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Clinical Neuropharmacology 1986
Review
Topics: Aged; Dose-Response Relationship, Drug; Drug Administration Schedule; Female; Humans; Levodopa; Male; Middle Aged; Parkinson Disease
PubMed: 3548951
DOI: 10.1097/00002826-198602000-00001 -
Journal of Neurochemistry Feb 1995The mechanism of cytotoxicity of L-DOPA was studied in the rat pheochromocytoma PC12 cell line. The cytotoxicity of L-DOPA to PC12 cells was time and concentration...
The mechanism of cytotoxicity of L-DOPA was studied in the rat pheochromocytoma PC12 cell line. The cytotoxicity of L-DOPA to PC12 cells was time and concentration dependent. Carbidopa, which inhibited the conversion of L-DOPA to dopamine, did not protect against L-DOPA cytotoxicity in PC12 cells. Furthermore, clorgyline, a selective inhibitor of monoamine oxidase type A, and pargyline, an inhibitor of both monoamine oxidase types A and B, both did not have an effect on L-DOPA toxicity. These findings suggest that cytotoxicity was not due to dopamine formed from L-DOPA. Catalase or superoxide dismutase each partially protected against L-DOPA toxicity in PC12 cells. In combination, the effects were synergistic and provided almost total protection against cytotoxicity. 6-Cyano-7-nitroquinoxaline-2,3-dione, an antagonist of non-NMDA receptors, did not protect against L-DOPA toxicity. These data suggest that toxicity of L-DOPA is most likely due to the action of free radicals formed as a result of its autoxidation. Furthermore, these findings suggest that patients on long-term L-DOPA therapy are potentially at risk from the toxic intermediates formed as a result of its autoxidation.
Topics: Animals; Catalase; Cell Survival; Dopamine; Levodopa; Oxidation-Reduction; PC12 Cells; Rats; Receptors, Amino Acid; Superoxide Dismutase
PubMed: 7830076
DOI: 10.1046/j.1471-4159.1995.64020825.x -
Journal of Neurochemistry Oct 1997In the presence of thiols, tyrosine hydroxylase (TH) oxidizes L-dihydroxyphenylalanine (L-DOPA) with a specific activity of up to 140 nmol min(-1) mg(-1) at 37 degrees C... (Comparative Study)
Comparative Study
In the presence of thiols, tyrosine hydroxylase (TH) oxidizes L-dihydroxyphenylalanine (L-DOPA) with a specific activity of up to 140 nmol min(-1) mg(-1) at 37 degrees C and pH 7.0, which is approximately 12-50% of its TH activity under similar experimental conditions. Using assay conditions that are optimal for measuring TH activity, the specific DOPA oxidase activity of human TH is similar to that of mushroom tyrosinase, but the two enzymes are clearly different in terms of substrate specificities, cofactor dependencies, and selectivity with respect to the effects of metal chelators and other inhibitors. In the presence of an excess of dithiothreitol, 2-mercaptoethanol, cysteine, or reduced glutathione, the reaction products of the two enzymes are identical and have been identified tentatively as thioether derivatives of DOPA. Theoretically, the oxidation of L-DOPA by TH may contribute to the formation of neuromelanin (pheomelanin) in catecholaminergic neurons and in the metabolism of DOPA to reactive intermediates that can react with free thiol groups in cellular proteins. The DOPA oxidase activity of TH can lead to errors in the estimation of in vivo or in vitro TH activity, and currently used assay protocols may have to be modified to avoid interference from this activity.
Topics: Antioxidants; Basidiomycota; Biopterins; Dihydroxyphenylalanine; Humans; Kinetics; Levodopa; Monophenol Monooxygenase; Recombinant Proteins; Substrate Specificity; Tyrosine 3-Monooxygenase
PubMed: 9326301
DOI: 10.1046/j.1471-4159.1997.69041720.x -
Soins; La Revue de Reference Infirmiere Apr 1985
Topics: Humans; Levodopa; Parkinson Disease
PubMed: 3848106
DOI: No ID Found -
International Journal of Biological... Apr 2018The current study comprises of an inclusive biophysical study, enlightening the binding of L-3, 4-dihydroxyphenylalanine (l-Dopa) with human lysozyme (HL) and hen egg...
The current study comprises of an inclusive biophysical study, enlightening the binding of L-3, 4-dihydroxyphenylalanine (l-Dopa) with human lysozyme (HL) and hen egg white lysozyme (HEWL). Spectroscopic and molecular docking tools have been utilized to study the interaction of l-Dopa with both HL and HEWL. Spectrofluorimetric measurements exhibited that l-Dopa quenched the HL and HEWL intrinsic fluorescence. A binding constant (K) of ∼10M for both HL and HEWL was obtained, asserting a significant binding. Negative value of ΔG affirmed that the reaction between proteins and l-Dopa was spontaneous. Far-UV CD spectra revealed a boost to the proteins helical content in the presence of l-Dopa. Furthermore, DLS measurements displayed the decrease in hydrodynamic radii (R) of HL and HEWL in the presence of l-Dopa. Molecular docking studies established that l-Dopa formed complexes with both the proteins through hydrogen bonding and hydrophobic interaction. The present study characterizing the l-Dopa interaction with lysozyme could be noteworthy in realizing both pharmaco-dynamics and/or -kinetics of drugs used in various diseases.
Topics: Animals; Biophysical Phenomena; Circular Dichroism; Dynamic Light Scattering; Humans; Levodopa; Molecular Conformation; Molecular Docking Simulation; Molecular Dynamics Simulation; Muramidase; Protein Binding; Spectroscopy, Fourier Transform Infrared; Spectrum Analysis
PubMed: 29157902
DOI: 10.1016/j.ijbiomac.2017.11.107 -
Amino Acids 2002The article traces the development of research on the naturally occurring amino acid L-3,4-dihydroxyphenylalanine (L-dopa), from the first synthesis of its D,L racemate...
The article traces the development of research on the naturally occurring amino acid L-3,4-dihydroxyphenylalanine (L-dopa), from the first synthesis of its D,L racemate in 1911, and the isolation of its L-isomer from seedling of Vicia faba beans to the amino acid's successful application, from 1961 onward, as the most efficacious drug treatment of Parkinson's disease (PD). Upon its isolation from legumes in 1913, L-dopa was declared to be biologically inactive. However, two early pharmacological studies, published in 1927 and 1930 respectively, proved (in the rabbit) that D,L-dopa exerted significant effects on glucose metabolism (causing marked hyperglycemia) and on arterial blood pressure. Interest in L-dopa's biological activity increased considerably following the discovery, in 1938, of the enzyme L-dopa decarboxylase and the demonstration that in the animal and human body L-dopa was enzymatically converted to dopamine (DA), the first biologically active amine in the biosynthetic chain of tissue catecholamines. This prompted, in the 1940s, many studies, both in animals and in humans, especially concerned with the vasopressor potential of L-dopa/DA. In the 1950s, the focus of L-dopa research shifted to its potential for replenishing the experimentally depleted (by insulin or reserpine) peripheral and brain catecholamine stores and the concomitant restoration of normal function. During that period, of special interest were the observations that L-dopa reversed the reserpine-induced state of "tranquilisation" and that its decarboxylation product DA occurred in high amounts in animal and human brain, with a preferential localization in the basal ganglia. These observations set the stage for the beginning of DA studies in PD brain. In 1960, the severe brain DA deficit, confined to patients with PD was discovered, and a year later L-dopa's strong therapeutic effect in patients with PD was demonstrated. In 1967, the chronic high-dose oral L-dopa regimen was successfully introduced into clinical practice. Despite some initial doubts about L-dopa's mechanism of action in PD, it is now generally recognized that L-dopa use in PD is a classic example of a brain neurotransmitter replacement therapy. However, the DA replacement potential of L-dopa may not be its sole action of interest, as suggested by recent evidence that L-dopa may also have its own biological activity in the CNS, independent of DA.
Topics: Animals; Antiparkinson Agents; Brain; Catecholamines; Dopamine; History, 20th Century; History, 21st Century; Humans; Levodopa; Molecular Structure; Parkinson Disease
PubMed: 12373520
DOI: 10.1007/s00726-001-0111-9 -
Parkinsonism & Related Disorders Dec 2009Chronic L-3,4-dihydroxyphenylalanine (L-dopa) treatment of Parkinson Disease (PD) often leads to debilitating involuntary movements, termed L-dopa-induced dyskinesia... (Review)
Review
Chronic L-3,4-dihydroxyphenylalanine (L-dopa) treatment of Parkinson Disease (PD) often leads to debilitating involuntary movements, termed L-dopa-induced dyskinesia (LID). The past few years have seen an unprecedented increase in understanding the neural mechanisms underlying LID manifestation in PD associating them mostly with D1 dopamine (DA) receptor sensitisation and deregulated homologous desensitisation as well as hyperactivity of both canonical and non-canonical DA signalling pathways. We here review these recent findings and demonstrate that decreasing DA receptor-mediated signalling (i) by increasing D1 receptor internalization and (ii) by inhibiting the Ras-Extracellular signal-Regulated Kinase 1/2 non-canonical DA signalling cascade, might reduced LID severity. Strategy (i) uses the lentivirus-mediated over-expression of the G protein-coupled receptor kinase 6 that control the desensitisation of DA receptors. Strategy (ii) proposes to use statins that, besides being specific inhibitors of the rate-limiting enzyme in cholesterol biosynthesis, can also inhibit Ras isoprenylation and activity and subsequently the phosphorylation of ERK1/2. Experiments were performed in both the rodent and primate models of LID. Those results strongly suggest that different strategies might represent a treatment option for managing LID in PD.
Topics: Animals; Dopamine Agents; Dyskinesia, Drug-Induced; Humans; Levodopa; Models, Biological; Protein Transport; Receptors, Dopamine D1; Signal Transduction
PubMed: 20083011
DOI: 10.1016/S1353-8020(09)70783-7 -
Materials Science & Engineering. C,... Mar 2017This paper describes the production and characterization of nanostructured lipid carriers (NLC) containing four different levodopa (LD) co-drugs (PD), named PDA... (Comparative Study)
Comparative Study
This paper describes the production and characterization of nanostructured lipid carriers (NLC) containing four different levodopa (LD) co-drugs (PD), named PDA (3,4-diacetyloxy-LD-caffeic acid co-drug), PDB (lipoic acid-dopamine co-drug), PDC (lipoic acid-3,4-diacetoxy-dopamine co-drug), and PDD (dimeric LD co-drug containing an alkyl linker), with therapeutic potential in Parkinson's disease. These co-drugs were produced with the aim of prolonging the pharmacological activity of LD, enhancing its absorption and protecting it from metabolism. These compounds were characterized by very low water solubility that limits their systemic administration. To improve the solubility of these LDPD, NLC were considered. The obtained NLC showed acceptable particle size and a good stability up to two months from preparation. Cryo-TEM morphological characterization revealed no substantial differences between unloaded and co-drug loaded NLC. In vitro studies showed that the LDPD loaded NLC provided a controlled drug release. Moreover, the enhancement of LDPD stability on the hydrolysis catalysed by foetal calf serum (FCS) esterases or in the presence of lipases was evaluated as compared to a labrasol solution. In presence of esterases PDA-NLC and PDD-NLC showed half-lives higher >3-fold as compared to the corresponding aqueous micellar solution. In the case of PDB-NLC it was found that the stability exceeds the 19h. It can be concluded that NLC represent good strategies to encapsulate lipophilic LD co-drugs, although further studies aimed to deeply evaluate anti-parkinsonian effects in vivo have to be carried on.
Topics: Caffeic Acids; Drug Carriers; Drug Liberation; Half-Life; Humans; Kinetics; Levodopa; Lipids; Microscopy, Electron, Transmission; Nanostructures; Parkinson Disease; Thioctic Acid
PubMed: 28024573
DOI: 10.1016/j.msec.2016.11.060 -
Clinical and Experimental Pharmacology... Nov 20061. Many studies have shown that administration of d-3, 4-dihydroxyphenylalanine (D-dopa) produces contralateral rotation in hemi-parkinsonian animals comparable to...
1. Many studies have shown that administration of d-3, 4-dihydroxyphenylalanine (D-dopa) produces contralateral rotation in hemi-parkinsonian animals comparable to L-dopa, with less potency and slower onset. It was postulated that D-dopa was converted to L-dopa to produce these effects. 2. To investigate the postulated chiral inversion of D-dopa to L-dopa and the related mechanism, an enantiomeric separation method for D- and L-dopa using HPLC was first established. Then, rat kidney homogenates containing D-dopa or L-dopa were incubated and subjected to HPLC to detect traces of respective enantiomer generation. The mechanism of the chiral inversion of d-dopa was explored by direct measurement of the production of L-dopa in kidney homogenates. D-dopa incubations containing different concentrations of an inhibitor of D-amino acid oxidase (DAAO) and an inhibitor of dopa transaminase were measured for L-dopa generation using HPLC. The role of DAAO in the chiral inversion of D-dopa to L-dopa was further investigated by using purified DAAO and mutant ddY/DAAO- mouse kidney lacking DAAO activity. 3. In rat kidney homogenate, D-dopa was, indeed, converted to L-dopa, whereas L-dopa was not converted to D-dopa. Sodium benzoate, a selective inhibitor of DAAO, blocked L-dopa generation in a concentration-dependant manner. In contrast with kidney homogenates of wild-type ddY/DAAO+ mice, those of mutant ddY/DAAO- mice lacking DAAO activity did not convert D-dopa to L-dopa unless exogenous DAAO protein was added. Conversely, when carbidopa, an inhibitor of dopa transaminase, was added to the homogenates, significant inhibition of L-dopa production was noted. 4. These results prove the proposal that d-dopa undergoes unidirectional chiral inversion and further suggest that D-dopa is first oxidatively deaminated by DAAO to its alpha-keto acid and then transaminated by dopa transaminase to L-dopa.
Topics: Animals; Carbidopa; D-Amino-Acid Oxidase; Dihydroxyphenylalanine; Enzyme Inhibitors; Kidney; Levodopa; Mice; Rats; Rats, Sprague-Dawley; Sodium Benzoate
PubMed: 17042912
DOI: 10.1111/j.1440-1681.2006.04484.x -
Scientific Reports Oct 2023L-DOPA is deficient in the developing albino eye, resulting in abnormalities of retinal development and visual impairment. Ongoing retinal development after birth has...
L-DOPA is deficient in the developing albino eye, resulting in abnormalities of retinal development and visual impairment. Ongoing retinal development after birth has also been demonstrated in the developing albino eye offering a potential therapeutic window in humans. To study whether human equivalent doses of L-DOPA/Carbidopa administered during the crucial postnatal period of neuroplasticity can rescue visual function, OCA C57BL/6 J-c2J OCA1 mice were treated with a 28-day course of oral L-DOPA/Carbidopa at 3 different doses from 15 to 43 days postnatal age (PNA) and for 3 different lengths of treatment, to identify optimum dosage and treatment length. Visual electrophysiology, acuity, and retinal morphology were measured at 4, 5, 6, 12 and 16 weeks PNA and compared to untreated C57BL/6 J (WT) and OCA1 mice. Quantification of PEDF, βIII-tubulin and syntaxin-3 expression was also performed. Our data showed impaired retinal morphology, decreased retinal function and lower visual acuity in untreated OCA1 mice compared to WT mice. These changes were diminished or eliminated when treated with higher doses of L-DOPA/Carbidopa. Our results demonstrate that oral L-DOPA/Carbidopa supplementation at human equivalent doses during the postnatal critical period of retinal neuroplasticity can rescue visual retinal morphology and retinal function, via PEDF upregulation and modulation of retinal synaptogenesis, providing a further step towards developing an effective treatment for albinism patients.
Topics: Humans; Mice; Animals; Levodopa; Carbidopa; Disease Models, Animal; Mice, Inbred C57BL; Albinism
PubMed: 37821525
DOI: 10.1038/s41598-023-44373-3