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1.
Exp Neurol ; 378: 114833, 2024 Aug.
Article En | MEDLINE | ID: mdl-38782350

Gamma oscillations have been frequently observed in levodopa-induced dyskinesia (LID), manifest as broadband (60-120 Hz) and narrowband (80-110 Hz) gamma activity in cortico-striatal projection. We investigated the electrophysiological mechanisms and correlation of gamma oscillations with dyskinesia severity, while assessing the administration of fenobam, a selective metabotropic glutamate receptor 5 (mGluR5) antagonist, in regulating dyskinesia-associated gamma activity. We conducted simultaneous electrophysiological recordings in Striatum (Str) and primary motor cortex (M1), together with Abnormal Involuntary Movement Scale scoring (AIMs). Phase-amplitude coupling (PAC), power, coherence, and Granger causality analyses were conducted for electrophysiological data. The findings demonstrated increased beta oscillations with directionality from M1 to Str in parkinsonian state. During on-state dyskinesia, elevated broadband gamma activity was modulated by the phase of theta activity in Str, while M1 â†’ Str gamma causality mediated narrowband gamma oscillations in Str. Striatal gamma power (both periodic and aperiodic power), periodic power, peak frequency, and PAC at 80 min (corresponding to the peak dyskinesia) after repeated levodopa injections across recording days (day 30, 33, 36, 39, and 42) increased progressively, correlating with total AIMs. Additionally, a time-dependent parabolic trend of PAC, peak frequency and gamma power was observed after levodopa injection on day 42 from 20 to 120 min, which also correlated with corresponding AIMs. Fenobam effectively alleviates dyskinesia, suppresses enhanced gamma oscillations in the M1-Str directionality, and reduces PAC in Str. The temporal characteristics of gamma oscillations provide parameters for classifying LID severity. Antagonizing striatal mGluR5, a promising therapeutic target for dyskinesia, exerts its effects by modulating gamma activity.


Corpus Striatum , Dyskinesia, Drug-Induced , Gamma Rhythm , Animals , Gamma Rhythm/drug effects , Gamma Rhythm/physiology , Rats , Male , Dyskinesia, Drug-Induced/physiopathology , Corpus Striatum/drug effects , Corpus Striatum/physiopathology , Rats, Sprague-Dawley , Levodopa/adverse effects , Levodopa/pharmacology , Motor Cortex/drug effects , Motor Cortex/physiopathology , Imidazoles
2.
Neurobiol Dis ; 159: 105491, 2021 11.
Article En | MEDLINE | ID: mdl-34461264

Parkinson's disease (PD) is a neurodegenerative movement disorder that is routinely treated with levodopa. Unfortunately, long-term dopamine replacement therapy using levodopa leads to levodopa-induced dyskinesias (LID), a significant and disabling side-effect. Clinical findings indicate that LID typically only occurs following the progression of PD motor symptoms from the unilateral (Hoehn and Yahr (HY) Stage I) to the bilateral stage (HY Stage II). This suggests the presence of some compensatory interhemispheric mechanisms that delay the occurrence of LID. We therefore investigated the role of interhemispheric connections of the nigrostriatal pathway on LID expression in a rat model of PD. The striatum of one hemisphere of rats was first injected with a retrograde tracer to label the ipsi- and cross-hemispheric nigrostriatal pathways. Rats were then split into groups and unilaterally lesioned in the striatum or medial forebrain bundle of the tracer-injected hemisphere to induce varying levels of hemiparkinsonism. Finally, rats were treated with levodopa and tested for the expression of LID. Distinct subsets emerged from rats that underwent the same lesioning paradigm based on LID. Strikingly, non-dyskinetic rats had significant sparing of their cross-hemispheric nigrostriatal pathway projecting from the unlesioned hemisphere. In contrast, dyskinetic rats only had a small proportion of this cross-hemispheric nigrostriatal pathway survive lesioning. Crucially, both non-dyskinetic and dyskinetic rats had nearly identical levels of ipsi-hemispheric nigrostriatal pathway survival and parkinsonian motor deficits. Our data suggest that the survival of the cross-hemispheric nigrostriatal pathway plays a crucial role in preventing the expression of LID and represents a potentially novel target to halt the progression of this devastating side-effect of a common anti-PD therapeutic.


Antiparkinson Agents/adverse effects , Dyskinesia, Drug-Induced/physiopathology , Levodopa/adverse effects , Neostriatum/physiology , Parkinsonian Disorders/physiopathology , Substantia Nigra/physiology , Animals , Disease Progression , Dyskinesia, Drug-Induced/etiology , Medial Forebrain Bundle/physiopathology , Oxidopamine/toxicity , Parkinsonian Disorders/chemically induced , Rats , Sympatholytics/toxicity
3.
Neuropharmacology ; 196: 108693, 2021 09 15.
Article En | MEDLINE | ID: mdl-34229013

Several lines of evidence have strongly implicated neuroinflammation in Parkinson's disease (PD) progression and l-dopa-induced dyskinesia. The present study investigated whether early subchronic pretreatment with the serotonin 5-HT1A/1B receptor agonist eltoprazine plus the adenosine A2A receptor antagonist preladenant counteracted l-dopa-induced abnormal involuntary movements (AIMs, index of dyskinesia), and neuroinflammation, in unilateral 6-hydroxydopamine(6-OHDA)-lesioned rat model of PD. The immunoreactivity of glial fibrillary acidic protein (GFAP), and the colocalization of ionized calcium binding adaptor molecule-1 (IBA-1), with interleukin (IL)-1ß, tumor-necrosis-factor-α (TNF-α) and IL-10 were evaluated in the denervated caudate-putamen (CPu) and substantia nigra pars-compacta (SNc). The combined subchronic pretreatment with l-dopa plus eltoprazine and preladenant reduced AIMs induced by acute l-dopa challenge in these rats and decreased GFAP and IBA-1 immunoreactivity induced by the drug in both CPu and SNc, with reduction in IL-1ß in IBA-1-positive cells in both CPu and SNc, and in TNF-α in IBA-1-positive cells in SNc. Moreover, a significant increase in IL-10 in IBA-1-positive cells was observed in SNc. Evaluation of immediate early-gene zif-268 (index of neuronal activation) after l-dopa challenge, showed an increase in its expression in denervated CPu of rats pretreated with l-dopa or l-dopa plus preladenant compared with vehicle, whereas rats pretreated with eltoprazine, with or without preladenant, had lower zif-268 expression. Finally, tyrosine hydroxylase and dopamine transporter examined to evaluate neurodegeneration, showed a significant equal decrease in all experimental groups. The present findings suggest that combination of l-dopa with eltoprazine and preladenant may be promising therapeutic strategy for delaying the onset of dyskinesia, preserving l-dopa efficacy and reducing neuroinflammation markers in nigrostriatal system of 6-OHDA-lesioned rats.


Adenosine A2 Receptor Antagonists/pharmacology , Antiparkinson Agents/adverse effects , Dyskinesia, Drug-Induced/physiopathology , Levodopa/adverse effects , Parkinsonian Disorders/physiopathology , Piperazines/pharmacology , Pyrimidines/pharmacology , Serotonin 5-HT1 Receptor Agonists/pharmacology , Triazoles/pharmacology , Animals , Calcium-Binding Proteins/drug effects , Calcium-Binding Proteins/metabolism , Caudate Nucleus/drug effects , Caudate Nucleus/metabolism , Dyskinesia, Drug-Induced/etiology , Dyskinesia, Drug-Induced/metabolism , Glial Fibrillary Acidic Protein/drug effects , Glial Fibrillary Acidic Protein/metabolism , Interleukin-10/metabolism , Interleukin-1beta/drug effects , Interleukin-1beta/metabolism , Microfilament Proteins/drug effects , Microfilament Proteins/metabolism , Neuroinflammatory Diseases/metabolism , Oxidopamine/toxicity , Parkinsonian Disorders/chemically induced , Parkinsonian Disorders/drug therapy , Parkinsonian Disorders/metabolism , Pars Compacta/drug effects , Pars Compacta/metabolism , Putamen/drug effects , Putamen/metabolism , Rats , Receptor, Serotonin, 5-HT1A , Receptor, Serotonin, 5-HT1B , Tumor Necrosis Factor-alpha/drug effects , Tumor Necrosis Factor-alpha/metabolism
4.
Neurobiol Dis ; 157: 105429, 2021 09.
Article En | MEDLINE | ID: mdl-34153463

L-DOPA-induced dyskinesia (LID) is a significant complication of dopamine replacement therapy in Parkinson's disease (PD), and the specific role of different dopamine receptors in this disorder is poorly understood. We set out to compare patterns of dyskinetic behaviours induced by the systemic administration of L-DOPA and D1 or D2 receptor (D1R, D2R) agonists in mice with unilateral 6-hydroxydopamine lesions. Mice were divided in four groups to receive increasing doses of L-DOPA, a D1R agonist (SKF38393), a D2/3 agonist (quinpirole), or a selective D2R agonist (sumanirole). Axial, limb and orofacial abnormal involuntary movements (AIMs) were rated using a well-established method, while dystonic features were quantified in different body segments using a new rating scale. Measures of abnormal limb and trunk posturing were extracted from high-speed videos using a software for markerless pose estimation (DeepLabCut). While L-DOPA induced the full spectrum of dyskinesias already described in this mouse model, SKF38393 induced mostly orofacial and limb AIMs. By contrast, both of the D2-class agonists (quinpirole, sumanirole) induced predominantly axial AIMs. Dystonia ratings revealed that these agonists elicited marked dystonic features in trunk/neck, forelimbs, and hindlimbs, which were overall more severe in sumanirole-treated mice. Accordingly, sumanirole induced pronounced axial bending and hindlimb divergence in the automated video analysis. In animals treated with SKF38393, the only appreciable dystonic-like reaction consisted in sustained tail dorsiflexion and stiffness. We next compared the effects of D1R or D2R selective antagonists in L-DOPA-treated mice, where only the D2R antagonist had a significant effect on dystonic features. Taken together these results indicate that the dystonic components of LID are predominantly mediated by the D2R.


Dyskinesia, Drug-Induced/physiopathology , Dystonia/physiopathology , Movement/drug effects , Parkinsonian Disorders/physiopathology , Receptors, Dopamine D1/metabolism , Receptors, Dopamine D2/metabolism , 2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-benzazepine/pharmacology , Animals , Antiparkinson Agents/adverse effects , Benzimidazoles/pharmacology , Dyskinesia, Drug-Induced/etiology , Dyskinesia, Drug-Induced/metabolism , Dystonia/chemically induced , Dystonia/metabolism , Mice , Oxidopamine/toxicity , Parkinsonian Disorders/chemically induced , Parkinsonian Disorders/metabolism , Quinpirole/pharmacology , Receptors, Dopamine D1/agonists , Receptors, Dopamine D2/agonists
5.
Exp Neurol ; 340: 113670, 2021 06.
Article En | MEDLINE | ID: mdl-33662379

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.


Dyskinesia, Drug-Induced/prevention & control , Dyskinesia, Drug-Induced/physiopathology , Gamma Rhythm/drug effects , Ketamine/therapeutic use , Levodopa/toxicity , Analgesics/pharmacology , Analgesics/therapeutic use , Animals , Antiparkinson Agents/toxicity , Dose-Response Relationship, Drug , Gamma Rhythm/physiology , Ketamine/pharmacology , Male , Oxidopamine/toxicity , Parkinsonian Disorders/chemically induced , Parkinsonian Disorders/drug therapy , Parkinsonian Disorders/physiopathology , Rats , Rats, Sprague-Dawley
6.
Am J Physiol Regul Integr Comp Physiol ; 320(4): R541-R546, 2021 04 01.
Article En | MEDLINE | ID: mdl-33533311

Physical exercise attenuates the development of l-3,4-dihydroxyphenylalanine (l-DOPA)-induced dyskinesia (LID) in 6-hydroxydopamine-induced hemiparkinsonian mice through unknown mechanisms. We now tested if exercise normalizes the aberrant corticostriatal neuroplasticity associated with experimental murine models of LID. C57BL/6 mice received two unilateral intrastriatal injections of 6-hydroxydopamine (12 µg) and were treated after 3 wk with l-DOPA/benserazide (25/12.5 mg/kg) for 4 wk, with individualized moderate-intensity running (60%-70% V̇o2peak) or not (untrained). l-DOPA converted the pattern of plasticity in corticostriatal synapses from a long-term depression (LTD) into a long-term potentiation (LTP). Exercise reduced LID severity and decreased aberrant LTP. These results suggest that exercise attenuates abnormal corticostriatal plasticity to decrease LID.


Antiparkinson Agents/toxicity , Cerebral Cortex/drug effects , Corpus Striatum/drug effects , Dyskinesia, Drug-Induced/prevention & control , Exercise Therapy , Levodopa/toxicity , Neuronal Plasticity/drug effects , Parkinsonian Disorders/drug therapy , Animals , Benserazide/toxicity , Cerebral Cortex/physiopathology , Corpus Striatum/physiopathology , Dihydroxyphenylalanine/analogs & derivatives , Disease Models, Animal , Dyskinesia, Drug-Induced/etiology , Dyskinesia, Drug-Induced/physiopathology , Long-Term Potentiation/drug effects , Long-Term Synaptic Depression/drug effects , Male , Mice, Inbred C57BL , Motor Activity/drug effects , Parkinsonian Disorders/chemically induced , Parkinsonian Disorders/physiopathology , Running , Time Factors
7.
J Neurosci ; 41(12): 2668-2683, 2021 03 24.
Article En | MEDLINE | ID: mdl-33563724

l-3,4-dihydroxyphenylalanine (l-DOPA) is an effective treatment for Parkinson's disease (PD); however, long-term treatment induces l-DOPA-induced dyskinesia (LID). To elucidate its pathophysiology, we developed a mouse model of LID by daily administration of l-DOPA to PD male ICR mice treated with 6-hydroxydopamine (6-OHDA), and recorded the spontaneous and cortically evoked neuronal activity in the external segment of the globus pallidus (GPe) and substantia nigra pars reticulata (SNr), the connecting and output nuclei of the basal ganglia, respectively, in awake conditions. Spontaneous firing rates of GPe neurons were decreased in the dyskinesia-off state (≥24 h after l-DOPA injection) and increased in the dyskinesia-on state (20-100 min after l-DOPA injection while showing dyskinesia), while those of SNr neurons showed no significant changes. GPe and SNr neurons showed bursting activity and low-frequency oscillation in the PD, dyskinesia-off, and dyskinesia-on states. In the GPe, cortically evoked late excitation was increased in the PD and dyskinesia-off states but decreased in the dyskinesia-on state. In the SNr, cortically evoked inhibition was largely suppressed, and monophasic excitation became dominant in the PD state. Chronic l-DOPA treatment partially recovered inhibition and suppressed late excitation in the dyskinesia-off state. In the dyskinesia-on state, inhibition was further enhanced, and late excitation was largely suppressed. Cortically evoked inhibition and late excitation in the SNr are mediated by the cortico-striato-SNr direct and cortico-striato-GPe-subthalamo-SNr indirect pathways, respectively. Thus, in the dyskinesia-on state, signals through the direct pathway that release movements are enhanced, while signals through the indirect pathway that stop movements are suppressed, underlying LID.SIGNIFICANCE STATEMENT Parkinson's disease (PD) is caused by progressive loss of midbrain dopaminergic neurons, characterized by tremor, rigidity, and akinesia, and estimated to affect around six million people world-wide. Dopamine replacement therapy is the gold standard for PD treatment; however, control of symptoms using l-3,4-dihydroxyphenylalanine (l-DOPA) becomes difficult over time because of abnormal involuntary movements (AIMs) known as l-DOPA-induced dyskinesia (LID), one of the major issues for advanced PD. Our electrophysiological data suggest that dynamic changes in the basal ganglia circuitry underlie LID; signals through the direct pathway that release movements are enhanced, while signals through the indirect pathway that stop movements are suppressed. These results will provide the rationale for the development of more effective treatments for LID.


Basal Ganglia/physiopathology , Cerebral Cortex/physiopathology , Disease Models, Animal , Dyskinesia, Drug-Induced/physiopathology , Levodopa/toxicity , Synaptic Transmission/physiology , Animals , Basal Ganglia/drug effects , Cerebral Cortex/drug effects , Male , Mice , Mice, Inbred ICR , Motor Activity/drug effects , Motor Activity/physiology , Synaptic Transmission/drug effects
8.
Sci Rep ; 11(1): 867, 2021 01 13.
Article En | MEDLINE | ID: mdl-33441571

Aim of the study was to evaluate possible associations between cognitive dysfunctions and development of Levodopa Induced Dyskinesia (LID). PD patients from the Parkinson's disease Cognitive impairment Study cohort who underwent a baseline and follow-up neuropsychological evaluations were enrolled. Mild Cognitive Impairment (PD-MCI) was diagnosed according to MDS level II criteria. The following cognitive domains were evaluated: episodic memory, attention, executive function, visuo-spatial function and language. A domain was considered as impaired when the subject scored 2 standard deviation below normality cut-off values in at least one test for each domain. Levodopa equivalent dose, UPDRS-ME and LID were recorded at baseline and follow-up. To identify possible neuropsychological predictors associated with the probability of LID development at follow-up, Cox proportional-hazards regression model was used. Out of 139 PD patients enrolled (87 men, mean age 65.7 ± 9.4), 18 (12.9%) were dyskinetic at baseline. Out of 121 patients non-dyskinetic at baseline, 22 (18.1%) developed LID at follow-up. The impairment of the attention and executive domains strongly predicted the development of LID (HR 4.45;95%CI 1.49-13.23 and HR 3.46; 95%CI 1.26-9.48 respectively). Impairment of the attention and executive domains increased the risk of dyskinesia reflecting the alteration of common cortical network.


Cognitive Dysfunction/physiopathology , Dyskinesia, Drug-Induced/physiopathology , Parkinson Disease/physiopathology , Aged , Attention/physiology , Cognitive Dysfunction/metabolism , Cohort Studies , Executive Function/physiology , Female , Humans , Levodopa/adverse effects , Levodopa/therapeutic use , Longitudinal Studies , Male , Middle Aged , Neuropsychological Tests , Parkinson Disease/metabolism , Proportional Hazards Models , Severity of Illness Index
9.
J Psychopharmacol ; 35(1): 3-14, 2021 01.
Article En | MEDLINE | ID: mdl-32900259

Dystonia is by far the most intrusive and invalidating extrapyramidal side effect of potent classical antipsychotic drugs. Antipsychotic drug-induced dystonia is classified in both acute and tardive forms. The incidence of drug-induced dystonia is associated with the affinity to inhibitory dopamine D2 receptors. Particularly acute dystonia can be treated with anticholinergic drugs, but the tardive form may also respond to such antimuscarinic treatment, which contrasts their effects in tardive dyskinesia. Combining knowledge of the pathophysiology of primary focal dystonia with the anatomical and pharmacological organization of the extrapyramidal system may shed some light on the mechanism of antipsychotic drug-induced dystonia. A suitable hypothesis is derived from the understanding that focal dystonia may be due to a faulty processing of somatosensory input, so leading to inappropriate execution of well-trained motor programmes. Neuroplastic alterations of the sensitivity of extrapyramidal medium-sized spiny projection neurons to stimulation, which are induced by the training of specific complex movements, lead to the sophisticated execution of these motor plans. The sudden and non-selective disinhibition of indirect pathway medium-sized spiny projection neurons by blocking dopamine D2 receptors may distort this process. Shutting down the widespread influence of tonically active giant cholinergic interneurons on all medium-sized spiny projection neurons by blocking muscarinic receptors may result in a reduction of the influence of extrapyramidal cortical-striatal-thalamic-cortical regulation. Furthermore, striatal cholinergic interneurons have an important role to play in integrating cerebellar input with the output of cerebral cortex, and are also targeted by dopaminergic nigrostriatal fibres affecting dopamine D2 receptors.


Antipsychotic Agents/pharmacology , Dyskinesia, Drug-Induced , Dystonia , Extrapyramidal Tracts , Interneurons , Receptors, Dopamine D2/metabolism , Cholinergic Antagonists/therapeutic use , Cholinergic Neurons/drug effects , Cholinergic Neurons/physiology , Dopamine D2 Receptor Antagonists/pharmacology , Dyskinesia, Drug-Induced/drug therapy , Dyskinesia, Drug-Induced/etiology , Dyskinesia, Drug-Induced/metabolism , Dyskinesia, Drug-Induced/physiopathology , Dystonia/chemically induced , Dystonia/drug therapy , Dystonia/metabolism , Dystonia/physiopathology , Extrapyramidal Tracts/drug effects , Extrapyramidal Tracts/physiopathology , Humans , Interneurons/drug effects , Interneurons/physiology , Muscarinic Antagonists/therapeutic use , Neuronal Plasticity
10.
J Parkinsons Dis ; 11(1): 177-186, 2021.
Article En | MEDLINE | ID: mdl-33164945

BACKGROUND: ND0612 is a continuous, subcutaneous levodopa/carbidopa delivery system in development for patients with Parkinson's disease (PD) experiencing motor fluctuationsObjective:Evaluate the efficacy and safety of two ND0612 dosing regimens in patients with PD. METHODS: This was a 28-day open-label study (NCT02577523) in PD patients with ≥2.5 hours/day of OFF time despite optimized treatment. Patients were randomized to treatment with either a 24-hour infusion (levodopa/carbidopa dose of 720/90 mg) or a 14-hour 'waking-day' infusion (levodopa/carbidopa dose of 538/68 mg plus a morning oral dose of 150/15 mg). Supplemental oral doses of levodopa were permitted for patients in both groups if required. In-clinic assessments of OFF time (primary endpoint) and ON time with or without dyskinesia were determined by a blinded rater over 8 hours (normalized to 16 hours). RESULTS: A total of 38 patients were randomized and 33 (87%) completed the study. Compared to baseline, OFF time for the overall population was reduced by a least squares (LS) mean[95% CI] of 2.0[- 3.3, - 0.7] hours (p = 0.003). ON time with no/mild dyskinesia (no troublesome dyskinesia) was increased from baseline by a LS mean of 3.3[2.0, 4.6] hours (p < 0.0001), and ON time with moderate/severe dyskinesia was reduced by a LS mean of 1.2[- 1.8, - 0.5] hours (p≤0.001). Reduction in OFF time was larger in the 24-hour group (- 2.8[- 4.6, - 0.9] hours; p = 0.004) than in the 14-hour group (- 1.3[- 3.1, 0.5] hours; p = 0.16). Complete resolution of OFF time was observed in 42% (n = 8) of patients in the 24-hour group. Infusion site reactions were the most common adverse event. CONCLUSION: This study demonstrates the feasibility and safety of continuous subcutaneous delivery of levodopa as a treatment for PD and provides preliminary evidence of efficacy.


Antiparkinson Agents/pharmacology , Carbidopa/pharmacology , Dyskinesia, Drug-Induced/physiopathology , Levodopa/pharmacology , Parkinson Disease/drug therapy , Aged , Antiparkinson Agents/administration & dosage , Antiparkinson Agents/adverse effects , Carbidopa/administration & dosage , Carbidopa/adverse effects , Drug Combinations , Dyskinesia, Drug-Induced/etiology , Feasibility Studies , Female , Humans , Infusions, Parenteral , Levodopa/administration & dosage , Levodopa/adverse effects , Male , Middle Aged , Outcome Assessment, Health Care , Severity of Illness Index , Single-Blind Method
11.
Int J Mol Sci ; 22(1)2020 Dec 22.
Article En | MEDLINE | ID: mdl-33374986

In previous work we evaluated an opioid glycopeptide with mixed µ/δ-opioid receptor agonism that was a congener of leu-enkephalin, MMP-2200. The glycopeptide analogue showed penetration of the blood-brain barrier (BBB) after systemic administration to rats, as well as profound central effects in models of Parkinson's disease (PD) and levodopa (L-DOPA)-induced dyskinesia (LID). In the present study, we tested the glycopeptide BBI-11008 with selective δ-opioid receptor agonism, an analogue of deltorphin, a peptide secreted from the skin of frogs (genus Phyllomedusa). We tested BBI-11008 for BBB-penetration after intraperitoneal (i.p.) injection and evaluated effects in LID rats. BBI-11008 (10 mg/kg) demonstrated good CNS-penetrance as shown by microdialysis and mass spectrometric analysis, with peak concentration levels of 150 pM in the striatum. While BBI-11008 at both 10 and 20 mg/kg produced no effect on levodopa-induced limb, axial and oral (LAO) abnormal involuntary movements (AIMs), it reduced the levodopa-induced locomotor AIMs by 50% after systemic injection. The N-methyl-D-aspartate receptor antagonist MK-801 reduced levodopa-induced LAO AIMs, but worsened PD symptoms in this model. Co-administration of MMP-2200 had been shown prior to block the MK-801-induced pro-Parkinsonian activity. Interestingly, BBI-11008 was not able to block the pro-Parkinsonian effect of MK-801 in the LID model, further indicating that a balance of mu- and delta-opioid agonism is required for this modulation. In summary, this study illustrates another example of meaningful BBB-penetration of a glycopeptide analogue of a peptide to achieve a central behavioral effect, providing additional evidence for the glycosylation technique as a method to harness therapeutic potential of peptides.


Disease Models, Animal , Dyskinesia, Drug-Induced/physiopathology , Glycopeptides/pharmacology , Motor Activity/drug effects , Parkinson Disease, Secondary/physiopathology , Receptors, Opioid, delta/agonists , Analgesics, Opioid/administration & dosage , Analgesics, Opioid/pharmacokinetics , Analgesics, Opioid/pharmacology , Animals , Corpus Striatum/metabolism , Dizocilpine Maleate/pharmacology , Dyskinesia, Drug-Induced/metabolism , Glycopeptides/administration & dosage , Glycopeptides/pharmacokinetics , Levodopa , Male , Motor Activity/physiology , Neuroprotective Agents/pharmacology , Parkinson Disease, Secondary/chemically induced , Parkinson Disease, Secondary/metabolism , Rats, Sprague-Dawley , Receptors, Opioid, delta/metabolism
12.
Article En | MEDLINE | ID: mdl-33178486

Background: Drug-induced movement disorders (DIMDs) are commonly encountered, but an often-under-reported subgroup of movement disorders. Objectives: We aimed to highlight the spectrum of DIMDs in patients taking different groups of drugs at our movement disorder center. Methods: It is a cross-sectional descriptive study including 97 consecutive DIMDs patients diagnosed over the past two years (2017-2019). Results: The mean ± standard deviation (SD) age of our study population was 35.89 ± 17.8 years (Range-2-80 years). There were 51 males and 46 females. Different DIMDs observed included tardive dystonia (n = 41; 42.2%), postural tremor (n = 38; 39.2%), parkinsonism (n = 32; 33%), tardive dyskinesia (n = 21; 21.6%), acute dystonia (n = 10; 10.3%), neuroleptic malignant syndrome (NMS) (n = 2; 2.1%), and others [(n = 10; 10.30%) including chorea and stereotypy each in 3; acute dyskinesia in 2; and myoclonic jerks and acute akathisia each in 1 patient]. Of these 97 patients, 49 had more than one type of DIMDs while 48 had a single type of DIMDs. In our study 37 (38%) patients had received non-dopamine receptor blocking agents (non-DRBA), 30 (31%) patients had received dopamine receptor blocking agents (DRBA), and 30 (31%) patients had received both DRBA and non-DRBA. Conclusions: Tardive dystonia was the most common DIMDs observed in our study. Our DIMDs patients were younger than other reported studies. We observed a significant number of non-DRBA drugs causing DIMD in our study as compared to previous studies. Drug-induced parkinsonism (DIP) was the most common DIMDs in the DRBA group. Tardive dystonia was the most common DIMDs seen in DRBA + non-DRBA group and the second most common in the DRBA and non-DRBA group. The postural tremor was the most common DIMDs in the non-DRBA group.


Antipsychotic Agents/adverse effects , Dopamine Antagonists/adverse effects , Dyskinesia, Drug-Induced/etiology , Adolescent , Adult , Aged , Anticonvulsants/adverse effects , Antidepressive Agents/adverse effects , Antiemetics/adverse effects , Antimanic Agents/adverse effects , Antineoplastic Agents/adverse effects , Child , Child, Preschool , Chorea/chemically induced , Cohort Studies , Dyskinesia, Drug-Induced/physiopathology , Dystonia/chemically induced , Female , Humans , Hypnotics and Sedatives/adverse effects , Infant , Infant, Newborn , Male , Middle Aged , Myoclonus/chemically induced , Neuroleptic Malignant Syndrome/etiology , Parkinsonian Disorders/chemically induced , Stereotypic Movement Disorder/chemically induced , Tardive Dyskinesia/chemically induced , Tremor/chemically induced , Young Adult
13.
Article En | MEDLINE | ID: mdl-33101763

Background: Ziconotide (ZCN), a nonopioid analgesic, is first-line intrathecal therapy for patients with severe chronic pain refractory to other management options. We describe three cases of ZCN-induced movement disorders. Cases: Case one is a 64-year-old woman who presented with oro-lingual (OL) dyskinesia with dysesthesias and bilateral upper extremity kinetic tremor. Case two is a 43-year-old man with a 20-month history of ZCN treatment who developed OL dyskinesia with dysesthesias, involuntary left hand and neck movements, hallucinations, dysesthesias on his feet, and gait imbalance. Case three is a 70-year-old man with a 4-month history of ZCN use who developed OL dyskinesia with dysesthesias. Conclusions: Intrathecal treatment of pain with ZCN may be complicated by a drug-induced movement disorder where OL dyskinesia is characteristic. The movement disorder is likely to be dose related and reversible with ZCN discontinuation, but a chronic movement disorder is also possible.


Analgesics, Non-Narcotic/adverse effects , Chronic Pain/drug therapy , Dyskinesia, Drug-Induced/physiopathology , omega-Conotoxins/adverse effects , Adult , Aged , Analgesics, Non-Narcotic/administration & dosage , Female , Humans , Male , Middle Aged , omega-Conotoxins/administration & dosage
14.
Article En | MEDLINE | ID: mdl-32775034

Background: The impact of slight-to-moderate levodopa-induced dyskinesia (LID) on the level of participation in active life in patients with Parkinson's disease (PD) has never been objectively determined. Methods: Levels of LID, tremor and bradykinesia were measured during best-ON state in 121 patients diagnosed with PD and having peak-dose LID using inertial sensors positioned on each body limb. Rigidity and postural instability were assessed using clinical evaluations. Cognition and depression were assessed using the MMSE and the GDS-15. Participation in active life was assessed in patients and in 69 healthy controls using the Activity Card Sort (ACS), which measures levels of activity engagement and activities affected by the symptomatology. Outcome measures were compared between patients and controls using ANCOVA, controlling for age or Wilcoxon-Mann-Whitney tests. Spearman correlations and multivariate analyses were then performed between symptomatology and ACS scores. Results: Patients had significantly lower activity engagement than controls and had significantly affected activities. LID was neither associated with activity engagement nor affected activities. Higher levels of tremor, postural instability, cognitive decline and depression were associated with lower activity engagement and higher affected activities. Multivariate analyses revealed that only tremor, postural instability and depression accounted significantly in the variances of these variables. Discussion: Slight-to-moderate LID had little impact compared to other symptoms on the level of participation in active life, suggesting that other symptoms should remain the treatment priority to maintain the level of participation of patients in an active lifestyle.


Activities of Daily Living , Dyskinesia, Drug-Induced , Parkinson Disease , Social Participation , Aged , Cross-Sectional Studies , Dopamine Agents/adverse effects , Dyskinesia, Drug-Induced/etiology , Dyskinesia, Drug-Induced/physiopathology , Dyskinesia, Drug-Induced/psychology , Female , Humans , Levodopa/adverse effects , Male , Middle Aged , Outcome Assessment, Health Care , Parkinson Disease/drug therapy , Parkinson Disease/physiopathology , Parkinson Disease/psychology
15.
Neurobiol Dis ; 144: 105044, 2020 10.
Article En | MEDLINE | ID: mdl-32798726

Acetylcholine muscarinic receptors (mAChRs) contribute to both the facilitation and inhibition of levodopa-induced dyskinesia operated by striatal cholinergic interneurons, although the receptor subtypes involved remain elusive. Cholinergic afferents from the midbrain also innervate the substantia nigra reticulata, although the role of nigral mAChRs in levodopa-induced dyskinesia is unknown. Here, we investigate whether striatal and nigral M1 and/or M4 mAChRs modulate dyskinesia and the underlying striato-nigral GABAergic pathway activation in 6-hydroxydopamine hemilesioned rats. Reverse microdialysis allowed to deliver the mAChR antagonists telenzepine (M1 subtype preferring), PD-102807 and tropicamide (M4 subtype preferring), as well as the selective M4 mAChR positive allosteric modulator VU0152100 in striatum or substantia nigra, while levodopa was administered systemically. Dyskinetic movements were monitored along with nigral GABA (and glutamate) and striatal glutamate dialysate levels, taken as neurochemical correlates of striato-nigral pathway and cortico-basal ganglia-thalamo-cortical loop activation. We observed that intrastriatal telenzepine, PD-102807 and tropicamide alleviated dyskinesia and inhibited nigral GABA and striatal glutamate release. This was partially replicated by intrastriatal VU0152100. The M2 subtype preferring antagonist AFDX-116, used to elevate striatal acetylcholine levels, blocked the behavioral and neurochemical effects of PD-102807. Intranigral VU0152100 prevented levodopa-induced dyskinesia and its neurochemical correlates whereas PD-102807 was ineffective. These results suggest that striatal, likely postsynaptic, M1 mAChRs facilitate dyskinesia and striato-nigral pathway activation in vivo. Conversely, striatal M4 mAChRs can both facilitate and inhibit dyskinesia, possibly depending on their localization. Potentiation of striatal and nigral M4 mAChR transmission leads to powerful multilevel inhibition of striato-nigral pathway and attenuation of dyskinesia.


Dopamine Agents/adverse effects , Dyskinesia, Drug-Induced/metabolism , Levodopa/adverse effects , Neostriatum/metabolism , Receptor, Muscarinic M1/metabolism , Receptor, Muscarinic M4/metabolism , Substantia Nigra/metabolism , Allosteric Regulation , Animals , Dyskinesia, Drug-Induced/etiology , Dyskinesia, Drug-Induced/physiopathology , Glutamic Acid/drug effects , Glutamic Acid/metabolism , Microdialysis , Muscarinic Antagonists/pharmacology , Neostriatum/drug effects , Neural Pathways , Oxidopamine/toxicity , Parkinsonian Disorders/drug therapy , Parkinsonian Disorders/etiology , Parkinsonian Disorders/metabolism , Rats , Receptor, Muscarinic M1/antagonists & inhibitors , Receptor, Muscarinic M4/antagonists & inhibitors , Substantia Nigra/drug effects , Sympatholytics/toxicity , gamma-Aminobutyric Acid/drug effects , gamma-Aminobutyric Acid/metabolism
16.
Naunyn Schmiedebergs Arch Pharmacol ; 393(11): 2157-2164, 2020 11.
Article En | MEDLINE | ID: mdl-32621059

Whereas monoamine oxidase (MAO) type B inhibitors are used as adjunct to L-3,4-dihydroxyphenylalanine (L-DOPA) in the treatment of Parkinson's disease (PD), the enzyme MAO type A (MAO-A) also participates in the metabolism of dopamine in the human and primate striatum. Here, we sought to assess the effect of the selective reversible MAO-A inhibitor moclobemide on L-DOPA anti-parkinsonian in the gold standard animal model of PD, the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-lesioned primate. We also assessed the effect of moclobemide on L-DOPA-induced dyskinesia and psychosis-like behaviours (PLBs). Experiments were performed in six MPTP-lesioned marmosets chronically treated with L-DOPA and exhibiting stable dyskinesia and PLBs upon each administration. In a randomised within-subject design, animals were administered a therapeutic dose of L-DOPA in combination with moclobemide (0.1, 1 and 10 mg/kg) or its vehicle, after which the severity of parkinsonism, dyskinesia, and PLBs was rated by an experienced blinded rater. Moclobemide significantly reduced the global parkinsonian disability (- 36% with 0.1 mg/kg, P < 0.05; - 38% with 1 mg/kg, P < 0.01; - 47% with 10 mg/kg, P < 0.01), when compared with its vehicle. This reduction of parkinsonism was not accompanied by an exacerbation of dyskinesia or PLBs. Reversible MAO-A inhibition with moclobemide appears as an effective way to increase the anti-parkinsonian action of L-DOPA, without negatively affecting dyskinesia or dopaminergic psychosis.


Antiparkinson Agents/pharmacology , Basal Ganglia/drug effects , Levodopa/pharmacology , Moclobemide/pharmacology , Monoamine Oxidase Inhibitors/pharmacology , Monoamine Oxidase/metabolism , Parkinsonian Disorders/drug therapy , 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine , Animals , Antiparkinson Agents/toxicity , Basal Ganglia/enzymology , Basal Ganglia/physiopathology , Behavior, Animal/drug effects , Callithrix , Disease Models, Animal , Drug Synergism , Drug Therapy, Combination , Dyskinesia, Drug-Induced/etiology , Dyskinesia, Drug-Induced/physiopathology , Female , Levodopa/toxicity , Male , Motor Activity/drug effects , Parkinsonian Disorders/chemically induced , Parkinsonian Disorders/enzymology , Parkinsonian Disorders/physiopathology , Psychoses, Substance-Induced/etiology , Psychoses, Substance-Induced/psychology
17.
Ann Clin Transl Neurol ; 7(5): 677-682, 2020 05.
Article En | MEDLINE | ID: mdl-32352220

INTRODUCTION: The brittle response (BR) in patients with Parkinson's disease (PD) refers to a special type of levodopa-induced dyskinesia (LID). This study aimed to describe the clinical characteristics of BR patients and to analyze the associated risk factors. METHODS: A retrospective study was conducted to analyze the data of 97 patients with PD. Patients were divided into a BR group and a non-brittle response (NBR) group. Demographic and clinical data, motor symptoms, and non-motor symptoms of the two groups were assessed. RESULTS: Among 97 PD patients, 11 were in the BR group and 86 were in the NBR group. The proportion of female patients was 72.7% and 38.3%, respectively, in the BR and NBR groups (P < 0.05). Compared to NBR patients, BR patients had relatively low body weight, low BMI, long disease duration, high levodopa equivalent daily dosage (LEDD), and high levodopa dose per weight (P < 0.05). The BR group had significantly higher scores of UPDRS (II, III, and IV) (P < 0.05). But no difference was found in the UPDRS I, emotional state, cognitive status, and accompanied by REM sleep behavior disorder (RBD) (P> 0.05). Multivariate logistic regression analysis showed that BR patients had lower body weight and higher levodopa dose per weight. CONCLUSION: BR is associated with being female, low body weight, low BMI, long disease duration, high LEDD, and high levodopa dose per weight. Body weight and levodopa dose per body weight are independent risk factors for BR.


Dopamine Agents/adverse effects , Dyskinesia, Drug-Induced/etiology , Dyskinesia, Drug-Induced/physiopathology , Levodopa/adverse effects , Parkinson Disease/physiopathology , Adult , Body Mass Index , Body Weight/physiology , Dopamine Agents/administration & dosage , Female , Humans , Levodopa/administration & dosage , Male , Middle Aged , Parkinson Disease/drug therapy , Retrospective Studies , Risk Factors , Sex Factors , Time Factors
18.
Expert Opin Emerg Drugs ; 25(2): 131-144, 2020 06.
Article En | MEDLINE | ID: mdl-32366130

INTRODUCTION: Prolonged treatment with L-3,4-dihydroxyphenylalanine (L-DOPA) leads to the development of uncontrolled movements (L-DOPA-induced dyskinesias (LID)) in Parkinson's disease (PD). There is currently only a single approved drug for the treatment of LID, a long-acting preparation of the NMDA antagonist, amantadine, that has variable benefits and side-effects. Therefore, new treatments for LID remain an unmet in PD. AREAS COVERED: We review the current strategies for the management of LID; the pathogenic mechanisms underlying the development of LID, which provides the rationale for clinical trials of novel targets for LID and provide a review of phase II/III trials for emerging drugs for LID, with either positive results, or ongoing studies, reported between January 2014 and December 2019. EXPERT OPINION: There are several ongoing studies for agents that showed possible benefit at phase Ib/IIa for reducing LID. However, there are no new positive phase III double-blind randomized controlled clinical trials (DBRCT) for emerging treatments for LID. Generating better preclinical models, more precise recruitment tools and better outcome measures remain a priority. The pharmacology of drugs investigated for LID may be too selective; therefore, evaluating combinations of drugs is worthy of consideration as is the repurposing of existing drugs with multiple pharmacological targets.


Antiparkinson Agents/adverse effects , Dyskinesia, Drug-Induced/drug therapy , Levodopa/adverse effects , Amantadine/administration & dosage , Amantadine/pharmacology , Animals , Antiparkinson Agents/administration & dosage , Drug Development , Drug Repositioning , Dyskinesia, Drug-Induced/etiology , Dyskinesia, Drug-Induced/physiopathology , Humans , Levodopa/administration & dosage , Parkinson Disease/drug therapy , Randomized Controlled Trials as Topic
19.
Neuropharmacology ; 167: 107997, 2020 05 01.
Article En | MEDLINE | ID: mdl-32057799

l-DOPA is the gold-standard pharmacotherapy for treatment of Parkinson's disease (PD) but can lead to the appearance of troubling dyskinesia which are attributable to 'false neurotransmitter' release of dopamine by serotonergic neurons. Reducing the activity of these neurons diminishes l-DOPA-induced dyskinesia (LID), but there are currently no clinically approved selective, high efficacy 5-HT1A receptor agonists. Here we describe the effects of NLX-112, a highly selective and efficacious 5-HT1A receptor agonist, on LID in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-treated marmosets, a non-human primate model of PD. NLX-112 exhibited modest plasma half-life (~2h) and marked plasma protein binding (96%). When administered to parkinsonian marmosets with l-DOPA (7 mg/kg p.o.), NLX-112 (0.025, 0.1 and 0.4 mg/kg p.o.) reduced LID scores at early time-points after administration, whilst only minimally interfering with the l-DOPA-induced reversal of motor disability. In contrast, the prototypical 5-HT1A receptor agonist, (+)8-OH-DPAT (0.6 and 2 mg/kg p. o.), reduced LID but also abolished l-DOPA's anti-disability activity. Administered by itself, NLX-112 (0.1, 0.2 mg/kg p.o.) produced very little dyskinesia or locomotor activity, but reduced motor disability scores by about half the extent elicited by l-DOPA, suggesting that it may have motor facilitation effects of its own. Both NLX-112 and (+)8-OH-DPAT induced unusual and dose-limiting behaviors in marmoset that resembled 'serotonin behavioral syndrome' observed previously in rat. Overall, the present study showed that NLX-112 has anti-LID activity at the doses tested as well as reducing motor disability. The data suggest that additional investigation of NLX-112 is desirable to explore its potential as a treatment for PD and PD-LID.


Anti-Dyskinesia Agents/therapeutic use , Antiparkinson Agents/therapeutic use , Dyskinesia, Drug-Induced/drug therapy , MPTP Poisoning/drug therapy , Piperidines/therapeutic use , Pyridines/therapeutic use , Serotonin 5-HT1 Receptor Agonists/therapeutic use , Animals , Anti-Dyskinesia Agents/pharmacology , Antiparkinson Agents/pharmacology , Callithrix , Dyskinesia, Drug-Induced/metabolism , Dyskinesia, Drug-Induced/physiopathology , Female , Levodopa/toxicity , Locomotion/drug effects , Locomotion/physiology , MPTP Poisoning/metabolism , MPTP Poisoning/physiopathology , Male , Piperidines/pharmacology , Pyridines/pharmacology , Receptor, Serotonin, 5-HT1A/metabolism , Serotonin 5-HT1 Receptor Agonists/pharmacology , Treatment Outcome
20.
Neuropharmacology ; 162: 107829, 2020 01 01.
Article En | MEDLINE | ID: mdl-31666199

Parkinson's disease (PD) is characterized by progressive loss of midbrain dopaminergic neurons and treated with the dopamine precursor, 3,4-dihydroxy-l-phenylalanine (L-DOPA). Prolonged L-DOPA treatment is however associated with waning efficacy and the induction of L-DOPA induced dyskinesia (LID). GPR88 is an orphan G-protein Coupled Receptor (GPCR) expressed in dopaminoceptive striatal medium spiny neurons (MSNs) and their afferent corticostriatal glutamatergic neurons. Here, we studied the role of GPR88 in experimental parkinsonism and LID. Chronic L-DOPA administration to male GPR88 KO mice, subjected to unilateral 6-hydroxydopamine (6-OHDA) lesions of the medial forebrain bundle, resulted in more rotations than in their WT counterparts. Conversely, GPR88 KO mice had a lower abnormal involuntary movements (AIMs) score. These behavioral responses were accompanied by altered transcription of L-DOPA upregulated genes in lesioned GPR88 KO compared to WT striata. In accordance with a role for serotonin neurons in LID development, WT but not GPR88 KO striata exhibited 5-hydroxytryptamine displacement upon repeated L-DOPA treatment. Intact male GPR88 KO mice showed diminished tacrine-induced PD-like tremor and spontaneous hyperlocomotion. Dopamine and its metabolites were not increased in male GPR88 KO mice, but biosensor recordings revealed increased spontaneous/basal and evoked glutamate release in striata of male GPR88 KO mice. In conclusion, genetic deletion of GPR88 promotes l-DOPA-induced rotation and spontaneous locomotion yet suppresses the induction of LIDs and also reduces tremor. These data provide behavioral, neurochemical and molecular support that GPR88 antagonism may favour motor relief in PD patients without aggravating the induction of motor side effects.


Antiparkinson Agents/pharmacology , Corpus Striatum/metabolism , Dyskinesia, Drug-Induced/genetics , Levodopa/pharmacology , Locomotion/drug effects , Movement/drug effects , Parkinsonian Disorders/genetics , Receptors, G-Protein-Coupled/genetics , Adrenergic Agents/toxicity , Animals , Cholinesterase Inhibitors/toxicity , Corpus Striatum/drug effects , Dopamine Plasma Membrane Transport Proteins/genetics , Dyskinesia, Drug-Induced/etiology , Dyskinesia, Drug-Induced/metabolism , Dyskinesia, Drug-Induced/physiopathology , GABAergic Neurons , Glutamic Acid/metabolism , Locomotion/genetics , Male , Medial Forebrain Bundle , Mice , Mice, Knockout , Neuronal Plasticity/genetics , Oxidopamine/toxicity , Parkinsonian Disorders/metabolism , Parkinsonian Disorders/physiopathology , RNA, Messenger/drug effects , RNA, Messenger/genetics , RNA, Messenger/metabolism , Receptors, G-Protein-Coupled/physiology , Serotonin/metabolism , Tacrine/toxicity , Tremor
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