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L-DOPA induced dyskinesia

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https://www.readbyqxmd.com/read/29758221/inhibition-of-striatal-cholinergic-interneuron-activity-by-the-kv7-opener-retigabine-and-the-nonsteroidal-anti-inflammatory-drug-diclofenac
#1
Rodrigo Manuel Paz, Cecilia Tubert, Agostina Stahl, Analía López Díaz, Roberto Etchenique, Mario Gustavo Murer, Lorena Rela
Striatal cholinergic interneurons provide modulation to striatal circuits involved in voluntary motor control and goal-directed behaviors through their autonomous tonic discharge and their firing "pause" responses to novel and rewarding environmental events. Striatal cholinergic interneuron hyperactivity was linked to the motor deficits associated with Parkinson's disease and the adverse effects of chronic antiparkinsonian therapy like l-DOPA-induced dyskinesia. Here we addressed whether Kv7 channels, which provide negative feedback to excitation in other neuron types, are involved in the control of striatal cholinergic interneuron tonic activity and response to excitatory inputs...
May 11, 2018: Neuropharmacology
https://www.readbyqxmd.com/read/29756234/inhaling-xenon-ameliorates-l-dopa-induced-dyskinesia-in-experimental-parkinsonism
#2
Jérôme Baufreton, Tomislav Milekovic, Qin Li, Steve McGuire, Eduardo Martin Moraud, Grégory Porras, Shiqi Sun, Wai Kin D Ko, Marine Chazalon, Stéphanie Morin, Elisabeth Normand, Géraldine Farjot, Aude Milet, Jan Pype, Elsa Pioli, Gregoire Courtine, Baptiste Bessière, Erwan Bezard
Parkinson's disease motor symptoms are treated with levodopa, but long-term treatment leads to disabling dyskinesia. Altered synaptic transmission and maladaptive plasticity of corticostriatal glutamatergic projections play a critical role in the pathophysiology of dyskinesia. Because the noble gas xenon inhibits excitatory glutamatergic signaling, primarily through allosteric antagonism of the N-methyl-d-aspartate receptors, we aimed to test its putative antidyskinetic capabilities. We first studied the direct effect of xenon gas exposure on corticostriatal plasticity in a murine model of levodopa-induced dyskinesia We then studied the impact of xenon inhalation on behavioral dyskinetic manifestations in the gold-standard rat and primate models of PD and levodopa-induced dyskinesia...
May 14, 2018: Movement Disorders: Official Journal of the Movement Disorder Society
https://www.readbyqxmd.com/read/29720658/diametric-neural-ensemble-dynamics-in-parkinsonian-and-dyskinetic-states
#3
Jones G Parker, Jesse D Marshall, Biafra Ahanonu, Yu-Wei Wu, Tony Hyun Kim, Benjamin F Grewe, Yanping Zhang, Jin Zhong Li, Jun B Ding, Michael D Ehlers, Mark J Schnitzer
Loss of dopamine in Parkinson's disease is hypothesized to impede movement by inducing hypo- and hyperactivity in striatal spiny projection neurons (SPNs) of the direct (dSPNs) and indirect (iSPNs) pathways in the basal ganglia, respectively. The opposite imbalance might underlie hyperkinetic abnormalities, such as dyskinesia caused by treatment of Parkinson's disease with the dopamine precursor L-DOPA. Here we monitored thousands of SPNs in behaving mice, before and after dopamine depletion and during L-DOPA-induced dyskinesia...
May 2, 2018: Nature
https://www.readbyqxmd.com/read/29704061/on-the-neuronal-circuitry-mediating-l-dopa-induced-dyskinesia
#4
REVIEW
M Angela Cenci, Henrik Jörntell, Per Petersson
With the advent of rodent models of L-DOPA-induced dyskinesia (LID), a growing literature has linked molecular changes in the striatum to the development and expression of abnormal involuntary movements. Changes in information processing at the striatal level are assumed to impact on the activity of downstream basal ganglia nuclei, which in turn influence brain-wide networks, but very little is actually known about systems-level mechanisms of dyskinesia. As an aid to approach this topic, we here review the anatomical and physiological organisation of cortico-basal ganglia-thalamocortical circuits, and the changes affecting these circuits in animal models of parkinsonism and LID...
April 27, 2018: Journal of Neural Transmission
https://www.readbyqxmd.com/read/29625424/mglu-receptors-in-the-treatment-of-parkinson-s-disease-and-l-dopa-induced-dyskinesia
#5
REVIEW
Irene Sebastianutto, Maria Angela Cenci
Parkinson's disease (PD) is a neurodegenerative disorder characterized by typical motor features that result from dopamine (DA) depletion in the striatum. DA replacement therapy with L-DOPA is the most efficacious symptomatic treatment, but causes complications that limit its utility, in particular, L-DOPA-induced dyskinesia (LID). LID is primarily caused by pre-synaptic and post-synaptic changes in DA neurotransmission, although it also depends on altered glutamatergic transmission at several nodes of the cortico-basal ganglia-thalamocortical network...
April 3, 2018: Current Opinion in Pharmacology
https://www.readbyqxmd.com/read/29611150/nociceptive-response-to-l-dopa-induced-dyskinesia-in-hemiparkinsonian-rats
#6
G C Nascimento, K Bariotto-Dos-Santos, C R A Leite-Panissi, E A Del-Bel, M Bortolanza
Non-motor symptoms are increasingly identified to present clinical and diagnostic importance for Parkinson's disease (PD). The multifactorial origin of pain in PD makes this symptom of great complexity. The dopamine precursor, L-DOPA (L-3,4-dihydroxyphenylalanine), the classic therapy for PD, seems to be effective in pain threshold; however, there are no studies correlating L-DOPA-induced dyskinesia (LID) and nociception development in experimental Parkinsonism. Here, we first investigated nociceptive responses in a 6-hydroxydopamine (6-OHDA)-lesioned rat model of Parkinson's disease to a hind paw-induced persistent inflammation...
April 2, 2018: Neurotoxicity Research
https://www.readbyqxmd.com/read/29578580/mao-b-and-comt-genetic-variations-associated-with-levodopa-treatment-response-in-patients-with-parkinson-s-disease
#7
Tiago Furtado Sampaio, Erinaldo Ubirajara Damasceno Dos Santos, Gessica Dayane Cordeiro de Lima, Rute Salgues Gueiros Dos Anjos, Ronaldo Celerino da Silva, Amdore Guescel C Asano, Nadja Maria Jorge Asano, Sergio Crovella, Paulo Roberto Eleutério de Souza
The most commonly used Parkinson's disease (PD) treatment is the replacement of dopamine by its levodopa precursor (l-dopa). Monoamine oxidase-B (MAO-B) and catechol-o-methyl transferase (COMT) are enzymes involved in the metabolism and regulation of dopamine availability. In our study we investigated the possible relation among selected single-nucleotide polymorphisms (SNPs) in the MAO-B (rs1799836) and COMT (rs4680) genes and the therapeutic response to levodopa (l-dopa). A total of 162 Brazilian patients from the Pro-Parkinson service of Clinics Hospital of Pernambuco diagnosed with sporadic PD and treated with levodopa were enrolled...
March 26, 2018: Journal of Clinical Pharmacology
https://www.readbyqxmd.com/read/29572645/effects-of-the-serotonin-5-ht-1a-receptor-biased-agonists-f13714-and-f15599-on-striatal-neurotransmitter-levels-following-l-dopa-administration-in-hemi-parkinsonian-rats
#8
Adrian Newman-Tancredi, Mark A Varney, Andrew C McCreary
Peak-dose dyskinesia is associated with the dramatic increase in striatal dopamine levels that follows L-DOPA administration. The 'false neurotransmitter' hypothesis postulates that the latter is likely due to an aberrant processing of L-DOPA by serotonergic neurons. In keeping with this hypothesis, two highly selective 'biased agonists' of 5-HT1A receptors-namely F13714 and F15599 (NLX-101)-were recently shown to exhibit exceptionally potent anti-dyskinetic activity without impairing L-DOPA therapeutic properties despite their differential targeting of 5-HT1A receptor sub-populations...
March 23, 2018: Neurochemical Research
https://www.readbyqxmd.com/read/29563862/caffeine-protects-dopaminergic-neurons-from-dopamine-induced-neurodegeneration-via-synergistic-adenosine-dopamine-d2-like-receptor-interactions-in-transgenic-caenorhabditis-elegans
#9
Rafael V M Manalo, Paul M B Medina
Previous studies have suggested that caffeine reduces the risk of L-DOPA-induced dyskinesia. However, caffeine is also known to promote dopamine signaling, which seemingly contradicts this observed effect. To this end, the study aimed to clarify the mechanism of caffeine neuroprotection in vivo when excess dopamine is present. Transgenic Caenorhabditis elegans (UA57) overproducing dopamine was exposed to caffeine for 7 days and monitored by observing GFP-tagged dopaminergic (DA) neurons via fluorescence microscopy...
2018: Frontiers in Neuroscience
https://www.readbyqxmd.com/read/29551735/identification-of-metabolite-biomarkers-for-l-dopa-induced-dyskinesia-in-a-rat-model-of-parkinson-s-disease-by-metabolomic-technology
#10
Yong Wang, Ge-Juan Zhang, Yi-Na Sun, Lu Yao, Hui-Sheng Wang, Cheng-Xue Du, Li Zhang, Jian Liu
L-DOPA-induced dyskinesia (LID) is a frequent complication of chronic L-DOPA therapy in the clinical treatment of Parkinson's disease (PD). The pathogenesis of LID involves complex molecular mechanisms in the striatum. Metabolomics can shed light on striatal metabolic alterations in LID. In the present study, we compared metabolomics profiles of striatum tissue from Parkinsonian rats with or without dyskinetic symptoms after chronic L-DOPA administration. A liquid chromatography-mass spectrometry based global metabolomics method combined with multivariate statistical analyses were used to detect candidate metabolites associated with LID...
March 15, 2018: Behavioural Brain Research
https://www.readbyqxmd.com/read/29541852/neuroinflammation-in-l-dopa-induced-dyskinesia-beyond-the-immune-function
#11
REVIEW
Augusta Pisanu, Laura Boi, Giovanna Mulas, Saturnino Spiga, Sandro Fenu, Anna R Carta
Neuroinflammation is a main component of Parkinson's disease (PD) neuropathology, where unremitting reactive microglia and microglia-secreted soluble molecules such as cytokines, contribute to the neurodegenerative process as part of an aberrant immune reaction. Besides, pro-inflammatory cytokines, predominantly TNF-α, play an important neuromodulatory role in the healthy and diseased brain, being involved in neurotransmitter metabolism, synaptic scaling and brain plasticity. Recent preclinical studies have evidenced an exacerbated neuroinflammatory reaction in the striatum of parkinsonian rats that developed dyskinetic responses following L-DOPA administration...
March 14, 2018: Journal of Neural Transmission
https://www.readbyqxmd.com/read/29530712/genetic-disruption-of-the-nuclear-receptor-nur77-nr4a1-in-rat-reduces-dopamine-cell-loss-and-l-dopa-induced-dyskinesia-in-experimental-parkinson-s-disease
#12
Claude Rouillard, Joanie Baillargeon, Brigitte Paquet, Michel St-Hilaire, Jérôme Maheux, Catherine Lévesque, Noémie Darlix, Simon Majeur, Daniel Lévesque
Parkinson's disease (PD) is an idiopathic progressive neurodegenerative disorder characterized by the loss of midbrain dopamine neurons. Levodopa (l-dopa) is the main pharmacological approach to relieve PD motor symptoms. However, chronic treatment with l-Dopa is inevitably associated with the generation of abnormal involuntary movements (l-Dopa-induced dyskinesia). We have previously shown that Nr4a1 (Nur77), a transcription factor of the nuclear receptor family, is closely associated with dopamine neurotransmission in the mature brain...
March 9, 2018: Experimental Neurology
https://www.readbyqxmd.com/read/29526790/selegiline-increases-on-time-without-exacerbation-of-dyskinesia-in-6-hydroxydopamine-lesioned-rats-displaying-l-dopa-induced-wearing-off-and-abnormal-involuntary-movements
#13
Hiroko Tsunekawa, Kazue Takahata, Motoki Okano, Toshiko Ishikawa, Hiroshi Satoyoshi, Tetsuya Nishimura, Naoya Hoshino, Shizuko Muraoka
3,4-Dihydroxy-l-phenylalanine (l-Dopa) remains the most effective drug for treating the motor symptoms of Parkinson's disease (PD). However, its long-term use is limited due to motor complications such as wearing-off and dyskinesia. A clinical study in PD patients with motor complications has demonstrated that selegiline, a monoamine oxidase type B inhibitor, is effective in reducing off time without worsening dyskinesia, although another study has shown worsening dyskinesia. Here, using unilateral 6-hydroxydopamine-lesioned rats showing degeneration of nigrostriatal dopaminergic neurons and l-Dopa-induced motor complications, we determined the efficacy of selegiline in controlling l-Dopa-induced motor fluctuations and exacerbated dyskinesia...
March 8, 2018: Behavioural Brain Research
https://www.readbyqxmd.com/read/29525397/correlation-between-dopamine-receptor-d2-expression-and-presence-of-abnormal-involuntary-movements-in-wistar-rats-with-hemiparkinsonism-and-dyskinesia
#14
P A Caro Aponte, C A Otálora, J C Guzmán, L F Turner, J P Alcázar, E L Mayorga
Parkinson's disease (PD) is characterised by motor alterations, which are commonly treated with L-DOPA. However, long-term L-DOPA use may cause dyskinesia. Although the pathogenic mechanism of L-DOPA-induced dyskinesia is unclear, the condition has been associated with alterations in dopamine receptors, among which D2 receptors (D2R) have received little attention. This study aims to: (i)develop and standardise an experimental model of L-DOPA-induced dyskinesia in rats with hemiparkinsonism; and (ii)evaluate the correlation between D2R expression and presence of abnormal involuntary movements (AIM)...
March 7, 2018: Neurología: Publicación Oficial de la Sociedad Española de Neurología
https://www.readbyqxmd.com/read/29511826/efficacy-and-safety-of-amantadine-for-the-treatment-of-l-dopa-induced-dyskinesia
#15
REVIEW
Santiago Perez-Lloret, Olivier Rascol
L-DOPA induced dyskinesias (LIDs) may affect up to 40% of Parkinson's disease (PD) and impact negatively health-related quality of life. Amantadine has demonstrated significant antidyskinetic effects in animal PD models and in randomized double-blind placebo-controlled trials (RCTs) in patients with PD. These effects are thought to be related to the blockade of NMDA receptors modulating cortico-striatal glutamatergic-dopaminergic interactions involved in the genesis of LIDs. There are three pharmaceutical forms of amantadine currently available in the market: an oral immediate-release (IR) formulation, which is widely available; an extended-release (ER) formulation (ADS-5102) which has been recently developed and approved by the FDA; and an intravenous infusion (IV) solution, which is not commonly used in clinical practice...
March 7, 2018: Journal of Neural Transmission
https://www.readbyqxmd.com/read/29508924/a-selective-phosphodiesterase-10a-inhibitor-reduces-l-dopa-induced-dyskinesias-in-parkinsonian-monkeys
#16
Goichi Beck, Shunsuke Maehara, Phat Ly Chang, Stella M Papa
BACKGROUND: Phosphodiesterase 10A is a member of the phosphodiesterase family whose brain expression is restricted to the striatum. Phosphodiesterase 10A regulates cyclic adenosine monophosphate and cyclic guanosine monophosphate, which mediate responses to dopamine receptor activation, and the levels of these cyclic nucleotides are decreased in experimental models of l-dopa-induced dyskinesia. The elevation of cyclic adenosine monophosphate/cyclic guanosine monophosphate levels by phosphodiesterase 10A inhibition may thus be targeted to reduce l-dopa-induced dyskinesia...
March 6, 2018: Movement Disorders: Official Journal of the Movement Disorder Society
https://www.readbyqxmd.com/read/29502255/pathophysiology-of-dyskinesia-and-behavioral-disorders-in-non-human-primates-the-role-of-serotonergic-fibers
#17
REVIEW
Véronique Sgambato, Léon Tremblay
The MPTP monkey model of Parkinson's disease (PD) has allowed huge advances regarding the understanding of the pathological mechanisms of PD and L-DOPA-induced adverse effects. Among the main findings were the imbalance between the efferent striatal pathways in opposite directions between the hypokinetic and hyperkinetic states of PD. In both normal and parkinsonian monkeys, the combination of behavioral and anatomical studies has allowed the deciphering of the cortico-basal ganglia circuits involved in both movement and behavioral disorders...
March 3, 2018: Journal of Neural Transmission
https://www.readbyqxmd.com/read/29492663/the-striatal-cholinergic-system-in-l-dopa-induced-dyskinesias
#18
REVIEW
X A Perez, T Bordia, M Quik
Cholinergic signaling plays a key role in regulating striatal function. The principal source of acetylcholine in the striatum is the cholinergic interneurons which, although low in number, densely arborize to modulate striatal neurotransmission. This modulation occurs via strategically positioned nicotinic and muscarinic acetylcholine receptors that influence striatal dopamine, GABA and other neurotransmitter release. Cholinergic interneurons integrate multiple striatal synaptic inputs and outputs to regulate motor activity under normal physiological conditions...
February 28, 2018: Journal of Neural Transmission
https://www.readbyqxmd.com/read/29492662/synaptic-plasticity-and-levodopa-induced-dyskinesia-electrophysiological-and-structural-abnormalities
#19
REVIEW
Barbara Picconi, Elvira De Leonibus, Paolo Calabresi
Parkinson's disease (PD) is a neurodegenerative disorder characterized by progressive degeneration of dopaminergic neurons located in the midbrain. The gold-standard therapy for PD is the restoration of dopamine (DA) levels through the chronic administration of the DA precursor levodopa (L-DOPA). Although levodopa therapy is the main therapeutic approach for PD, its use is limited by the development of very disabling dyskinetic movements, mainly due to the fluctuation of DA cerebral content. Experimental animal models of PD identified in DA D1/ERK-signaling pathway aberrant activation, occurring in striatal projection neurons, coupled with structural spines abnormalities, the molecular and neuronal basis of L-DOPA-induced dyskinesia (LIDs) occurrence...
February 28, 2018: Journal of Neural Transmission
https://www.readbyqxmd.com/read/29488257/animal-models-of-l-dopa-induced-dyskinesia-in-parkinson-s-disease
#20
REVIEW
M Angela Cenci, Alan R Crossman
Understanding the biological mechanisms of l-dopa-induced motor complications is dependent on our ability to investigate these phenomena in animal models of Parkinson's disease. The most common motor complications consist in wearing-off fluctuations and abnormal involuntary movements appearing when plasma levels of l-dopa are high, commonly referred to as peak-dose l-dopa-induced dyskinesia. Parkinsonian models exhibiting these features have been well-characterized in both rodent and nonhuman primate species...
February 28, 2018: Movement Disorders: Official Journal of the Movement Disorder Society
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