-
BMC Biotechnology Aug 2023Dopamine is high-value compound of pharmaceutical interest, but its industrial scale production mostly focuses on chemical synthesis, possessing environment pollution....
Dopamine is high-value compound of pharmaceutical interest, but its industrial scale production mostly focuses on chemical synthesis, possessing environment pollution. Bio-manufacturing has caused much attention for its environmental characteristic. Resting cells were employed to as biocatalysts with extraordinary advantages like offering stable surroundings, the inherent presence of expensive cofactors. In this study, whole-cell bioconversion was employed to convert dopa to dopamine. To increase the titer and yield of dopamine production through whole-cell catalysis, three kinds of aromatic amino acid transport protein, AroP, PheP and TyrP, were selected to be co-expressed. The effects of the concentration of L-dopa, pyridoxal-5'- phosphate (PLP), reaction temperature and pH were characterized for improvement of bioconversion. Under optimal conditions, dopamine titer reached 1.44 g/L with molar yield of 46.3%, which is 6.62 times than that of initial conditions. The catalysis productivity of recombinant E. coli co-expressed L-dopa decarboxylase(DDC) and AroP was further enhanced by repeated cell recycling, which maintained over 50% of its initial ability with eight consecutive catalyses. This study was the first to successfully bioconversion of dopamine by whole-cell catalysis. This research provided reference for whole-cell catalysis which is hindered by cell membrane.
Topics: Levodopa; Dopamine; Escherichia coli; Carrier Proteins; Catalysis
PubMed: 37644483
DOI: 10.1186/s12896-023-00794-6 -
BMC Neuroscience Jul 2016We evaluated the effects of 3-O-methyldopa (3-OMD), a metabolite of L-DOPA which is formed by catechol-O-methyltransferase (COMT), on the uptake, metabolism, and...
BACKGROUND
We evaluated the effects of 3-O-methyldopa (3-OMD), a metabolite of L-DOPA which is formed by catechol-O-methyltransferase (COMT), on the uptake, metabolism, and neuroprotective effects of L-DOPA in striatal astrocytes. We examined changes in the numbers of dopaminergic neurons after treatment with L-DOPA and 3-OMD or entacapone, a peripheral COMT inhibitor, using primary cultured mesencephalic neurons and striatal astrocytes.
RESULTS
The number of tyrosine hydroxylase-positive dopaminergic neurons was not affected by L-DOPA treatment in mesencephalic neurons alone. However, the increase in viability of dopaminergic neurons in the presence of astrocytes was further enhanced after methyl-L-DOPA treatment (25 µM) in mixed cultured mesencephalic neurons and striatal astrocytes. The neuroprotective effect of 25 µM L-DOPA was almost completely inhibited by simultaneous treatment with 3-OMD (10 or 100 µM), and was enhanced by concomitant treatment with entacapone (0.3 µM). The uptake of L-DOPA into and the release of glutathione from striatal astrocytes after L-DOPA treatment (100 µM) were inhibited by simultaneous exposure to 3-OMD (100 µM).
CONCLUSIONS
These data suggest that L-DOPA exerts its neuroprotective effect on dopaminergic neurons via astrocytes and that 3-OMD competes with L-DOPA by acting on target molecule(s) (possibly including glutathione) released from astrocytes. Since some amount of entacapone can cross the blood-brain barrier, this reagent may enhance L-DOPA transportation by inhibiting COMT and increase the astrocyte-mediated neuroprotective effects of L-DOPA on dopaminergic neurons.
Topics: Animals; Astrocytes; Catechol O-Methyltransferase Inhibitors; Catechols; Cells, Cultured; Corpus Striatum; Dihydroxyphenylalanine; Dopamine Agents; Dopaminergic Neurons; Dose-Response Relationship, Drug; Glutathione; Levodopa; Mesencephalon; Neuroprotection; Neuroprotective Agents; Nitriles; Rats, Sprague-Dawley; Tyrosine
PubMed: 27456338
DOI: 10.1186/s12868-016-0289-0 -
Basic & Clinical Pharmacology &... Feb 2012L-dopa is still the gold standard in the symptomatic treatment of Parkinson's disease (PD), and thus, it is the most commonly used drug in the non-clinical assessment of...
L-dopa is still the gold standard in the symptomatic treatment of Parkinson's disease (PD), and thus, it is the most commonly used drug in the non-clinical assessment of new drug therapies to PD, including those intended to improve the effect of L-dopa. In unilaterally 6-hydroxydopamine (6-OHDA)-lesioned rat model of PD, the results from L-dopa-induced rotation tests are often unpredictable. While repeated administration of L-dopa improves the rotation, the exact mechanisms underlying the extensive variability in rotation responses between rats and testing times are unclear. In the present study, we aimed to assess whether the route of administration (oral or intraperitoneal) or the form of L-dopa (base or methyl ester) is associated with the extensive variation in rotation responses to L-dopa in 6-OHDA rats. We also wanted to examine the dependence between L-dopa (base or methyl ester)-induced rotational behaviour and the extent of dopamine and dopa decarboxylase enzyme loss in the lesioned striatum. It was found that variation in plasma levels of L-dopa as well as the administration route explains a part of the variability in rotation. There were small but significant differences in striatal dopamine depletion (indicative of degree of lesion) between the groups, which may partially account for the various patterns in L-dopa-induced rotational behaviour. While apomorphine-induced rotation test is a useful tool for primary screening of the success of 6-OHDA lesion, it is not useful at predicting the rotational performance of 6-OHDA rats to L-dopa. The exact mechanisms and causes of the variability in the rotation responses to L-dopa in 6-OHDA rats still remain to be clarified.
Topics: Administration, Oral; Animals; Corpus Striatum; Disease Models, Animal; Injections, Intraperitoneal; Levodopa; Male; Motor Activity; Oxidopamine; Parkinson Disease; Rats; Rats, Wistar; Rotation
PubMed: 21848668
DOI: 10.1111/j.1742-7843.2011.00782.x -
Movement Disorders : Official Journal... Nov 2017Increased extracellular glutamate may contribute to l-dopa induced dyskinesia, a debilitating side effect faced by Parkinson's disease patients 5 to 10 years after...
BACKGROUND
Increased extracellular glutamate may contribute to l-dopa induced dyskinesia, a debilitating side effect faced by Parkinson's disease patients 5 to 10 years after l-dopa treatment. Therapeutic strategies targeting postsynaptic glutamate receptors to mitigate dyskinesia may have limited success because of significant side effects. Increasing glutamate uptake may be another approach to attenuate excess glutamatergic neurotransmission to mitigate dyskinesia severity or prolong the time prior to onset. Initiation of a ceftriaxone regimen at the time of nigrostriatal lesion can attenuate tyrosine hydroxylase loss in conjunction with increased glutamate uptake and glutamate transporter GLT-1 expression in a rat 6-hydroxydopamine model. In this article, we examined if a ceftriaxone regimen initiated 1 week after nigrostriatal lesion, but prior to l-dopa, could reduce l-dopa-induced dyskinesia in an established dyskinesia model.
METHODS
Ceftriaxone (200 mg/kg, intraperitoneal, once daily, 7 consecutive days) was initiated 7 days post-6-hydroxydopamine lesion (days 7-13) and continued every other week (days 21-27, 35-39) until the end of the study (day 39 postlesion, 20 days of l-dopa).
RESULTS
Ceftriaxone significantly reduced abnormal involuntary movements at 5 time points examined during chronic l-dopa treatment. Partial recovery of motor impairment from nigrostriatal lesion by l-dopa was unaffected by ceftriaxone. The ceftriaxone-treated l-dopa group had significantly increased striatal GLT-1 expression and glutamate uptake. Striatal tyrosine hydroxylase loss in this group was not significantly different when compared with the l-dopa alone group.
CONCLUSIONS
Initiation of ceftriaxone after nigrostriatal lesion, but prior to and during l-dopa, may reduce dyskinesia severity without affecting l-dopa efficacy or the reduction of striatal tyrosine hydroxylase loss. © 2017 International Parkinson and Movement Disorder Society.
Topics: Animals; Anti-Bacterial Agents; Ceftriaxone; Disease Models, Animal; Dopamine Agents; Dyskinesia, Drug-Induced; Excitatory Amino Acid Transporter 2; Levodopa; Male; Oxidopamine; Parkinson Disease; Rats; Rats, Sprague-Dawley; Sympatholytics
PubMed: 28631864
DOI: 10.1002/mds.27077 -
Nature Communications Sep 2023Dopamine fundamentally contributes to reinforcement learning, but recent accounts also suggest a contribution to specific action selection mechanisms and the regulation...
Dopamine fundamentally contributes to reinforcement learning, but recent accounts also suggest a contribution to specific action selection mechanisms and the regulation of response vigour. Here, we examine dopaminergic mechanisms underlying human reinforcement learning and action selection via a combined pharmacological neuroimaging approach in male human volunteers (n = 31, within-subjects; Placebo, 150 mg of the dopamine precursor L-dopa, 2 mg of the D2 receptor antagonist Haloperidol). We found little credible evidence for previously reported beneficial effects of L-dopa vs. Haloperidol on learning from gains and altered neural prediction error signals, which may be partly due to differences experimental design and/or drug dosages. Reinforcement learning drift diffusion models account for learning-related changes in accuracy and response times, and reveal consistent decision threshold reductions under both drugs, in line with the idea that lower dosages of D2 receptor antagonists increase striatal DA release via an autoreceptor-mediated feedback mechanism. These results are in line with the idea that dopamine regulates decision thresholds during reinforcement learning, and may help to bridge action selection and response vigor accounts of dopamine.
Topics: Humans; Male; Dopamine; Levodopa; Haloperidol; Men; Plastic Surgery Procedures
PubMed: 37666865
DOI: 10.1038/s41467-023-41130-y -
Molecules (Basel, Switzerland) Dec 2022An electrochemical sensor for simultaneous determination of Benserazide (BEZ) and levodopa (L-dopa) was successfully developed using a glassy carbon electrode (GCE)...
An electrochemical sensor for simultaneous determination of Benserazide (BEZ) and levodopa (L-dopa) was successfully developed using a glassy carbon electrode (GCE) modified with multi-walled carbon nanotube and nitrogen-doped titanium dioxide nanoparticles (GCE/MWCNT/N-TiO). Cyclic voltammetry and square wave voltammetry were employed to investigate the electrochemical behavior of different working electrodes and analytes. In comparison with unmodified GCE, the modified electrode exhibited better electrocatalytic activity towards BEZ and L-dopa and was efficient in providing a satisfactory separation for oxidation peaks, with a potential difference of 140 mV clearly allows the simultaneous determination of these compounds. Under the optimized conditions, linear ranges of 2.0-20.0 and 2.0-70.0 μmol L were obtained for BEZ and L-dopa, respectively, with a limit of detection of 1.6 µmol L for BEZ and 2.0 µmol L for L-dopa. The method was applied in simultaneous determination of the analytes in pharmaceutical samples, and the accuracy was attested by comparison with HPLC-DAD as the reference method, with a relative error lower than 4.0%.
Topics: Nanotubes, Carbon; Levodopa; Benserazide; Electrodes; Oxidation-Reduction; Electrochemical Techniques
PubMed: 36500705
DOI: 10.3390/molecules27238614 -
The American Journal of Medicine Mar 2016Age-related macular degeneration (AMD) is a leading cause of visual loss among the elderly. A key cell type involved in AMD, the retinal pigment epithelium, expresses a...
BACKGROUND
Age-related macular degeneration (AMD) is a leading cause of visual loss among the elderly. A key cell type involved in AMD, the retinal pigment epithelium, expresses a G protein-coupled receptor that, in response to its ligand, L-DOPA, up-regulates pigment epithelia-derived factor, while down-regulating vascular endothelial growth factor. In this study we investigated the potential relationship between L-DOPA and AMD.
METHODS
We used retrospective analysis to compare the incidence of AMD between patients taking vs not taking L-DOPA. We analyzed 2 separate cohorts of patients with extensive medical records from the Marshfield Clinic (approximately 17,000 and approximately 20,000) and the Truven MarketScan outpatient and databases (approximately 87 million) patients. We used International Classification of Diseases, 9th Revision codes to identify AMD diagnoses and L-DOPA prescriptions to determine the relative risk of developing AMD and age of onset with or without an L-DOPA prescription.
RESULTS
In the retrospective analysis of patients without an L-DOPA prescription, AMD age of onset was 71.2, 71.3, and 71.3 in 3 independent retrospective cohorts. Age-related macular degeneration occurred significantly later in patients with an L-DOPA prescription, 79.4 in all cohorts. The odds ratio of developing AMD was also significantly negatively correlated by L-DOPA (odds ratio 0.78; confidence interval, 0.76-0.80; P <.001). Similar results were observed for neovascular AMD (P <.001).
CONCLUSIONS
Exogenous L-DOPA was protective against AMD. L-DOPA is normally produced in pigmented tissues, such as the retinal pigment epithelium, as a byproduct of melanin synthesis by tyrosinase. GPR143 is the only known L-DOPA receptor; it is therefore plausible that GPR143 may be a fruitful target to combat this devastating disease.
Topics: Age Distribution; Age of Onset; Aged; Antiparkinson Agents; Cohort Studies; Data Mining; Eye Proteins; Humans; Levodopa; Macular Degeneration; Membrane Glycoproteins; Retrospective Studies; United States
PubMed: 26524704
DOI: 10.1016/j.amjmed.2015.10.015 -
NeuroImage. Clinical 2020Parkinson's disease (PD) is a movement disorder caused by dopaminergic neurodegeneration. Levodopa (L-dopa) is an effective medication for alleviating motor symptoms in...
Parkinson's disease (PD) is a movement disorder caused by dopaminergic neurodegeneration. Levodopa (L-dopa) is an effective medication for alleviating motor symptoms in PD that has been shown previously to reduce subcortical beta (13-30 Hz) oscillations. How L-dopa influences oscillations in the motor cortex is unclear. In this study, 21 PD patients were recorded with magnetoencephalography (MEG) in L-dopa ON and OFF states. Oscillatory components of resting-state power spectra were compared between the two states and the significant effect was localized using beamforming. Unified Parkinson's Disease Rating Scale (UPDRS) III akinesia and rigidity sub-scores for the most affected hemibody were correlated with source power values for the contralateral hemisphere. An L-dopa-induced power increase was found over the central sensors significant in the 18-30 Hz range (F > 14.8, P < 0.05, cluster size inference with P = 0.001 cluster-forming threshold). Beamforming localization of this effect revealed distinct peaks at the bilateral sensorimotor cortex. A significant correlation between the magnitude of L-dopa induced 18-30 Hz oscillatory motor-cortical power increase and the degree of improvement in contralateral akinesia and rigidity was found (F = 4.9, p = 0.02, R = 0.2). Power in the same range was also inversely correlated with combined akinesia and rigidity scores in the L-dopa OFF state (F = 9.2, p = 0.007, R = 0.33) but not in the L-dopa ON state (F = 0.27, p = 0.6, R = 0.01). These results suggest that the role of motor cortical beta oscillations in PD is distinct from that of subcortical beta.
Topics: Adult; Aged; Antiparkinson Agents; Female; Humans; Levodopa; Magnetoencephalography; Male; Middle Aged; Motor Cortex; Parkinson Disease
PubMed: 32361482
DOI: 10.1016/j.nicl.2020.102255 -
British Journal of Pharmacology Apr 19941. In this study the renal selectivity of dopamine and its prodrugs L-dopa and gludopa, with respect to their effects on regional blood flow, vascular resistance and...
1. In this study the renal selectivity of dopamine and its prodrugs L-dopa and gludopa, with respect to their effects on regional blood flow, vascular resistance and central haemodynamics was investigated in normal rats and in rats with glycerol-induced acute renal failure (ARF). 2. In normal, anaesthetized rats, dopamine as well as its prodrugs caused a dose-dependent reduction of vascular resistance in the kidney (RR), mesentery (MR) and hindquarters (HQR) (dose range: dopamine: 0.1-5 mumol kg-1 h-1; L-dopa and gludopa: 1-200 mumol kg-1 h-1). Blood pressure and heart rate were affected at the highest dose only. 3. Administration of glycerol induced a preferential renal vasoconstriction; renal blood flow (-60%) and vascular resistance (+190%) were significantly more affected than MR (+40%) and HQR (+60%). This was only ameliorated by a low rate (10 mumol kg-1 h-1) infusion of gludopa: the glycerol-induced reduction of renal flow and increase in RR were significantly attenuated. A high dose of gludopa (100 mumol kg-1 h-1) or any dose of L-dopa or dopamine did not induce this beneficial effect. The glycerol-induced increase in MR and HQR was not attenuated by any of the treatments used. 4. The results indicate that gludopa is not renally selective at a pharmacodynamic level in normal, anaesthetized rats. Contrary to this, a low dose of gludopa does cause a renal selective vasodilatation and reduction of RR in rats with glycerol-induced ARF. This difference could be explained by a difference in renal vascular tone between normal rats and glycerol-induced ARF rats. A high dose ofgludopa does not cause these renal-selective effects: renal resistance and renal flow are at the same level as following glycerol and saline. This is probably due to the systemic effects of the released dopamine.
Topics: Acute Kidney Injury; Animals; Dihydroxyphenylalanine; Dopamine; Glycerol; Hemodynamics; Kidney; Levodopa; Male; Rats; Rats, Wistar; Renal Circulation
PubMed: 8032598
DOI: 10.1111/j.1476-5381.1994.tb14860.x -
Acta Neurologica Scandinavica Nov 2017Several different strategies are effective for medical treatment of motor problems in Parkinson's disease (PD). Many guidelines and evidence-based reviews are available,... (Review)
Review
Several different strategies are effective for medical treatment of motor problems in Parkinson's disease (PD). Many guidelines and evidence-based reviews are available, but there is no documentation or consensus in favor of just one treatment strategy. This review presents two algorithms that may be helpful when deciding how to treat a PD patient at various stages of the disease. The first algorithm suggests one way to treat PD from the first onset of motor symptoms. It is largely based on treatment recommendations from the Scandinavian countries and Germany. The other algorithm is meant as assistance for choosing among the different device-aided treatments for advanced PD. There is not sufficient comparative data to recommend one particular line of treatment, neither in early PD nor in advanced disease with motor complications. Individualized treatment is needed for each patient. The current algorithms only represent an alternative for aiding treatment decisions.
Topics: Algorithms; Antiparkinson Agents; Carbidopa; Consensus; Deep Brain Stimulation; Humans; Levodopa; Parkinson Disease
PubMed: 28133726
DOI: 10.1111/ane.12733