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Ideggyogyaszati Szemle May 2021Despite the continuous development of diagnosis and treatment of patients with Parkinson's disease and the arrival of new therapeutic options in recent years the... (Review)
Review
Despite the continuous development of diagnosis and treatment of patients with Parkinson's disease and the arrival of new therapeutic options in recent years the treatment and care of people with Parkinson's disease especially in the advanced stage remains a major challenge for neurologists specialized in movement disorders. The treatment of Parkinson's disease is adversely affected by several factors: the disease progresses relentlessly, the symptoms and rate of progression, other concomitant non-motor symptoms, and the appearance of complications caused by treatment show great heterogeneity. Based on all these factors it is difficult to develop and apply a uniform routine therapeutic guideline. This summary seeks to shed light on aspects of the treatment of Parkinson's disease particularly in advanced-stage cases drawing on data from a professional college recommendation and the literature.
Topics: Antiparkinson Agents; Humans; Levodopa; Parkinson Disease
PubMed: 34106553
DOI: 10.18071/isz.74.0151 -
Neurology India 2020Neuromodulation therapies, including deep brain stimulation (DBS) and pump therapies, are currently the standard of care for PD patients with advanced disease and motor... (Review)
Review
Neuromodulation therapies, including deep brain stimulation (DBS) and pump therapies, are currently the standard of care for PD patients with advanced disease and motor complications that are difficult to control with medical management alone. The quest for alternate lesser invasive approaches led to the development of several novel therapies like intrajejunal levodopa infusions (IJLI), continuous subcutaneous apomorphine infusions (CSAI) and Magnetic Resonance guided Focused Ultrasound (MRgFUS) in recent years. To achieve good outcomes with any of these therapeutic modalities, careful patient selection, multidisciplinary evaluation and technical expertise are equally important. In this review, we will provide an overview of the neuromodulation strategies currently available for PD, emphasizing on patient selection and choosing among the various strategies.
Topics: Antiparkinson Agents; Deep Brain Stimulation; Humans; Levodopa; Parkinson Disease; Patient Selection
PubMed: 33318347
DOI: 10.4103/0028-3886.302473 -
Current Neuropharmacology 2016Patients with Parkinson's disease (PD) receiving L-3,4-dihydroxyphenylalanine (L-DOPA, the gold-standard treatment for this disease) frequently develop abnormal... (Review)
Review
Patients with Parkinson's disease (PD) receiving L-3,4-dihydroxyphenylalanine (L-DOPA, the gold-standard treatment for this disease) frequently develop abnormal involuntary movements, termed L-DOPA-induced dyskinesias (LID). Glutamate overactivity is well documented in PD and LID. An approach to manage LID is to add to L-DOPA specific agents to reduce dyskinesias such as metabotropic glutamate receptor (mGlu receptor) drugs. This article reviews the contribution of mGlu type 5 (mGlu5) receptors in animal models of PD. Several mGlu5 negative allosteric modulators acutely attenuate LID in 1-methyl-4-phenyl-1,2,3,6- tetrahydropyridine (MPTP) monkeys and 6-hydroxydopamine(6-OHDA)-lesioned rats. Chronic administration of mGlu5 negative allosteric modulators to MPTP monkeys and 6-OHDA rats also attenuates LID while maintaining the antiparkinsonian effect of L-DOPA. Radioligand autoradiography shows an elevation of striatal mGlu5 receptors of dyskinetic L-DOPA-treated MPTP monkeys but not in those without LID. The brain molecular correlates of the long-term effect of mGlu5 negative allosteric modulators treatments with L-DOPA attenuating development of LID was shown to extend beyond mGlu5 receptors with normalization of glutamate activity in the basal ganglia of L-DOPA-induced changes of NMDA, AMPA, mGlu2/3 receptors and VGlut2 transporter. In the basal ganglia, mGlu5 receptor negative allosteric modulators also normalize the L-DOPA-induced changes of dopamine D2receptors, their associated signaling proteins (ERK1/2 and Akt/GSK3β) and neuropeptides (preproenkephalin, preprodynorphin) as well as the adenosine A2A receptors expression. These results show in animal models of PD reduction of LID with mGlu5 negative allosteric modulation associated with normalization of glutamate, dopamine and adenosine receptors suggesting a functional link of these receptors in chronic treatment with L-DOPA.
Topics: Animals; Antiparkinson Agents; Dyskinesia, Drug-Induced; Humans; Levodopa; Neostriatum; Parkinsonian Disorders; Receptor, Adenosine A2A; Receptor, Metabotropic Glutamate 5; Receptors, Dopamine D2
PubMed: 26639458
DOI: 10.2174/1570159x14666151201185652 -
Scientific Reports Aug 2022Dopa-responsive dystonia (DRD) is caused by an impaired dopamine biosynthesis due to a GTP-cyclohydrolase-1 (GCH1) deficiency, resulting in a combination of dystonia...
Dopa-responsive dystonia (DRD) is caused by an impaired dopamine biosynthesis due to a GTP-cyclohydrolase-1 (GCH1) deficiency, resulting in a combination of dystonia and parkinsonism. However, the effect of GCH1 mutations and levodopa treatment on motor control beyond simple movements, such as timing, action preparation and feedback processing, have not been investigated so far. In an active time estimation task with trial-by-trial feedback, participants indicated a target interval (1200 ms) by a motor response. We compared 12 patients tested (in fixed order) under their current levodopa medication ("ON") and after levodopa withdrawal ("OFF") to matched healthy controls (HC), measured twice to control for repetition effects. We assessed time estimation accuracy, trial-to-trial adjustment, as well as task- and feedback-related pupil-linked arousal responses. Patients showed comparable time estimation accuracy ON medication as HC but reduced performance OFF medication. Task-related pupil responses showed the reverse pattern. Trial-to-trial adjustments of response times were reduced in DRD, particularly OFF medication. Our results indicate differential alterations of time estimation accuracy and task-related arousal dynamics in DRD patients as a function of dopaminergic medication state. A medication-independent alteration of task repetition effects in DRD cannot be ruled out with certainty but is discussed as less likely.
Topics: Arousal; Case-Control Studies; Dystonic Disorders; GTP Cyclohydrolase; Humans; Levodopa
PubMed: 35995805
DOI: 10.1038/s41598-022-17545-w -
Scientific Reports Jun 2015Mucuna pruriens is the best known natural source of L-dopa, the gold standard for treatment of Parkinsonism. M. pruriens varieties are protein rich supplements, and are...
Mucuna pruriens is the best known natural source of L-dopa, the gold standard for treatment of Parkinsonism. M. pruriens varieties are protein rich supplements, and are used as food and fodder worldwide. Here, we report L-dopa contents in seeds of fifty six accessions of four M. pruriens varieties, M. pruriens var. pruriens, M. pruriens var. hirsuta, M. pruriens var. utilis and M. pruriens var. thekkadiensis, quantified by HPTLC-densitometry. L-dopa contents varied between 0.58 to 6.42 (%, dr. wt.). High and low L-dopa yielding genotypes/chemotypes of M. pruriens could be multiplied for medicinal and nutritional purposes, respectively. HPTLC profiles of M. pruriens seeds on repeated extraction (24 h) in 1:1 formic acid-alcohol followed by development in butanol:acetic acid:water (4:1:1, v/v) showed consistent degradation of L-dopa (Rf 0.34 ± 0.02) into a second peak (Rf 0.41 ± 0.02). An average of 52.11% degradation of L-dopa was found in seeds of M. pruriens varieties. Since M. pruriens seeds and/or L-dopa are used for treatment of Parkinson's disease and as an aphrodisiac both in modern and/or traditional systems of medicine, the finding of high level of L-dopa degradation (in pure form and in M. pruriens extracts) into damaging quinones and ROS is very significant.
Topics: Biodegradation, Environmental; Chromatography, Thin Layer; Hydrolysis; Levodopa; Mucuna
PubMed: 26058043
DOI: 10.1038/srep11078 -
Laboratory Animals Apr 2022Preclinical drug studies routinely administer experimental compounds to animal models with the goal of minimizing potential adverse events from the procedure. In this...
Preclinical drug studies routinely administer experimental compounds to animal models with the goal of minimizing potential adverse events from the procedure. In this study, we assessed the ability to train adult male Long Evans rats to accept daily voluntarily syringe feedings of l-3,4-dihydroxyphenylalanine (L-DOPA) compared to intraperitoneal (IP) injections. Rats were trained to become familiar with the syringe and then fed a training solution that did not contain the experimental compound. If the rat was compliant during the training phase, the dilution of training solution was continuously decreased and replaced with the experimental solution. Voluntary oral dosing compliance was recorded and quantified throughout the study. To assess drug activity within the drug-targeted tissues, the striatum and retina were collected and analyzed for L-DOPA, dopamine and 3,4-dihydroxyphenylacetic acid (DOPAC) levels by high performance liquid chromatography (HPLC). Drug delivery efficiency by oral dosing was directly compared to IP injection by collecting plasma and analyzing L-DOPA levels with HPLC. Adult male rats had high compliance for voluntary oral dosing. HPLC showed that oral administration of the compound at the same dose as IP injection yielded significantly lower plasma levels, and that higher oral L-DOPA doses yield higher plasma L-DOPA content. This study describes detailed methodology to train adult rats to syringe feed experimental compounds and provides important preclinical research on drug dosing and drug delivery to the striatum and retina.
Topics: 3,4-Dihydroxyphenylacetic Acid; Animals; Corpus Striatum; Dopamine; Levodopa; Male; Rats; Rats, Long-Evans
PubMed: 34392713
DOI: 10.1177/00236772211016926 -
PloS One 2021To prospectively evaluate nocturnal sleep problems and excessive daytime sleepiness (EDS) in Parkinson's disease (PD) patients, and analyze the influence of motor...
OBJECTIVE
To prospectively evaluate nocturnal sleep problems and excessive daytime sleepiness (EDS) in Parkinson's disease (PD) patients, and analyze the influence of motor symptoms, treatment, and sex differences on sleep problems in PD.
METHODS
Sleep disturbances of 103 PD patients were assessed with Parkinson's Disease Sleep Scale (PDSS) and the Epworth Sleepiness Scale (ESS). Student's t-test for related samples, one-way ANOVA with Tukey's HSD post hoc test were used to assess group differences. Bivariate correlations and mixed-effects linear regression models were used to analyze the association between clinical aspects and sleep disturbances over time.
RESULTS
At baseline, 48.5% of PD patients presented nocturnal problems and 40% of patients presented EDS. The PDSS and ESS total score slightly improve over time. Nocturnal problems were associated with age and motor impartment, explaining the 51% of the variance of the PDSS model. Males presented less nocturnal disturbances and more EDS than females. Higher motor impairment and combined treatment (L-dopa and agonist) were related to more EDS, while disease duration and L-dopa in monotherapy were related to lower scores, explaining the 59% of the model.
CONCLUSIONS
Sleep disturbances changed over time and age, diseases duration, motor impairment, treatment and sex were associated with nocturnal sleep problems and EDS. Agonist treatment alone or in combination with L-dopa might predict worse daytime sleepiness, while L-dopa in monotherapy is related to lower EDS, which significantly affects the quality of life of PD patients.
Topics: Age Factors; Antiparkinson Agents; Female; Humans; Levodopa; Male; Middle Aged; Parkinson Disease; Photoperiod; Sex Factors; Sleep Wake Disorders
PubMed: 34851977
DOI: 10.1371/journal.pone.0259935 -
Neuroscience Nov 2020Dopamine loss in Parkinson's disease (PD) is associated with abnormal oscillatory activity in the cortico-basal ganglia network. However, the oscillatory pattern of...
Dopamine loss in Parkinson's disease (PD) is associated with abnormal oscillatory activity in the cortico-basal ganglia network. However, the oscillatory pattern of striatal neurons in PD remains poorly defined. Here, we analyzed the local field potentials in one untreated and five MPTP-treated non-human primates (NHP) with chronic, advanced parkinsonism. Oscillatory activities in the alpha (8-13 Hz) and low-beta (13-20 Hz) frequency bands were found in the striatum similarly to the motor cortex and globus pallidus of the NHP model of PD. Both alpha and low-beta frequency band oscillations of the striatum were highly coherent with the cortical and pallidal oscillations, confirming the presence of abnormal 8-20 Hz oscillatory activity in the cortico-basal ganglia network in parkinsonian NHPs. The reversal of parkinsonism induced by acute levodopa administration was associated with reduced 8-20 Hz oscillations in the striatum. These findings indicate that pathological oscillations at alpha and low-beta bands are also present in the striatum concordant with basal ganglia network changes in the primate model of PD.
Topics: Animals; Basal Ganglia; Corpus Striatum; Globus Pallidus; Levodopa; Primates
PubMed: 32905842
DOI: 10.1016/j.neuroscience.2020.09.004 -
Molecules (Basel, Switzerland) Nov 2017l-Dopa, the metabolic precursor of dopamine, is the treatment of choice for the symptomatic relief of the advanced stages of Parkinson's disease. The oral...
l-Dopa, the metabolic precursor of dopamine, is the treatment of choice for the symptomatic relief of the advanced stages of Parkinson's disease. The oral bioavailability of l-dopa, however, is only about 10% to 30%, and less than 1% of the oral dose is estimated to reach the brain unchanged. l-Dopa's physicochemical properties are responsible for its poor bioavailability, short half-life and the wide range of inter- and intrapatient variations of plasma levels. An l-dopa-lazabemide prodrug is proposed to overcome the problems associated with l-dopa absorption. Lazabemide is a monoamine oxidase (MAO)-B inhibitor, a class of compounds that slows the depletion of dopamine stores in Parkinson's disease and elevates dopamine levels produced by exogenously administered l-dopa. l-Dopa was linked at the carboxylate with the primary aminyl functional group of lazabemide via an amide, a strategy which is anticipated to protect l-dopa against peripheral decarboxylation and possibly also enhance the membrane permeability of the prodrug. Selected physicochemical and biochemical properties of the prodrug were determined and included lipophilicity (logD), solubility, passive diffusion permeability, p, chemical and metabolic stability as well as cytotoxicity. Although oral and i.p. treatment of mice with the prodrug did not result in enhanced striatal dopamine levels, 3,4-dihydroxyphenylacetic acid (DOPAC) levels were significantly depressed compared to saline, l-dopa and carbidopa/l-dopa treatment. Based on the results, further preclinical evaluation of the l-dopa-lazabemide prodrug should be undertaken with the aim of discovering prodrugs that may be advanced to the clinical stages of development.
Topics: 3,4-Dihydroxyphenylacetic Acid; Animals; Biological Availability; Carbidopa; Corpus Striatum; Dopamine; Drug Combinations; HeLa Cells; Humans; Levodopa; Male; Mice, Inbred C57BL; Monoamine Oxidase; Monoamine Oxidase Inhibitors; Parkinson Disease; Permeability; Picolinic Acids; Prodrugs; Solubility; Structure-Activity Relationship
PubMed: 29186917
DOI: 10.3390/molecules22122076 -
Biomolecules Feb 2022The discovery of the D3 receptor (D3R) subtypes of dopamine (DA) has generated an understandable increase in interest in the field of neurological diseases, especially... (Review)
Review
The discovery of the D3 receptor (D3R) subtypes of dopamine (DA) has generated an understandable increase in interest in the field of neurological diseases, especially Parkinson's disease (PD). Indeed, although DA replacement therapy with l-DOPA has provided an effective treatment for patients with PD, it is responsible for invalidating abnormal involuntary movements, known as L-DOPA-induced dyskinesia, which constitutes a serious limitation of the use of this therapy. Of particular interest is the finding that chronic l-DOPA treatment can trigger the expression of D1R-D3R heteromeric interactions in the dorsal striatum. The D3R is expressed in various tissues of the central nervous system, including the striatum. Compelling research has focused on striatal D3Rs in the context of PD and motor side effects, including dyskinesia, occurring with DA replacement therapy. Therefore, this review will briefly describe the basal ganglia (BG) and the DA transmission within these brain regions, before going into more detail with regard to the role of D3Rs in PD and their participation in the current treatments. Numerous studies have also highlighted specific interactions between D1Rs and D3Rs that could promote dyskinesia. Finally, this review will also address the possibility that D3Rs located outside of the BG may mediate some of the effects of DA replacement therapy.
Topics: Dyskinesia, Drug-Induced; Humans; Levodopa; Parkinson Disease; Receptors, Dopamine D1; Receptors, Dopamine D3
PubMed: 35204744
DOI: 10.3390/biom12020243