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Nutrients Feb 2023Levodopa (L-dopa) and catechol-O-methyltransferase (COMT) inhibition are widely used therapeutics in Parkinson's disease (PD). Despite their therapeutic effects, it was... (Meta-Analysis)
Meta-Analysis
Levodopa (L-dopa) and catechol-O-methyltransferase (COMT) inhibition are widely used therapeutics in Parkinson's disease (PD). Despite their therapeutic effects, it was raised that nutrients involved in one-carbon metabolism can be deteriorated by PD therapies. The aim of this meta-analysis was to investigate the impact of L-dopa and COMT inhibitors on levels of homocysteine (Hcy), vitamin B and folate in patients with PD. A total of 35 case-control studies from 14 different countries were selected through PubMed, MEDLINE and Google Scholar and were meta-analyzed. In the L-dopa group, the Hcy level was higher compared to the PD without L-dopa group (SMD: 5.11 μmol/L, 95% CI: 3.56 to 6.66). Moreover, vitamin B and folate levels in the L-dopa group were lower compared to the healthy control (SMD: -62.67 pg/mL, 95% CI: -86.53 to -38.81; SMD: -0.89 ng/mL, 95% CI: -1.44 to -0.33, respectively). The COMT inhibitor group showed lower levels of Hcy (SMD: -3.78 μmol/L, 95% CI: -5.27 to -2.29) and vitamin B (SMD: -51.01 pg/mL, 95% CI: -91.45 to -10.57), but higher folate levels (SMD: 1.78 ng/mL, 95% CI: -0.59 to 4.15) compared to the L-dopa group. COMT inhibitors may ameliorate L-dopa-induced hyper-homocysteine and folate deficiency but exacerbate vitamin B deficiency.
Topics: Humans; Carbon; Folic Acid; Homocysteine; Levodopa; Parkinson Disease; Vitamin B 12; Vitamins; Catechol O-Methyltransferase Inhibitors
PubMed: 36839259
DOI: 10.3390/nu15040901 -
Experimental Biology and Medicine... May 2023The economic and visual burdens associated with age-related macular degeneration (AMD) are expected to significantly increase in the coming years. As of now,... (Review)
Review
The economic and visual burdens associated with age-related macular degeneration (AMD) are expected to significantly increase in the coming years. As of now, interventions to delay or prevent AMD are limited. Hence, there is an urgent and unmet need to expand our therapeutic tools for AMD in a manner, that is, both efficient and cost-effective. In this review, we consider the idea of drug repurposing, in which existing medications with other indications can be re-imagined for treating AMD. We detail the results of several population-level studies that have shown associations between several candidates and decreased risk of AMD development or progression. Such candidates include the more extensively studied metformin and statins, in addition to recently identified candidates fluoxetine and DOPA (levodopa) that show promise. We then briefly explore results from an advanced bioinformatics study, which provides further evidence that existing medications are associated with AMD risk genes. Many of these candidates warrant further study in prospective, clinical trials, where their potential causal relationships with AMD can be thoroughly assessed.
Topics: Humans; Prospective Studies; Drug Repositioning; Macular Degeneration; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Levodopa; Data Mining
PubMed: 37452694
DOI: 10.1177/15353702231181188 -
Biosensors Oct 2022The interaction of tyrosinase with sulfonated starch--polyaniline@graphene (SSt--PANI@G) nanocomposite was investigated by electrochemical methods. The activity of the...
The interaction of tyrosinase with sulfonated starch--polyaniline@graphene (SSt--PANI@G) nanocomposite was investigated by electrochemical methods. The activity of the immobilized tyrosinase (Tyase) was proved by the electrochemical detection of three substrates (L-dopa, caffeic acid, and catechol). The SSt--PANI@G nanocomposite was characterized by Fourier-transform infrared spectra (FT-IR), X-ray diffraction (XRD), field emission scanning electron microscopy (FESEM), energy-dispersive X-ray analysis (EDX), and thermogravimetric analysis (TGA). To immobilize tyrosinase on the surface of the nanocomposite, a simple drop-casting technique was used. The presence of sulfuric acid and hydroxyl groups in SSt, amine groups in PANI, and high surface-to-volume ratio and electrical conductivity of graphene in the prepared nanocomposite led to good enzyme immobilization on the electrode surface. The modified electrode showed a suitable catalytic effect on the electrochemical redox agent, compared with the bare electrode. The peak current responses for three substrates were studied with a calibration curve derived using cyclic voltammetry (CV) and differential pulse voltammetry (DPV). In addition, the fabricated SSt-g-PANI@G/Tyase/GCE showed a more suitable response to catechol, L-dopa, and caffeic acid substrates, respectively.
Topics: Graphite; Monophenol Monooxygenase; Spectroscopy, Fourier Transform Infrared; Starch; Levodopa; Nanocomposites; Electric Conductivity
PubMed: 36354447
DOI: 10.3390/bios12110939 -
NeuroImage Dec 2022Previous studies indicate a role of dopamine in spatial navigation. Although neural representations of direction are an important aspect of spatial cognition, it is not... (Randomized Controlled Trial)
Randomized Controlled Trial
Previous studies indicate a role of dopamine in spatial navigation. Although neural representations of direction are an important aspect of spatial cognition, it is not well understood whether dopamine directly affects these representations, or only impacts other aspects of spatial brain function. Moreover, both dopamine and spatial cognition decline sharply during age, raising the question which effect dopamine has on directional signals in the brain of older adults. To investigate these questions, we used a double-blind cross-over L-DOPA/Placebo intervention design in which 43 younger and 37 older adults navigated in a virtual spatial environment while undergoing functional magnetic resonance imaging (fMRI). We studied the effect of L-DOPA, a dopamine precursor, on fMRI activation patterns that encode spatial walking directions that have previously been shown to lose specificity with age. This was done in predefined regions of interest, including the early visual cortex, retrosplenial cortex, and hippocampus. Classification of brain activation patterns associated with different walking directions was improved across all regions following L-DOPA administration, suggesting that dopamine broadly enhances neural representations of direction. No evidence for differences between regions was found. In the hippocampus these results were found in both age groups, while in the retrosplenial cortex they were only observed in younger adults. Taken together, our study provides evidence for a link between dopamine and the specificity of neural responses during spatial navigation. SIGNIFICANCE STATEMENT: The sense of direction is an important aspect of spatial navigation, and neural representations of direction can be found throughout a large network of space-related brain regions. But what influences how well these representations track someone's true direction? Using a double-blind cross-over L-DOPA/Placebo intervention design, we find causal evidence that the neurotransmitter dopamine impacts the fidelity of direction selective neural representations in the human hippocampus and retrosplenial cortex. Interestingly, the effect of L-DOPA was either equally present or even smaller in older adults, despite the well-known age related decline of dopamine. These results provide novel insights into how dopamine shapes the neural representations that underlie spatial navigation.
Topics: Humans; Aged; Levodopa; Dopamine; Spatial Navigation; Brain Mapping; Magnetic Resonance Imaging
PubMed: 36243268
DOI: 10.1016/j.neuroimage.2022.119670 -
Neurobiology of Aging Oct 2022Vigor reflects how motivated people are to respond to stimuli. We previously showed that, on average, humans are more vigorous when a higher rate of reward is available,...
Vigor reflects how motivated people are to respond to stimuli. We previously showed that, on average, humans are more vigorous when a higher rate of reward is available, and that this relationship is modulated by the dopamine precursor levodopa. Dopamine signaling and probabilistic reward learning deteriorate across the adult life span, and thus, the relationship between vigor and reward may also change in aging. We tested this assertion and assessed whether it correlates with D1 dopamine receptor availability, measured using Positron Emission Tomography. We registered response times of 30 older and 30 younger participants during an oddball discrimination task where rewards varied systematically between trials. The average reward rate had a similar impact on vigor in both age groups. There was a weak positive association between ventral striatal dopamine receptor availability and the effect of average reward rate on response time. Overall, the effect of reward on response vigor was similar in younger and older adults, and weakly correlated with dopamine D1 receptor availability.
Topics: Aged; Dopamine; Humans; Learning; Levodopa; Reaction Time; Reward
PubMed: 35858491
DOI: 10.1016/j.neurobiolaging.2022.06.003 -
Movement Disorders : Official Journal... Aug 2021Advanced Parkinson's disease is inconsistently defined, and evidence is lacking in relation to device-aided therapies. To update existing reviews of intrajejunal... (Review)
Review
Advanced Parkinson's disease is inconsistently defined, and evidence is lacking in relation to device-aided therapies. To update existing reviews of intrajejunal infusion of levodopa/carbidopa (LCIG), we performed a literature search for relevant articles (to November 3, 2020) using PubMed supplemented by hand searching. Retrieved articles were categorized by relevance to identified research questions, including motor complications and symptoms; nonmotor symptoms; functioning, quality of life, and caregiver burden; optimal timing of treatment initiation and administration duration; discontinuation; and complications. Most eligible studies (n = 56) were open-label, observational studies including relatively small patient numbers. LCIG consistently reduces OFF time and increased ON time without troublesome dyskinesia with varying effects regarding ON time with troublesome dyskinesia and the possibility of diphasic dyskinesia. More recent evidence provides some increased support for the benefits of LCIG in relation to nonmotor symptoms, quality of life, activities of daily living, and reduced caregiver burden. Patient age does not appear to significantly impact the effectiveness of LCIG. Discontinuation rates with LCIG (~17%-26%) commonly relate to device-related issues, although the ability to easily discontinue LCIG may represent a potential benefit. LCIG may be a favorable option for patients with advanced Parkinson's disease who show predominant nonmotor symptoms and vulnerability to complications of other advanced therapy modalities. Larger, well-controlled studies, including precise investigation of cost effectiveness, would further assist treatment selection. © 2021 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.
Topics: Activities of Daily Living; Antiparkinson Agents; Carbidopa; Drug Combinations; Gels; Humans; Levodopa; Parkinson Disease; Quality of Life
PubMed: 33899262
DOI: 10.1002/mds.28595 -
British Journal of Pharmacology Jun 2021l-DOPA prolonged treatment leads to disabling motor complications as dyskinesia that could be decreased by drugs acting on 5-HT receptors. Since the internal segment of...
BACKGROUND AND PURPOSE
l-DOPA prolonged treatment leads to disabling motor complications as dyskinesia that could be decreased by drugs acting on 5-HT receptors. Since the internal segment of the globus pallidus, homologous to the entopeduncular nucleus in rodents, seems to be involved in the etiopathology of l-DOPA-induced dyskinesia, we investigated whether the entopeduncular nucleus is modulated by the 5-HT receptor partial and full agonists, buspirone, and 8-hydroxy-2-(di-n-propylamino)-tetralin (8-OH-DPAT) in control and 6-hydroxydopamine (6-OHDA)-lesioned rats with or without long-term l-DOPA treatment.
EXPERIMENTAL APPROACH
Extracellular single-unit electrocorticogram and local field potential recordings under anaesthesia, immunostaining assays and optogenetic manipulation coupled to electrophysiological recordings were performed.
KEY RESULTS
Systemic buspirone reduced the entopeduncular nucleus firing rate in the sham animals and burst activity in the 6-OHDA-lesioned rats (with or without l-DOPA treatment), while local administration reduced entopeduncular nucleus activity in all the groups, regardless of DA integrity. Systemic 8-OH-DPAT also induced inhibitory effects only in the sham animals. Effects triggered by buspirone and 8-OH-DPAT were reversed by the 5-HT receptor antagonist, WAY-100635. Neither buspirone nor 8-OH-DPAT modified the low-frequency oscillatory activity in the entopeduncular nucleus or its synchronization with the motor cortex. Buspirone did not alter the response induced by subthalamic nucleus opto-stimulation in the entopeduncular nucleus.
CONCLUSION AND IMPLICATIONS
Systemic 5-HT receptor activation elicits different effects on the electrophysiological properties of the entopeduncular nucleus depending on the integrity of the nigrostriatal pathway and it does not alter the relationship between subthalamic nucleus and entopeduncular nucleus neuron activity.
Topics: 8-Hydroxy-2-(di-n-propylamino)tetralin; Animals; Buspirone; Entopeduncular Nucleus; Levodopa; Oxidopamine; Rats; Rats, Sprague-Dawley; Receptor, Serotonin, 5-HT1A
PubMed: 33686657
DOI: 10.1111/bph.15437 -
Biosensors May 2023The electrochemical behavior of the immobilized tyrosinase (Tyrase) on a modified glassy carbon electrode with carboxymethyl starch--polyaniline/multi-walled carbon...
The electrochemical behavior of the immobilized tyrosinase (Tyrase) on a modified glassy carbon electrode with carboxymethyl starch--polyaniline/multi-walled carbon nanotubes nanocomposite (CMS--PANI@MWCNTs) was investigated. The molecular properties of CMS--PANI@MWCNTs nanocomposite and its morphological characterization were examined by Fourier transform infrared spectroscopy (FTIR), X-ray diffraction (XRD), and field emission scanning electron microscopy (FESEM). A simple drop-casting method was employed to immobilize Tyrase on the CMS--PANI@MWCNTs nanocomposite. In the cyclic voltammogram (CV), a pair of redox peaks were observed at the potentials of +0.25 to -0.1 V and E°' was equal to 0.1 V and the apparent rate constant of electron transfer (K) was calculated at 0.4 s. Using differential pulse voltammetry (DPV), the sensitivity and selectivity of the biosensor were investigated. The biosensor exhibits linearity towards catechol and L-dopa in the concentration range of 5-100 and 10-300 μM with a sensitivity of 2.4 and 1.11 μA μΜ cm and limit of detection (LOD) 25 and 30 μM, respectively. The Michaelis-Menten constant (K) was calculated at 42 μΜ for catechol and 86 μΜ for L-dopa. After 28 working days, the biosensor provided good repeatability and selectivity, and maintained 67% of its stability. The existence of -COO and -OH groups in carboxymethyl starch, -NH groups in polyaniline, and high surface-to-volume ratio and electrical conductivity of multi-walled carbon nanotubes in the CMS--PANI@MWCNTs nanocomposite cause good Tyrase immobilization on the surface of the electrode.
Topics: Monophenol Monooxygenase; Nanotubes, Carbon; Levodopa; Nanocomposites; Biosensing Techniques; Electrodes
PubMed: 37232923
DOI: 10.3390/bios13050562 -
Proceedings of the Japan Academy.... 2023L-DOPA is an amino acid that is used as a treatment for Parkinson's disease. A simple enzymatic synthesis method of L-DOPA had been developed using bacterial L-tyrosine... (Review)
Review
L-DOPA is an amino acid that is used as a treatment for Parkinson's disease. A simple enzymatic synthesis method of L-DOPA had been developed using bacterial L-tyrosine phenol-lyase (Tpl). This review describes research on screening of bacterial strains, culture conditions, properties of the enzyme, reaction mechanism of the enzyme, and the reaction conditions for the production of L-DOPA. Furthermore, molecular bleeding of constitutively Tpl-overproducing strains is described, which were developed based on mutations in a DNA binding protein, TyrR, which controls the induction of tpl gene expression.
Topics: Tyrosine Phenol-Lyase; Levodopa; Bacteria
PubMed: 36908174
DOI: 10.2183/pjab.99.006 -
International Journal of Molecular... Feb 2023To determine the efficacy of PT320 on L-DOPA-induced dyskinetic behaviors, and neurochemistry in a progressive Parkinson's disease (PD) MitoPark mouse model. To...
To determine the efficacy of PT320 on L-DOPA-induced dyskinetic behaviors, and neurochemistry in a progressive Parkinson's disease (PD) MitoPark mouse model. To investigate the effects of PT320 on the manifestation of dyskinesia in L-DOPA-primed mice, a clinically translatable biweekly PT320 dose was administered starting at either 5 or 17-weeks-old mice. The early treatment group was given L-DOPA starting at 20 weeks of age and longitudinally evaluated up to 22 weeks. The late treatment group was given L-DOPA starting at 28 weeks of age and longitudinally observed up to 29 weeks. To explore dopaminergic transmission, fast scan cyclic voltammetry (FSCV) was utilized to measure presynaptic dopamine (DA) dynamics in striatal slices following drug treatments. Early administration of PT320 significantly mitigated the severity L-DOPA-induced abnormal involuntary movements; PT320 particularly improved excessive numbers of standing as well as abnormal paw movements, while it did not affect L-DOPA-induced locomotor hyperactivity. In contrast, late administration of PT320 did not attenuate any L-DOPA-induced dyskinesia measurements. Moreover, early treatment with PT320 was shown to not only increase tonic and phasic release of DA in striatal slices in L-DOPA-naïve MitoPark mice, but also in L-DOPA-primed animals. Early treatment with PT320 ameliorated L-DOPA-induced dyskinesia in MitoPark mice, which may be related to the progressive level of DA denervation in PD.
Topics: Animals; Mice; Antiparkinson Agents; Delayed-Action Preparations; Disease Models, Animal; Dopamine; Dyskinesia, Drug-Induced; Glucagon-Like Peptide-1 Receptor; Levodopa; Oxidopamine; Parkinson Disease
PubMed: 36902115
DOI: 10.3390/ijms24054687