqxmd.com/read/28131725/the-5-alpha-reductase-inhibitor-finasteride-reduces-dyskinesia-in-a-rat-model-of-parkinson-s-disease
#15
Roberto Frau, Paola Savoia, Silvia Fanni, Chiara Fiorentini, Camino Fidalgo, Elisabetta Tronci, Roberto Stancampiano, Mario Meloni, Antonino Cannas, Francesco Marrosu, Marco Bortolato, Paola Devoto, Cristina Missale, Manolo Carta
Levodopa-induced dyskinesia (LID) is a disabling motor complication occurring in Parkinson's disease patients (PD) after long-term l-DOPA treatment. Although its etiology remains unclear, there is accumulating evidence that LID relies on an excessive dopamine receptor transmission, particularly at the downstream signaling of D1 receptors. We previously reported that the pharmacological blockade of 5-alpha reductase (5AR), the rate limiting enzyme in neurosteroids synthesis, rescued a number of behavioral aberrations induced by D1 receptor-selective and non-selective agonists, without inducing extrapyramidal symptoms...
January 26, 2017: Experimental Neurology
https://www.readbyqxmd.com/read/28130646/the-effect-of-mirtazapine-on-dopaminergic-psychosis-and-dyskinesia-in-the-parkinsonian-marmoset
#16
Adjia Hamadjida, Stephen G Nuara, Nicolas Veyres, Imane Frouni, Cynthia Kwan, Lamia Sid-Otmane, Mery-Jane Harraka, Jim C Gourdon, Philippe Huot
BACKGROUND: Parkinson's disease (PD) psychosis is encountered in as many as 50% of patients with advanced disease. Treatment options for PD psychosis are few. In fact, only clozapine and pimavanserin have shown efficacy in randomised controlled trials. Clinicians are often reluctant to prescribe the former, due to the risk of agranulocytosis, while the latter is not widely available yet. Because it is already clinically available and exhibits high affinity for serotonin 2A receptors, a target with which both clozapine and pimavanserin interact, we hypothesised that the anti-depressant mirtazapine might be effective to alleviate PD psychosis...
March 2017: Psychopharmacology
https://www.readbyqxmd.com/read/28125015/polymorphisms-of-dopamine-receptor-genes-and-risk-of-l-dopa-induced-dyskinesia-in-parkinson-s-disease
#17
Cristoforo Comi, Marco Ferrari, Franca Marino, Luca Magistrelli, Roberto Cantello, Giulio Riboldazzi, Maria Laura Ester Bianchi, Giorgio Bono, Marco Cosentino
L-dopa-induced dyskinesia (LID) is a frequent motor complication of Parkinson's disease (PD), associated with a negative prognosis. Previous studies showed an association between dopamine receptor (DR) gene (DR) variants and LID, the results of which have not been confirmed. The present study is aimed to determine whether genetic differences of DR are associated with LID in a small but well-characterized cohort of PD patients. To this end we enrolled 100 PD subjects, 50 with and 50 without LID, matched for age, gender, disease duration and dopaminergic medication in a case-control study...
January 24, 2017: International Journal of Molecular Sciences
https://www.readbyqxmd.com/read/28112685/chemogenetic-stimulation-of-striatal-projection-neurons-modulates-responses-to-parkinson-s-disease-therapy
#18
Cristina Alcacer, Laura Andreoli, Irene Sebastianutto, Johan Jakobsson, Tim Fieblinger, Maria Angela Cenci
Parkinson's disease (PD) patients experience loss of normal motor function (hypokinesia), but can develop uncontrollable movements known as dyskinesia upon treatment with L-DOPA. Poverty or excess of movement in PD has been attributed to overactivity of striatal projection neurons forming either the indirect (iSPNs) or the direct (dSPNs) pathway, respectively. Here, we investigated the two pathways' contribution to different motor features using SPN type-specific chemogenetic stimulation in rodent models of PD (PD mice) and L-DOPA-induced dyskinesia (LID mice)...
February 1, 2017: Journal of Clinical Investigation
https://www.readbyqxmd.com/read/28105331/opioid-system-in-l-dopa-induced-dyskinesia
#19
REVIEW
Jing Pan, Huaibin Cai
L-3, 4-Dihydroxyphenylalanine (L-DOPA)-induced dyskinesia (LID) is a major clinical complication in the treatment of Parkinson's disease (PD). This debilitating side effect likely reflects aberrant compensatory responses for a combination of dopaminergic neuron denervation and repeated L-DOPA administration. Abnormal endogenous opioid signal transduction pathways in basal ganglia have been well documented in LID. Opioid receptors have been targeted to alleviate the dyskinesia. However, the exact role of this altered opioid activity is remains under active investigation...
2017: Translational Neurodegeneration
https://www.readbyqxmd.com/read/27981510/aberrant-cpg-methylation-mediates-abnormal-transcription-of-mao-a-induced-by-acute-and-chronic-l-3-4-dihydroxyphenylalanine-administration-in-sh-sy5y-neuronal-cells
#20
Zhaofei Yang, Xuan Wang, Jian Yang, Min Sun, Yong Wang, Xiaomin Wang
L-3,4-dihydroxyphenylalanine (L-dopa) remains the most effective drug for therapy of Parkinson's disease (PD); however, long-term use of it causes serious side effects. L-dopa-induced dyskinesia (LID) has consistently been related to L-dopa-derived excessive dopamine release, but the mechanisms have not been addressed very clear. Monoamine oxidase A (MAO-A) is one of the key enzymes in dopamine metabolism and therefore may be involved in L-dopa-induced side effects. And, epigenetic modification controls MAO-A gene transcription...
April 2017: Neurotoxicity Research
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