Pathophysiological Mechanisms and Experimental Pharmacotherapy for L-Dopa-Induced Dyskinesia.
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ABSTRACT:
SUBMITTER: Fabbrini A
PROVIDER: S-EPMC8092630 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Parkinson's disease is caused primarily by degeneration of brain dopaminergic neurons in the substantia nigra and the consequent deficit of dopamine in the striatum. Dopamine replacement therapy with the dopamine precursor l-dopa is the mainstay of current treatment. After several years, however, the patients develop l-dopa-induced dyskinesia, or abnormal involuntary movements, thought to be due to excessive signaling via dopamine receptors. G protein-coupled receptor kinases (GRKs) control desensitization of dopamine receptors. We found that dyskinesia is attenuated by lentivirus-mediated overexpression of GRK6 in the striatum in rodent and primate models of Parkinson's disease. Conversely, reduction of GRK6 concentration by microRNA delivered with lentiviral vector exacerbated dyskinesia in parkinsonian rats. GRK6 suppressed dyskinesia in monkeys without compromising the antiparkinsonian effects of l-dopa and even prolonged the antiparkinsonian effect of a lower dose of l-dopa. Our finding that increased availability of GRK6 ameliorates dyskinesia and increases duration of the antiparkinsonian action of l-dopa suggests a promising approach for controlling both dyskinesia and motor fluctuations in Parkinson's disease.
| S-EPMC2933751 | biostudies-literature
Project description:The dopamine (DA) precursor l-DOPA has been the most effective treatment for Parkinson's disease (PD) for over 40?years. However, the response to this treatment changes with disease progression, and most patients develop dyskinesias (abnormal involuntary movements) and motor fluctuations within a few years of l-DOPA therapy. There is wide consensus that these motor complications depend on both pre- and post-synaptic disturbances of nigrostriatal DA transmission. Several presynaptic mechanisms converge to generate large DA swings in the brain concomitant with the peaks-and-troughs of plasma l-DOPA levels, while post-synaptic changes engender abnormal functional responses in dopaminoceptive neurons. While this general picture is well-accepted, the relative contribution of different factors remains a matter of debate. A particularly animated debate has been growing around putative players on the presynaptic side of the cascade. To what extent do presynaptic disturbances in DA transmission depend on deficiency/dysfunction of the DA transporter, aberrant release of DA from serotonin neurons, or gliovascular mechanisms? And does noradrenaline (which is synthetized from DA) play a role? This review article will summarize key findings, controversies, and pending questions regarding the presynaptic mechanisms of l-DOPA-induced dyskinesia. Intriguingly, the debate around these mechanisms has spurred research into previously unexplored facets of brain plasticity that have far-reaching implications to the treatment of neuropsychiatric disease.
| S-EPMC4266027 | biostudies-literature
Project description:BackgroundParkinsonism is caused by dopamine (DA) insufficiency and results in a hypokinetic movement disorder. Treatment with L-Dopa can restore DA availability and improve motor function, but patients can develop L-Dopa-induced dyskinesia (LID), a secondary hyperkinetic movement disorder. The mechanism underlying LID remains unknown, and new treatments are needed. Experiments in mice have shown that DA deficiency promotes an imbalance between striatal acetylcholine (ACh) and DA that contributes to motor dysfunction. While treatment with L-Dopa improves DA availability, it promotes a paradoxical rise in striatal ACh and a further increase in the ACh to DA ratio may promote LID.MethodsWe used conditional Slc6a3DTR/+ mice to model progressive DA deficiency and the ?-adrenergic receptor (?-AR) antagonist propranolol to limit the activity of striatal cholinergic interneurons (ChIs). DA-deficient mice were treated with L-Dopa and the dopa decarboxylase inhibitor benserazide. LID and motor performance were assessed by rotarod, balance beam, and open field testing. Electrophysiological experiments characterized the effects of ?-AR ligands on striatal ChIs.ResultsLID was observed in a subset of DA-deficient mice. Treatment with propranolol relieved LID and motor hyperactivity. Electrophysiological experiments showed that ?-ARs can effectively modulate ChI firing.ConclusionsThe work suggests that pharmacological modulation of ChIs by ?-ARs might provide a therapeutic option for managing LID.
| S-EPMC7760026 | biostudies-literature
Project description:L-3,4-dihydroxyphenylalanine (L-DOPA)-induced dyskinesia is a side effect of Parkinson's disease treatment and it is characterized by atypical involuntary movements. A link between neuroinflammation and L-DOPA-induced dyskinesia has been documented. Hydrogen gas (H2) has neuroprotective effects in Parkinson's disease models and has a major anti-inflammatory effect. Our objective is to test the hypothesis that H2 inhalation reduces L-DOPA-induced dyskinesia. 15 days after 6-hydroxydopamine lesions of dopaminergic neurons were made (microinjection into the medial forebrain bundle), chronic L-DOPA treatment (15 days) was performed. Rats were exposed to H2 (2% gas mixture, 1 h) or air (controls) before L-DOPA injection. Abnormal involuntary movements and locomotor activity were conducted. Striatal microglia and astrocyte was analyzed and striatal and plasma samples for cytokines evaluation were collected after the abnormal involuntary movements analysis. H2 inhalation attenuated L-DOPA-induced dyskinesia. The gas therapy did not impair the improvement of locomotor activity achieved by L-DOPA treatment. H2 inhalation reduced activated microglia in the lesioned striatum, which is consistent with the observed reduced pro-inflammatory cytokines levels. Display of abnormal involuntary movements was positively correlated with plasma IL-1β and striatal TNF-α levels and negatively correlated with striatal IL-10 levels. Prophylactic H2 inhalation decreases abnormal involuntary movements in a preclinical L-DOPA-induced dyskinesia model. The H2 antidyskinetic effect was associated with decreased striatal and peripheral inflammation. This finding has a translational importance to L-DOPA-treated parkinsonian patients' well-being.
| S-EPMC10121822 | biostudies-literature
Project description:We have examined the pattern of striatal messenger RNA expression of over 8000 genes in a rat model of levodopa (L-DOPA)-induced dyskinesia and Parkinson disease (PD). 6-Hydroxydopamine (6-OHDA)-lesioned rats were treated with L-DOPA or physiological saline for 22 days and repeatedly tested for antiakinetic response to L-DOPA and the development of abnormal involuntary movements (AIMs). In a comparison of rats that developed a dyskinetic motor response to rats that did not, we found striking differences in gene expression patterns. In rats that developed dyskinesia, GABA neurons had an increased transcriptional activity, and genes involved in Ca2+ homeostasis, in Ca2+ -dependent signaling, and in structural and synaptic plasticity were upregulated. The gene expression patterns implied that the dyskinetic striatum had increased transcriptional, as well as synaptic activity, and decreased capacity for energy production. Some basic maintenance chores such as ribosome protein biosynthesis were downregulated, possibly a response to expended ATP levels.
| S-EPMC4208672 | biostudies-literature
Project description:A large body of work during the past several decades has been focused on therapeutic strategies to control L-DOPA-induced dyskinesias (LIDs), common motor complications of long-term L-DOPA therapy in Parkinson's disease (PD). Yet, LIDs remain a clinical challenge for the management of patients with advanced disease. Glutamatergic dysregulation of striatal projection neurons (SPNs) appears to be a key contributor to altered motor responses to L-DOPA. Targeting striatal hyperactivity at the glutamatergic neurotransmission level led to significant preclinical and clinical trials of a variety of antiglutamatergic agents. In fact, the only FDA-approved treatment for LIDs is amantadine, a drug with NMDAR antagonistic actions. Still, novel agents with improved pharmacological profiles are needed for LID therapy. Recently other therapeutic targets to reduce dysregulated SPN activity at the signal transduction level have emerged. In particular, mechanisms regulating the levels of cyclic nucleotides play a major role in the transduction of dopamine signals in SPNs. The phosphodiesterases (PDEs), a large family of enzymes that degrade cyclic nucleotides in a specific manner, are of special interest. We will review the research for antiglutamatergic and PDE inhibition strategies in view of the future development of novel LID therapies.
| S-EPMC10706484 | biostudies-literature
Project description:L-DOPA-induced dyskinesias (LID) are debilitating motor symptoms of dopamine-replacement therapy for Parkinson's disease (PD) that emerge after years of L-DOPA treatment. While there is an abundance of research into the cellular and synaptic origins of LID, less is known about how LID impacts systems-level circuits and neural synchrony, how synchrony is affected by the dose and duration of L-DOPA exposure, or how potential novel treatments for LID, such as sub-anesthetic ketamine, alter this activity. Sub-anesthetic ketamine treatments have recently been shown to reduce LID, and ketamine is known to affect neural synchrony. To investigate these questions, we measured movement and local-field potential (LFP) activity from the motor cortex (M1) and the striatum of preclinical rodent models of PD and LID. In the first experiment, we investigated the effect of the LID priming procedures and L-DOPA dose on neural signatures of LID. Two common priming procedures were compared: a high-dose procedure that exposed unilateral 6-hydroxydopamine-lesioned rats to 12 mg/kg L-DOPA for 7 days, and a low-dose procedure that exposed rats to 7 mg/kg L-DOPA for 21 days. Consistent with reports from other groups, 12 mg/kg L-DOPA triggered LID and 80-Hz oscillations; however, these 80-Hz oscillations were not observed after 7 mg/kg administration despite clear evidence of LID, indicating that 80-Hz oscillations are not an exclusive signature of LID. We also found that weeks-long low-dose priming resulted in the emergence of non-oscillatory broadband gamma activity (> 30 Hz) in the striatum and theta-to-high-gamma cross-frequency coupling (CFC) in M1. In a second set of experiments, we investigated how ketamine exposure affects spectral signatures of low-dose L-DOPA priming. During each neural recording session, ketamine was delivered through 5 injections (20 mg/kg, i.p.) administered every 2 h. We found that ketamine exposure suppressed striatal broadband gamma associated with LID but enhanced M1 broadband activity. We also found that M1 theta-to-high-gamma CFC associated with the LID on-state was suppressed by ketamine. These results suggest that ketamine's therapeutic effects are region specific. Our findings also have clinical implications, as we are the first to report novel oscillatory signatures of the common low-dose LID priming procedure that more closely models dopamine replacement therapy in individuals with PD. We also identify neural correlates of the anti-dyskinetic activity of sub-anesthetic ketamine treatment.
| S-EPMC9191762 | biostudies-literature
Project description:Parkinson's Disease (PD) is characterized by primary and secondary plasticity that occurs in response to progressive degeneration and long-term L-DOPA treatment. Some of this plasticity contributes to the detrimental side effects associated with chronic L-DOPA treatment, namely L-DOPA-induced dyskinesia (LID). The dopamine D3 receptor (D3R) has emerged as a promising target in LID management as it is upregulated in LID. This upregulation occurs primarily in the D1-receptor-bearing (D1R) cells of the striatum, which have been repeatedly implicated in LID manifestation. D3R undergoes dynamic changes both in PD and in LID, making it difficult to delineate D3R's specific contributions, but recent genetic and pharmacologic tools have helped to clarify its role in LID. The following review will discuss these changes, recent advances to better clarify D3R in both PD and LID and potential steps for translating these findings.
| S-EPMC8003204 | biostudies-literature
Project description:AimParkinson's disease (PD) is a pervasive neurodegenerative disease, and levodopa (L-dopa) is its preferred treatment. The pathophysiological mechanism of levodopa-induced dyskinesia (LID), the most common complication of long-term L-dopa administration, remains obscure. Accumulated evidence suggests that the dopaminergic as well as non-dopaminergic systems contribute to LID development. As a 5-hydroxytryptamine 1A/1B receptor agonist, eltoprazine ameliorates dyskinesia, although little is known about its electrophysiological mechanism. The aim of this study was to investigate the cumulative effects of chronic L-dopa administration and the potential mechanism of eltoprazine's amelioration of dyskinesia at the electrophysiological level in rats.MethodsNeural electrophysiological analysis techniques were conducted on the acquired local field potential (LFP) data from primary motor cortex (M1) and dorsolateral striatum (DLS) during different pathological states to obtain the information of power spectrum density, theta-gamma phase-amplitude coupling (PAC), and functional connectivity. Behavior tests and AIMs scoring were performed to verify PD model establishment and evaluate LID severity.ResultsWe detected exaggerated gamma activities in the dyskinetic state, with different features and impacts in distinct regions. Gamma oscillations in M1 were narrowband manner, whereas that in DLS had a broadband appearance. Striatal exaggerated theta-gamma PAC in the LID state contributed to broadband gamma oscillation, and aperiodic-corrected cortical beta power correlated robustly with aperiodic-corrected gamma power in M1. M1-DLS coherence and phase-locking values (PLVs) in the gamma band were enhanced following L-dopa administration. Eltoprazine intervention reduced gamma oscillations, theta-gamma PAC in the DLS, and coherence and PLVs in the gamma band to alleviate dyskinesia.ConclusionExcessive cortical gamma oscillation is a compelling clinical indicator of dyskinesia. The detection of enhanced PAC and functional connectivity of gamma-band oscillation can be used to guide and optimize deep brain stimulation parameters. Eltoprazine has potential clinical application for dyskinesia.
| S-EPMC10493666 | biostudies-literature
Project description:l-DOPA treatment for Parkinson's disease frequently leads to dyskinesias, the pathophysiology of which is poorly understood. We used MALDI-MSI to map the distribution of l-DOPA and monoaminergic pathways in brains of dyskinetic and nondyskinetic primates. We report elevated levels of l-DOPA, and its metabolite 3-O-methyldopa, in all measured brain regions of dyskinetic animals and increases in dopamine and metabolites in all regions analyzed except the striatum. In dyskinesia, dopamine levels correlated well with l-DOPA levels in extrastriatal regions, such as hippocampus, amygdala, bed nucleus of the stria terminalis, and cortical areas, but not in the striatum. Our results demonstrate that l-DOPA-induced dyskinesia is linked to a dysregulation of l-DOPA metabolism throughout the brain. The inability of extrastriatal brain areas to regulate the formation of dopamine during l-DOPA treatment introduces the potential of dopamine or even l-DOPA itself to modulate neuronal signaling widely across the brain, resulting in unwanted side effects.
| S-EPMC7787486 | biostudies-literature