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L-DOPA induced dyskinesia

Fernanda F Peres, Raquel Levin, Mayra A Suiama, Mariana C Diana, Douglas A Gouvêa, Valéria Almeida, Camila M Santos, Lisandro Lungato, Antônio W Zuardi, Jaime E C Hallak, José A Crippa, D'Almeida Vânia, Regina H Silva, Vanessa C Abílio
Cannabidiol (CBD) is a non-psychotomimetic compound from Cannabis sativa that presents antipsychotic, anxiolytic, anti-inflammatory, and neuroprotective effects. In Parkinson's disease patients, CBD is able to attenuate the psychotic symptoms induced by L-DOPA and to improve quality of life. Repeated administration of reserpine in rodents induces motor impairments that are accompanied by cognitive deficits, and has been applied to model both tardive dyskinesia and Parkinson's disease. The present study investigated whether CBD administration would attenuate reserpine-induced motor and cognitive impairments in rats...
2016: Frontiers in Pharmacology
Giovanna Mulas, Elena Espa, Sandro Fenu, Saturnino Spiga, Giovanni Cossu, Elisabetta Pillai, Ezio Carboni, Gabriella Simbula, Dragana Jadžić, Fabrizio Angius, Stefano Spolittu, Barbara Batetta, Daniela Lecca, Andrea Giuffrida, Anna R Carta
Neuroinflammation is associated with l-DOPA treatment in Parkinson's disease (PD), suggesting a role in l-DOPA-induced dyskinesia (LID), however it is unclear whether increased inflammation is specifically related to the dyskinetic outcome of l-DOPA treatment. Diversely from oral l-DOPA, continuous intrajejunal l-DOPA infusion is associated with very low dyskinetic outcome in PD patients. We reproduced these regimens of administration in 6-OHDA-lesioned hemiparkinsonian rats, where dyskinetic responses and striatal neuroinflammation induced by chronic pulsatile (DOPAp) or continuous (DOPAc) l-DOPA were compared...
September 30, 2016: Experimental Neurology
Elizabeth S Smith, Gwendolyn A Hardy, Timothy Schallert, Hongjoo J Lee
Attentional deficits including difficulty in switching attention between tasks or rules, sustaining attention, and selectively attending to specific stimuli are commonly seen in patients with Parkinson's disease (PD). While these deficits are frequently reported, it is unclear how traditional dopamine replacement therapy such as l-dopa affects these deficits. In a rat model of PD in which dopamine is unilaterally depleted with a 6-hydroxydopamine infusion to the medial forebrain bundle, we first examined the impact of acute and chronic l-dopa treatment on attention switching as modeled by disengagement behavior (i...
September 21, 2016: Neuroscience
Ariana Q Farrand, Rebecca A Gregory, Cristina M Bäckman, Kristi L Helke, Heather A Boger
Mitochondrial dysfunction has been implicated in the degeneration of dopamine (DA) neurons in Parkinson's disease (PD). In addition, animal models of PD utilizing neurotoxins, such as 6-hydroxydopamine and 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine, have shown that these toxins disrupt mitochondrial respiration by targeting complex I of the electron transport chain, thereby impairing DA neurons in these models. A MitoPark mouse model was created to mimic the mitochondrial dysfunction observed in the DA system of PD patients...
September 19, 2016: Brain Research
Elaine Del-Bel, Mariza Bortolanza, Maurício Dos-Santos-Pereira, Keila Bariotto, Rita Raisman-Vozari
Inflammation in Parkinson's disease (PD) is a new concept that has gained ground due to the potential of mitigating dopaminergic neuron death by decreasing inflammation. The solution to this question is likely to be complex. We propose here that the significance of inflammation in PD may go beyond the nigral cell death. The pathological process that underlies PD requires years to reach its full extent. A growing body of evidence has been accumulated on the presence of multiple inflammatory signs in the brain of PD patients even in very late stages of the disease...
December 2016: Synapse
Maowen Ba, Min Kong, Lina Guan, Maoli Yi, Hongli Zhang
Fluctuations of dopamine levels and upregulations of NR2B tyrosine phosphorylation in the striatum have been connected with levodopa (L-dopa)-induced dyskinesia (LID) in Parkinson's disease (PD). Repetitive transcranial magnetic stimulation (rTMS) is one of the noninvasive and potential method treating dyskinesia. Yet, the effect of rTMS on the above key pathological events remains unclear. In this study, we gave L-dopa treatment intraperitoneally for 22 days to 6-hydroxydopamine-lesioned PD rats to prepare LID rats model, and subsequently applied rTMS daily for 3 weeks to LID rats model...
August 24, 2016: Oncotarget
Luz M Suarez, Oscar Solis, Carolina Aguado, Rafael Lujan, Rosario Moratalla
Dopamine depletion in Parkinson's disease (PD) produces dendritic spine loss in striatal medium spiny neurons (MSNs) and increases their excitability. However, the synaptic changes that occur in MSNs in PD, in particular those induced by chronic L-3,4-dihydroxyphenylalanine (L-DOPA) treatment, are still poorly understood. We exposed BAC-transgenic D1-tomato and D2-eGFP mice to PD and dyskinesia model paradigms, enabling cell type-specific assessment of changes in synaptic physiology and morphology. The distinct fluorescence markers allowed us to identify D1 and D2 MSNs for analysis using intracellular sharp electrode recordings, electron microscopy, and 3D reconstructions with single-cell Lucifer Yellow injections...
September 9, 2016: Cerebral Cortex
Irene Sebastianutto, Natallia Maslava, Corey R Hopkins, M Angela Cenci
Rodent models of l-DOPA-induced dyskinesia (LID) are essential to investigate pathophysiological mechanisms and treatment options. Ratings of abnormal involuntary movements (AIMs) are used to capture both qualitative and quantitative features of dyskinetic behaviors. Thus far, validated rating scales for the mouse have anchored the definition of severity to the time during which AIMs are present. Here we have asked whether the severity of axial, limb, and orolingual AIMs can be objectively assessed with scores based on movement amplitude...
September 2, 2016: Neurobiology of Disease
Hye-Yeon Park, Young-Kyoung Ryu, Jun Go, Eunjung Son, Kyoung-Shim Kim, Mee Ree Kim
L-3,4-dihydroxyphenylalanine (L-DOPA) is the most common treatment for patients with Parkinson's disease (PD). However, long term use of L-DOPA for PD therapy lead to abnormal involuntary movements (AIMs) known as dyskinesia. Fatty acid amide hydrolase (FAAH) is enriched protein in basal ganglia, and inhibition of the protein reduces dyskinetic behavior of mice. Palmitoyl serotonin (PA-5HT) is a hybrid molecule patterned after arachidonoyl serotonin, antagonist of FAAH. However, the effect of PA-5HT on L-DOPA-induced dyskinesia (LID) in PD have not yet been elucidated...
August 2016: Experimental Neurobiology
Melissa M Conti, Samantha M Meadows, Mitchell Melikhov-Sosin, David Lindenbach, Joy Hallmark, David F Werner, Christopher Bishop
l-DOPA is the standard treatment for Parkinson's disease (PD), but chronic treatment typically leads to abnormal involuntary movement or dyskinesia (LID) development. Although poorly understood, dyskinetic mechanisms involve a complex interaction between the remaining dopamine system and the semi-homologous serotonin and norepinephrine systems. Serotonin and norepinephrine transporters (SERT and NET, respectively) have affinity for dopamine uptake especially when dopamine transporters (DAT) are scant. Monoamine reuptake inhibitors have been reported to modulate l-DOPA's anti-parkinsonian effects, but DAT, SERT, and NET's contribution to dyskinesia has not been well delineated...
November 2016: Neuropharmacology
Wai Kin D Ko, Sandrine M Camus, Qin Li, Jianzhong Yang, Steve McGuire, Elsa Y Pioli, Erwan Bezard
Istradefylline (KW-6002), an adenosine A2A receptor antagonist, is used adjunct with optimal doses of L-3,4-dihydroxyphenylalanine (l-DOPA) to extend on-time in Parkinson's disease (PD) patients experiencing motor fluctuations. Clinical application of istradefylline for the management of other l-DOPA-induced complications, both motor and non-motor related (i.e. dyskinesia and cognitive impairments), remains to be determined. In this study, acute effects of istradefylline (60-100 mg/kg) alone, or with optimal and sub-optimal doses of l-DOPA, were evaluated in two monkey models of PD (i) the gold-standard 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-treated macaque model of parkinsonian and dyskinetic motor symptoms and (ii) the chronic low dose (CLD) MPTP-treated macaque model of cognitive (working memory and attentional) deficits...
November 2016: Neuropharmacology
Jeffrey H Kordower, Angel Vinuela, Yaping Chu, Ole Isacson, D Eugene Redmond
Clinical trials testing the hypothesis that fetal dopamine grafts would provide antiparkinsonian benefit in patients who had already developed side-effects from their long-terms use of L-dopa revealed, in some cases, the presence of dyskinesias even in the absence of L-dopa. The form, intensity, and frequency of these dyskinesias were quite variable, but their manifestation slowed down the clinical development of cell replacement therapies. Rodent models of graft-induced dyskinesias (GIDs) have been proposed, however their accuracy in modeling GIDs has been questioned since they usually require amphetamine for their presentation...
July 15, 2016: Journal of Comparative Neurology
Maurício Dos-Santos-Pereira, Célia Aparecida da-Silva, Francisco Silveira Guimarães, Elaine Del-Bel
No abstract text is available yet for this article.
October 2016: Neurobiology of Disease
Paolo Calabresi, Antonio Pisani, John Rothwell, Veronica Ghiglieri, Josè A Obeso, Barbara Picconi
Recent clinical and preclinical studies have shown that hyperkinetic disorders such as Huntington's disease, dystonia and l-DOPA-induced dyskinesia in Parkinson's disease are all characterized by loss of the ability to reverse synaptic plasticity and an associated increase in the excitability of excitatory neuronal inputs to a range of cortical and subcortical brain areas. Moreover, these changes have been detected in humans with hyperkinetic disorders either via direct recordings from implanted deep brain electrodes or noninvasively using transcranial magnetic stimulation...
June 28, 2016: Nature Neuroscience
Martin Klietz, Ursula Keber, Thomas Carlsson, Wei-Hua Chiu, Günter U Höglinger, Eberhard Weihe, Martin K-H Schäfer, Candan Depboylu
l-3,4-Dihydroxyphenylalanine (l-DOPA) is the therapeutic gold standard in Parkinson's disease. However, most patients develop debilitating abnormal involuntary movements termed l-DOPA-induced dyskinesia (LID) as therapy-complicating side effects. The underlying mechanisms of LID pathogenesis are still not fully understood. Recent evidence suggests an involvement of striatal tyrosine hydroxylase (TH) protein-expressing neurons, as they are capable of endogenously producing l-DOPA and possibly dopamine. The aim of this study was to elucidate changes of TH transcription in the striatum and nucleus accumbens that occur under experimental conditions of LID...
September 7, 2016: Neuroscience
Rajib Paul, Anupom Borah
BACKGROUND: Dopamine replacement therapy by its precursor, L-3.4-dihydroxyphenylalanine (L-DOPA), has been the treatment of choice for Parkinson's disease. However, the possible contributory effect of L-DOPA therapy on the progression of Parkinson's disease mediated by the L-DOPA-induced toxic metabolites remains elusive. SCOPE OF REVIEW: Prolong use of L-DOPA leads to behavioral impediments and instigate the generation of several toxic metabolites. One such metabolite is homocysteine, the level of which increases in the plasma of Parkinson's disease patients undergoing L-DOPA therapy, as well as in brain of animal models of the disease...
September 2016: Biochimica et Biophysica Acta
Francesco Bez, Veronica Francardo, M Angela Cenci
Mice with striatal 6-hydroxydopamine (6-OHDA) lesions are widely used as a model to study the effects of neurorestorative, symptomatic, or antidyskinetic treatments for Parkinson's disease (PD). The standard praxis is to utilize young adult mice with relatively acute 6-OHDA lesions. However, long post-lesion intervals may be required for longitudinal studies of treatment interventions, and the long-term stability of the model's behavioral and cellular phenotypes is currently unknown. In this study, C57Bl/6J mice sustained unilateral striatal 6-OHDA lesions at approx...
October 2016: Neurobiology of Disease
David A Figge, Karen L Eskow Jaunarajs, David G Standaert
UNLABELLED: Levodopa-induced dyskinesia (LID) is a persistent behavioral sensitization that develops after repeated levodopa (l-DOPA) exposure in Parkinson disease patients. LID is a consequence of sustained changes in the transcriptional behavior of striatal neurons following dopaminergic stimulation. In neurons, transcriptional regulation through dynamic DNA methylation has been shown pivotal to many long-term behavioral modifications; however, its role in LID has not yet been explored...
June 15, 2016: Journal of Neuroscience: the Official Journal of the Society for Neuroscience
Yan Shen, Jinsha Huang, Ling Liu, Xiaoyun Xu, Chao Han, Guoxin Zhang, Haiyang Jiang, Jie Li, Zhicheng Lin, Nian Xiong, Tao Wang
Parkinson's Disease (PD) is a progressively neurodegenerative disorder, implicitly characterized by a stepwise loss of dopaminergic (DA) neurons in the substantia nigra pars compacta (SNpc) and explicitly marked by bradykinesia, rigidity, resting tremor and postural instability. Currently, therapeutic approaches available are mainly palliative strategies, including L-3,4-dihydroxy-phenylalanine (L-DOPA) replacement therapy, DA receptor agonist and deep brain stimulation (DBS) procedures. As the disease proceeds, however, the pharmacotherapeutic efficacy is inevitably worn off, worse still, implicated by side effects of motor response oscillations as well as L-DOPA induced dyskinesia (LID)...
2016: Frontiers in Aging Neuroscience
Scott J Sherman, Miguel Estevez, Ari B Magill, Torsten Falk
Ketamine is an FDA-approved drug with a known safety profile. Low-dose subanesthetic intravenous ketamine infusion treatment has led to long-term reduction of treatment-resistant depression and of chronic pain states. We report on low-dose subanesthetic intravenous ketamine infusion treatment in Parkinson's disease (PD) patients by 5 case studies and show a long-lasting therapeutic benefit to reduce l-DOPA-induced dyskinesia (LID), improve on time, and reduce depression. Based on the literature we hypothesize that low-dose ketamine may act as a 'chemical deep brain stimulation', by desynchronizing hypersynchronous oscillatory brain activity, including in the basal ganglia and the motor cortex...
January 2016: Case Reports in Neurology
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