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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 -
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 -
Neuroscience Bulletin Oct 2013Continuous dopaminergic stimulation (CDS) is a prominent therapeutic concept for the treatment of Parkinson's disease (PD), which proposes that continuous brain... (Review)
Review
Continuous dopaminergic stimulation (CDS) is a prominent therapeutic concept for the treatment of Parkinson's disease (PD), which proposes that continuous brain dopamine-receptor stimulation, rather than intermittent doses of oral L-dopa, prevents or manages L-dopa-induced dyskinesias (LIDs). In the normal situation, dopaminergic neurons in the substantia nigra pars compacta fire tonically to keep the dopamine receptor stimulation at a steady-state level. But when the dopaminergic pathway is impaired, the dopamine receptor stimulation becomes intermittent or pulsatile. This pulsatile stimulation causes a series of gene and protein changes in striatal neurons, leading to alterations in the fi ring patterns of basal ganglia neurons that result in LIDs. Studies in animal models and clinical trials of PD have shown that approaches providing CDS, currently including patches, extended-release formulations of L-dopa or dopamine agonists, continuous delivery of apomorphine and duodenal L-dopa infusion, are associated with a decreased risk of LIDs. In this review, we summarize both preclinical and clinical evidence for the five methods that may provide CDS in theory and compare the advantages and disadvantages of these methods.
Topics: Animals; Dopamine Agonists; Humans; Levodopa; Parkinson Disease
PubMed: 23512740
DOI: 10.1007/s12264-013-1329-8 -
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 -
Biomolecules Jun 2019Parkinson's disease (PD) is a neurodegenerative disorder characterized by loss of dopaminergic neurons at level of . To date, there is no cure for this pathology, except...
Parkinson's disease (PD) is a neurodegenerative disorder characterized by loss of dopaminergic neurons at level of . To date, there is no cure for this pathology, except for some drugs able to alleviate the symptoms of PD. In this paper we report the synthesis and biological evaluation of novel sulfur- and selenyl-l-Dopa (LD) derivatives () obtained through the amide junction between the amino group of LD and carboxylic moiety of sulfur- and selenyl-organic compounds, which are commercially available. Biological activity was evaluated on human undifferentiated and retinoic acid/phorbol myristyl acetate (RA/PMA)-differentiated SY-SH5Y neuroblastoma cell line using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay. Antioxidant activity against oxidative stress was measured using nitroblue tetrazolium (NBT) and 2',7'-dichlorodihydrofluorescein diacetate (HDCFDA) assays. Finally, physico-chemical characterization and plasma stability studies of were also performed. Biological data revealed that has a significant protective action against the neurotoxic action of 6-hydroxydopamine (6-OHDA) and HO in a RA/PMA-differentiated SY-SH5Y neuroblastoma cell line that proved to be an effective antioxidant and protective compound. , endowed with a lipophilic nature, low molecular weight, and plasma stability, can easily cross biological membranes via passive diffusion such as through the blood-brain barrier. has great potential for developing novel pharmacological approach for neurodegenerative diseases, such as PD. Further studies will help define its exact antioxidant mechanism and determine whether the neuroprotective action is mediated or modulated by glutathione peroxidase (GPx).
Topics: Antioxidants; Cell Line, Tumor; Chemistry Techniques, Synthetic; Dose-Response Relationship, Drug; Humans; Hydrophobic and Hydrophilic Interactions; Levodopa; Neuroprotective Agents; Oxidative Stress; Parkinson Disease; Sulfur
PubMed: 31216771
DOI: 10.3390/biom9060239 -
Biomolecules Nov 2023L-DOPA is the mainstay of treatment for Parkinson's disease (PD). However, over time this drug can produce dyskinesia. A useful acute PD model for screening novel...
L-DOPA is the mainstay of treatment for Parkinson's disease (PD). However, over time this drug can produce dyskinesia. A useful acute PD model for screening novel compounds for anti-parkinsonian and L-DOPA-induced dyskinesia (LID) are dopamine-depleted dopamine-transporter KO (DDD) mice. Treatment with α-methyl--tyrosine rapidly depletes their brain stores of DA and renders them akinetic. During sensitization in the open field (OF), their locomotion declines as vertical activities increase and upon encountering a wall they stand on one leg or tail and engage in climbing behavior termed "three-paw dyskinesia". We have hypothesized that L-DOPA induces a stereotypic activation of locomotion in DDD mice, where they are unable to alter the course of their locomotion, and upon encountering walls engage in "three-paw dyskinesia" as reflected in vertical counts or beam-breaks. The purpose of our studies was to identify a valid index of LID in DDD mice that met three criteria: (a) sensitization with repeated L-DOPA administration, (b) insensitivity to a change in the test context, and (c) stimulatory or inhibitory responses to dopamine D1 receptor agonists (5 mg/kg SKF81297; 5 and 10 mg/kg MLM55-38, a novel compound) and amantadine (45 mg/kg), respectively. Responses were compared between the OF and a circular maze (CM) that did not hinder locomotion. We found vertical counts and climbing were specific for testing in the OF, while oral stereotypies were sensitized to L-DOPA in both the OF and CM and responded to D1R agonists and amantadine. Hence, in DDD mice oral stereotypies should be used as an index of LID in screening compounds for PD.
Topics: Mice; Animals; Levodopa; Dopamine Agonists; Dopamine; Dopamine Plasma Membrane Transport Proteins; Dyskinesia, Drug-Induced; Mice, Knockout; Parkinson Disease; Amantadine
PubMed: 38002340
DOI: 10.3390/biom13111658 -
Pharmaceutical Biology Dec 2020L-DOPA is the first-line drug for Parkinson's disease (PD). However, chronic use can lead to dyskinesia. Caffeine, which is a known neuroprotectant, can potentially act...
CONTEXT
L-DOPA is the first-line drug for Parkinson's disease (PD). However, chronic use can lead to dyskinesia. Caffeine, which is a known neuroprotectant, can potentially act as an adjunct to minimise adverse effects of L-DOPA.
OBJECTIVES
This study determined changes in terms of neurodegeneration, locomotion and mechanosensation in (Rhabditidae) strain UA57 overexpressing tyrosine hydroxylase (CAT-2) when treated with caffeine, L-DOPA or their combinations.
MATERIALS AND METHODS
Neurodegeneration was monitored via fluorescence microscopy of GFP-tagged dopaminergic neurons in the head and tail regions of ( = 20). Meanwhile, mechanosensation and locomotion under vehicle (0.1% DMSO), L-DOPA (60 mM), caffeine (10 mM) or 60 mM L-DOPA + 10 or 20 mM caffeine (60LC10 and 60LC20) treatments were scored for 3 days.
RESULTS
L-DOPA (60 mM) reduced CEP and ADE neurons by 4.3% on day 3, with a concomitant decrease in fluorescence by 44.6%. This correlated with reductions in gentle head (-35%) and nose touch (-40%) responses, but improved locomotion (20-75%) compared with vehicle alone. CEP and ADE neuron counts were preserved with caffeine (10 mM) or 60LC10 (98-100%), which correlated with improved mechanosensation (10-23%) and locomotion (18-76%). However, none of the treatments was able to preserve PDE neuron count, reducing the basal slowing response. Taken together, we show that caffeine can protect DAergic neurons and can reduce aberrant locomotion and loss of sensation when co-administered with L-DOPA, which can potentially impact PD treatment and warrants further investigation.
Topics: Animals; Animals, Genetically Modified; Antiparkinson Agents; Caenorhabditis elegans; Caffeine; Dopaminergic Neurons; Dose-Response Relationship, Drug; Levodopa; Locomotion; Neuroprotective Agents; Parkinsonian Disorders
PubMed: 32715838
DOI: 10.1080/13880209.2020.1791192 -
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