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1
Eldrup, Ebbe, and Erik A. Richter. "DOPA, dopamine, and DOPAC concentrations in the rat gastrointestinal tract decrease during fasting." American Journal of Physiology-Endocrinology and Metabolism 279, no. 4 (October 1, 2000): E815—E822. http://dx.doi.org/10.1152/ajpendo.2000.279.4.e815.
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The aim of the present study was to test the hypothesis that 3,4-dihydroxyphenylalanine (DOPA) and dopamine (DA) in the gastrointestinal tract are to a large extent of exogenous origin and derived from food. Tissue concentrations of norepinephrine (NE), epinephrine (Epi), DA, DOPA, and 3,4-dihydroxyphenylacetic acid (DOPAC), as measured by reverse-phase HPLC with electrochemical detection, were studied in fed and 4-day-fasted Wistar rats as well as in sympathectomized and adrenodemedullated rats. Sympathectomy and adrenal demedullectomy decreased tissue concentrations of NE and Epi, respectively, but had no effect on the level of tissue DOPA. Large amounts of DOPA and DA were present in the gastrointestinal tract. Fasting decreased DOPA and DA in the stomach and DOPA concentrations in the quadriceps muscle but no concentrations in other organs. DOPAC in the heart decreased both in response to sympathectomy and to fasting, whereas DOPAC decreased in plasma after fasting and in skeletal muscle after sympathectomy. We conclude that the food content of DOPA and DA is of major importance for the metabolism of DA and, thus, for the dopamine-sulfate content in the gastrointestinal tract and in plasma. The decrease in muscle DOPA after fasting may be explained by less insulin being available during fasting for stimulation of DOPA uptake in the muscle depot. DOPAC in the organism seems to be of a dual origin, derived partly from DA in the food and partly from DA synthesized in sympathetic nerves.
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Eldrup, Ebbe, Svend Erik Møller, JAN Andreasen, and Niels Juel Christensen. "Effects of Ordinary Meals on Plasma Concentrations of 3,4-Dihydroxyphenylalanine, Dopamine Sulphate and 3,4-Dihydroxyphenylacetic Acid." Clinical Science 92, no. 4 (April 1, 1997): 423–30. http://dx.doi.org/10.1042/cs0920423.
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1. Plasma concentrations of 3,4-dihydroxyphenylalanine (DOPA), dopamine sulphate (DA-S), and 3,4-dihydroxyphenylacetic acid (DOPAC) in humans have been claimed to be indexes of sympathetic nervous activity, but the source and significance of plasma DOPA, DOPAC and DA-S have not been completely elucidated. 2. The effects of ordinary meals on plasma concentrations of total dopamine, mainly DA-S, DOPAC and DOPA were studied in seven healthy subjects. Venous blood was collected every hour for 25 h, while subjects were either fasting or received three meals at 9.00 hours, 13.00 hours and 18.00 hours. Catecholamines and metabolites were determined by reverse-phase HPLC with electrochemical detection. Neutral amino acids were measured by ionexchange chromatography with photometric detection. 3. The food contained relatively little DOPA as compared with phenylalanine, tyrosine, isoleucine and tryptophan. The content of DA and DA-S varied considerably, with the greatest amount in the evening meal of open sandwiches. 4. Plasma DOPA decreased significantly after the meals at 13.00 hours and 18.00 hours, whereas concentrations of the other amino acids increased as expected. 5. Plasma DA-S increased significantly after meals and especially after the evening meal. Increments in DA-S above basal values after a meal were closely related to the content of DOPA+DA+DA-S in the meal. Plasma DOPAC increased significantly after the evening meal. 6. The decrease in plasma DOPA observed after a meal was probably due to uptake of DOPA by muscle tissue. Changes in plasma DA-S and DOPAC during this 25-h study reflected to a large extent the content of DOPA, DA and DA-S in the meals.
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Okada, Maki, Ryuji Nakao, Rie Hosoi, Ming-Rong Zhang, Toshimitsu Fukumura, Kazutoshi Suzuki, and Osamu Inoue. "Microdialysis with Radiometric Monitoring of L-[β-11C]DOPA to Assess Dopaminergic Metabolism: Effect of Inhibitors of L-Amino Acid Decarboxylase, Monoamine Oxidase, and Catechol-O-Methyltransferase on Rat Striatal Dialysate." Journal of Cerebral Blood Flow & Metabolism 31, no. 1 (April 21, 2010): 124–31. http://dx.doi.org/10.1038/jcbfm.2010.58.
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The catecholamine, dopamine (DA), is synthesized from 3,4-dihydroxy-L-phenylalanine (L-DOPA) by aromatic L-amino acid decarboxylase (AADC). Dopamine metabolism is regulated by monoamine oxidase (MAO) and catechol- O-methyltransferase (COMT). To measure dopaminergic metabolism, we used microdialysis with radiometric detection to monitor L-[β-11C]DOPA metabolites in the extracellular space of the rat striatum. We also evaluated the effects of AADC, MAO, and COMT inhibitors on metabolite profiles. The major early species measured after administration of L-[β-11C]DOPA were [11C]3,4-dihydroxyphenylacetic acid ([11C]DOPAC) and [11C]homovanillic acid ([11C]HVA) in a 1:1 ratio, which shifted toward [11C]HVA with time. An AADC inhibitor increased the uptake of L-[β-11C]DOPA and L-3- O-methyl-[11C]DOPA and delayed the accumulation of [11C]DOPAC and [11C]HVA. The MAO and COMT inhibitors increased the production of [11C]3-methoxytyramine and [11C]DOPAC, respectively. These results reflect the L-DOPA metabolic pathway, suggesting that this method may be useful for assessing dopaminergic metabolism.
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Soares-da-Silva, P., M. Pestana, and M. H. Fernandes. "Involvement of tubular sodium in the formation of dopamine in the human renal cortex." Journal of the American Society of Nephrology 3, no. 9 (March 1993): 1591–99. http://dx.doi.org/10.1681/asn.v391591.
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This study has examined the influence of sodium (0, 20, 40, 80, 120, and 160 mM) and ouabain (100, 500, and 1,000 microM), an inhibitor of the enzyme Na(+)-K+ ATPase, on the synthesis of dopamine in slices of human renal cortex loaded with exogenous L-dihydroxyphenylalanine (L-DOPA). The deamination of newly formed dopamine into 3,4-dihydroxyphenylacetic acid (DOPAC) was also examined. The formation of dopamine and its deamination to DOPAC in slices and homogenates of human renal cortex closely depended on the concentration of L-DOPA added to the medium; in homogenates of renal cortex, the production of dopamine was found to be 74% of that occurring in the renal medulla. Decarboxylation of L-DOPA was found saturable at 1,000 microM L-DOPA, which had Vmax and Km values for L-amino acid decarboxylase activity of, respectively, 5.8 +/- 0.6 nmol/mg of protein per hour and 62 +/- 8 microM. The accumulation of newly formed dopamine and DOPAC in kidney slices loaded with L-DOPA (50 and 100 microM) was found to be partially dependent on the concentration of sodium in the medium; at 0 mM sodium, the synthesis of dopamine from L-DOPA was found to be half of that occurring at 160 mM sodium. A similar picture could be observed for DOPAC. The fractional rate of accumulation (k; mM sodium-1) at 50 and 100 microM L-DOPA was, respectively, 0.0016 +/- 0.0002 and 0.0016 +/- 0.0005 for dopamine and 0.0018 +/- 0.0002 and 0.0021 +/- 0.0005 for DOPAC.(ABSTRACT TRUNCATED AT 250 WORDS)
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Buu, N. T., and C. Lussier. "Origin of dopamine in the rat adrenal cortex." American Journal of Physiology-Renal Physiology 258, no. 2 (February 1, 1990): F287—F291. http://dx.doi.org/10.1152/ajprenal.1990.258.2.f287.
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The hypothesis that dopamine (DA) is involved in the control of aldosterone secretion is given some support by the finding of DA in the adrenal cortex of several species, but the source of this DA is not known. This study showed that the administration of L-dopa to intact rats or medullectomized rats caused a significant DA increase in the adrenal cortex. The DA increase in the cortex was more pronounced than in the medulla, coincident with higher L-dopa uptake by the cortical tissue. Tyrosine administration raised DA levels only in the medulla. Sympathectomy of the rat by 6-hydroxydopamine treatment did not affect DA basal levels in the cortex or the DA increase in this tissue after L-dopa injection. 3,4-Dihydroxyphenylacetic acid (DOPAC) is detectable in the adrenal cortex but not in the adrenal medulla, and DOPAC levels increased significantly after L-dopa, which indicates monoamine oxidase (MAO) activity within the adrenal cortex. Because 6-hydroxydopamine pretreatment did not alter DOPAC levels, cortical MAO may be located outside catecholaminergic neurons. The results established circulating L-dopa as a precursor for DA in the adrenal cortex of the rat. They also showed that tyrosine hydroxylase activity is absent from the adrenal cortex of this species.
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Armando, I., S. Nowicki, J. Aguirre, and M. Barontini. "A decreased tubular uptake of dopa results in defective renal dopamine production in aged rats." American Journal of Physiology-Renal Physiology 268, no. 6 (June 1, 1995): F1087—F1092. http://dx.doi.org/10.1152/ajprenal.1995.268.6.f1087.
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A major proportion of urinary dopamine derives from the renal decarboxylation of circulating dopa. This study evaluates the effects of aging on renal production of dopamine using 3- and 12-mo-old male Wistar rats. Urinary excretion of Na+, norepinephrine (NE), 3,4-dihydroxyphenylglycol, and dopa were similar in the two groups. Urinary dopamine and 3,4-dihydroxyphenylacetic acid (DOPAC) were lower in older animals (dopamine, 20 +/- 6 vs. 47 +/- 7 nmol/24 h, P < 0.001; DOPAC, 142 +/- 36 vs. 304 +/- 56 nmol/24 h, P < 0.03). Urinary 3-O-methyldopa (OM-dopa) was higher in 12-mo-old rats (6.2 +/- 2.0 vs. 3.3 +/- 0.20 nmol/24 h, P < 0.03). Levels of dopa and NE in renal cortex from 12-mo-old rats were higher (P < 0.001) than in younger animals. Dopamine content in renal cortex from 3-mo-old rats was 295 +/- 64 pmol/g, whereas it was undetectable in 12-mo-old animals. Aromatic-L-amino-acid decarboxylase and monoamine oxidase activities were higher (P < 0.001) in renal cortex from 12-mo-old animals. Catechol-O-methyltransferase activity was similar in both groups. The uptake of dopa by the luminal membrane was explored using brush-border membrane vesicles. The Na(+)-gradient-driven (100 mM) uptake of dopa into vesicles from 3-mo-old animals showed at 10 s an overshoot threefold greater than the equilibrium uptake. The overshoot was blunted in 12-mo-old rats.(ABSTRACT TRUNCATED AT 250 WORDS)
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Lavoie, Mark P., Meg Palmatier, Frank T. Gentile, Faith A. Kaplan, Deborah M. Fiore, Tyrone F. Hazlett, William J. Bell, and Thomas R. Flanagan. "Two PC 12 Pheochromocytoma Lines Sealed in Hollow Fiber-Based Capsules Tonically Release L-Dopa In Vitro." Cell Transplantation 2, no. 2 (March 1993): 163–73. http://dx.doi.org/10.1177/096368979300200209.
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Two PC12 cell-derived lines have been studied following encapsulation into polymer-based hollow fibers with respect to secreted catecholamines and their metabolites. Cellular encapsulation provides a chronic microperfusion environment within which basally secreted PC12 products can be readily measured. Encapsulated PC12 cells grown and held under the conditions specified in this report basally release amounts exceeding their total cellular stores of the dopamine precursor L-DOPA and the electrochemically active dopamine metabolites DOPAC and HVA during 45-min static incubations. Under these same conditions, these cells release less than 0.1% of their total cellular store of dopamine. Depolarizing incubations enhance dopamine secretion eightyfold and enhance secretion of L-DOPA, HVA, and DOPAC about twofold. The relative composition of products basally secreted differs between PC12-derived cell lines, and an inverse relationship exists between basal release of L-DOPA and total cellular store of dopamine. These results further indicate that selected PC12 cell lines are potentially a source of both dopamine and L-DOPA in therapeutic cellular replacement applications.
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Dutton, J., L. G. Copeland, J. R. Playfer, and N. B. Roberts. "Measuring L-dopa in plasma and urine to monitor therapy of elderly patients with Parkinson disease treated with L-dopa and a dopa decarboxylase inhibitor." Clinical Chemistry 39, no. 4 (April 1, 1993): 629–34. http://dx.doi.org/10.1093/clinchem/39.4.629.
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Abstract We have established a method for measuring L-dopa in plasma and urine, including the metabolites dopamine and L-dopac, using separation by ion-pair reversed-phase HPLC and quantification with an electrochemical detector. The assay was applied to the therapeutic monitoring of elderly patients with established Parkinson disease being treated with L-dopa plus a dopa decarboxylase inhibitor. Plasma L-dopa was evaluated in relation to dosage and postdose sampling time in 71 outpatients with Parkinson disease. L-Dopa concentrations were greatest in the patients taking the highest dosages prescribed and decreased significantly with increasing time after postdose sampling. Comparison of plasma L-dopa concentrations with a published therapeutic range established by intravenous administration of L-dopa was helpful in assessing the suitability of each patient's drug dosage, assessing patients' compliance, and avoiding overdosage but was not useful in the overall clinical assessment of progression of disease or of the long-term therapeutic response. Urine measurements confirmed the plasma concentrations but showed no further advantage. The recommended time for sample collection is between 1.5 and 3 h after the first morning dose. Plasma is the preferred matrix but if blood sampling is difficult, particularly from elderly/infirm individuals, an untimed urine collection could be used.
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Abbas, Ghulam, Alfredo E. Cardenas, and Ron Elber. "The Structures of Heterogeneous Membranes and Their Interactions with an Anticancer Peptide: A Molecular Dynamics Study." Life 12, no. 10 (September 22, 2022): 1473. http://dx.doi.org/10.3390/life12101473.
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We conduct molecular dynamics simulations of model heterogeneous membranes and their interactions with a 24-amino acid peptide—NAF-144–67. NAF-144–67 is an anticancer peptide that selectively permeates and kills malignant cells; it does not permeate normal cells. We examine three membranes with different binary mixtures of lipids, DOPC–DOPA, DOPC–DOPS, and DOPC–DOPE, with a single peptide embedded in each as models for the diversity of biological membranes. We illustrate that the peptide organization in the membrane depends on the types of nearby phospholipids and is influenced by the charge and size of the head groups. The present study sheds light on early events of permeation and the mechanisms by which an amphiphilic peptide crosses from an aqueous solution to a hydrophobic membrane. Understanding the translocation mechanism is likely to help the design of new permeants.
10
Eisenhofer, G., D. S. Goldstein, R. Stull, H. R. Keiser, T. Sunderland, D. L. Murphy, and I. J. Kopin. "Simultaneous liquid-chromatographic determination of 3,4-dihydroxyphenylglycol, catecholamines, and 3,4-dihydroxyphenylalanine in plasma, and their responses to inhibition of monoamine oxidase." Clinical Chemistry 32, no. 11 (November 1, 1986): 2030–33. http://dx.doi.org/10.1093/clinchem/32.11.2030.
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Abstract This is a reversed-phase liquid-chromatographic method, with electrochemical detection, for simultaneously measuring, in plasma, the concentrations of the catecholamine precursor dihydroxyphenylalanine (DOPA); the endogenous catecholamines norepinephrine, epinephrine, and dopamine; and the deaminated catecholamine metabolites dihydroxyphenylacetic acid (DOPAC) and dihydroxyphenylglycol (DHPG). We used this method to assess effects of monoamine oxidase (EC 1.4.3.4) inhibition in humans. Plasma DHPG concentrations as determined by the present method (mean 826, SEM 61 ng/L) were similar to those found by other methods. Inhibition of monoamine oxidase (by administering deprenyl or tranylcypromine) decreased plasma DHPG by greater than 65%, plasma DOPAC by greater than 50%, and plasma DOPA by about 20%, without consistently affecting norepinephrine or epinephrine. Simultaneous measurement of DOPA, catecholamines, and DHPG may be useful for examining the synthesis, release, and intraneuronal metabolism of norepinephrine. The assay method is rapid, reliable, and simple, and it provides a more comprehensive assessment of noradrenergic nervous function than does measurement only of catecholamines.
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Ash, Caroline. "The dope on L-dopa metabolism." Science 364, no. 6445 (June 13, 2019): 1043.11–1045. http://dx.doi.org/10.1126/science.364.6445.1043-k.
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Xu, Suxia, Qingyun Huang, Chunsong Lin, Lixian Lin, Qun Zhou, Fucong Lin, and Enming He. "Transcriptome comparison reveals candidate genes responsible for the betalain-/anthocyanidin-production in bougainvilleas." Functional Plant Biology 43, no. 3 (2016): 278. http://dx.doi.org/10.1071/fp15246.
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The occurrence of betalains and anthocyanins is mutually exclusive, which is a curious phenomenon in the plant kingdom, and the biochemical mechanisms for this restriction are unknown. In the present study, we performed transcriptome analysis of two betalain-producing species, red Bougainvillea glabra Choisy. ‘Sanderiana’ (R) and white B. glabra ‘Alba’ (W) by transcriptome sequencing. In total, we obtained 69 692 (Red) and 60 727 (White) genes with an average length of 665 and 728 bp respectively. Out of 3106 significantly differentially-expressed genes (71%), 1003 were R-specific (32%), and 1605 were W-specific (52%). To validate betalain-/anthocyanidin-biosynthesis genes detected (cytochrome P 450 76AD1 (CYP76AD1), dihydroxy-phenylalanine (DOPA)-4,5-dioxygenase (DODA), cyclo DOPA-5-O-glycosyltransferase (cyclo-DOPA-5-GT) dihydroflavonol 4-reductase (DFR), leucoanthocyanidin dioxygenase (LDOX)), real-time PCR was performed in leaves and three development stages of flowers in four Bougainvilleas, red R, white W, orange Bougainvillea × buttiana ‘Salmoea’ (O) and purple B. glabra ‘Formosa’ (P). Contents of betalains were also measured. The results showed that betalains accumulation was consistent with the expression level of DODA in O. A correlation between expression of CYP76AD1 and cyclo-DOPA-5GT and betalains was not discovered. This suggests that production of betacyanins was under the regulation of more complex factors. Both DFR and LDOX responsible for anthocyanidin production were first validated in floral organs and leaves in betalain-producing plants by real-time PCR. These findings suggest a fully functioning anthocyanin pathway, at least, to the stage of LDOX in bougainvilleas.
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Zalyalova, Z. A., D. M. Khasanova, and M. V. Ugrumov. "Plasma catecholamine levels in the early stages of treatment-naïve Parkinson’s disease." Almanac of Clinical Medicine 46, no. 8 (December 31, 2018): 792–801. http://dx.doi.org/10.18786/2072-0505-2018-46-8-792-801.
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Rationale: Parkinson's disease (PD) is a neurodegenerative disorder with predominant involvement of catecholamine-producing neurons of the central and peripheral nervous system. Taking into account the relative availability and low costs of plasma catecholamine measurements, it is worthwhile to study these parameters as biomarkers of the early stages of PD.Aim: To determinate whether plasma levels of dopamine (DA), norepinephrine (NE), L-3,4-dihydroxyphenylalanine (DOPA) and dihydroxyphenylacetic acid (DOPAC) in patients with early stages of PD are related with akinetic-rigid and tremor-dominant variants and to compare the results to healthy volunteers.Materials and methods: This was an observational cross-sectional cohort study performed from 2012 to 2015. The main study group included unselected outpatients who attended the Republican Consultative and Diagnostic Center of Movement Disorders and Botulinotherapy (Kazan, Russia) with newly diagnosed early PD (Hoehn and Yahr stages I and II, 1967), of various ages and both genders, who had not been given any specific antiparkinsonian treatment. The control group included healthy volunteers with no clinical signs of PD (they could have other chronic diseases of the non-extrapyramidal origin). Plasma catecholamine levels were measured by gas liquid chromatography.Results: One hundred and thirty (130) treatment-naïve patients with newly diagnosed PD (mean age 59.34 ± 8.42 years, male gender 45.38%) were enrolled into the main study group. The control group included 56 healthy volunteers matched for age and gender. The distribution of various PD forms and stages was as follows: PD tremor-dominant variant 56.9%, PD akinetic-rigid variant 43.1%; PD stage I 76.9%, PD stage II 23.1%. Irrespective of the variant and stage, the PD patients demonstrated decreased NE levels, compared to the controls (95% confidence intervals 124–216 and 248–428 pg/mL, respectively, р < 0.026). DOPA plasma level was reduced only in the patients with akinetic-rigid PD variant (р = 0.017), while DOPAC level in the patients with PD stage II (р = 0.008). The average DA:NE:DOPA:DOPAC ratio was 1:32:105:64 in the control group, 1:62:238:88 in the patients with PD tremor-dominant variant (the difference is significant for NE and DOPA, р < 0.05), and 1:29:96:32 in those with PD akinetic-rigid variant (p > 0.05). In the healthy controls the changes in DOPA levels account for 84% of the DA and NE variability; no correlation between DOPAC and other catecholamines was found. On the contrary, in the PD patients regardless of the stage and the disease variant, DOPAC levels directly correlated with DA (p < 0.04). The PD tremor-dominant variant patients demonstrated a direct correlation between plasma NE and DOPA levels (p < 0.05).Conclusion: The results obtained on absolute and relative parameters catecholamine turnover in the patients with early PD stages support the hypothesis on different pathophysiology of the tremor-dominant and akinetic-rigid variants of PD.
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Ibarra, F. R., J. Aguirre, S. Nowicki, M. Barontini, E. E. Arrizurieta, and I. Armando. "Demethylation of 3-O-methyldopa in the kidney: a possible source for dopamine in urine." American Journal of Physiology-Renal Physiology 270, no. 5 (May 1, 1996): F862—F868. http://dx.doi.org/10.1152/ajprenal.1996.270.5.f862.
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The possibility that demethylation of 3-O-methyldopa (OM-dopa) in the kidney could provide a source for dopamine in the urine was explored in male Wistar rats aged 60-90 days, using in vivo and in vitro approaches. The results showed that endogenous OM-dopa is filtered, reabsorbed and extensively metabolized in the kidney. Infusion of OM-dopa into anesthetized rats increased significantly urinary excretion of Na+, dopa, dopamine, and 3,4 dihydroxyphenylacetic acid. Whole kidney homogenates, slices from renal cortex, and microdissected proximal tubules produced significant amounts of both dopa and dopamine when incubated with OM-dopa. Renal cortex slices produced dose-dependent amounts of dopa and dopa-mine when incubated with 1-100 microM OM-dopa. Incubation of microdissected proximal tubule segments with 1 microM OM-dopa produced a fourfold (P < 0.025) increment in dopa and a twofold (P < 0.05) increment in dopamine (an effect similar to that observed with 1 microM L-dopa). One micromolar OM-dopa or 1 microM L-dopa decreased (P < 0.05) Na(+)-K(+)-adenosinetriphosphatase activity measured at maximal velocity condition in proximal tubules. In conclusion, these experiments show that in vitro the kidney is able to produce dopamine by demethylation of OM-dopa, while the results of the OM-dopa infusion suggest that this conversion may also occur in vivo.
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Grossman, Ehud, Aaron Hoffman, Ines Armando, Zaid Abassi, Irwin J. Kopin, and David S. Goldstein. "Sympathoadrenal contribution to plasma dopa (3,4-dihydroxyphenylalanine) in rats." Clinical Science 83, no. 1 (July 1, 1992): 65–74. http://dx.doi.org/10.1042/cs0830065.
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1. To determine the sources of dopa (3,4-dihydroxyphenylalanine) in plasma, we measured regional arteriovenous differences, tissue concentrations and urinary excretion of dopa during systemic intravenous infusions of I-[3H]dopa into anaesthetized intact rats and rats pretreated with the sympathetic neurotoxin, 6-hydroxydopamine. 2. In intact rats, large arteriovenous increments in plasma dopa concentrations were noted in the femoral (47%) and adrenal (141%) beds, with a small arterial-portal venous increment (11%), whereas in the kidney there was a substantial (47%) arteriovenous decrement in plasma dopa levels. Skeletal muscle appeared to be a major source of dopa in arterial plasma. 3. Treatment with 6-hydroxydopamine abolished the afferent-efferent increment of plasma dopa concentrations in the femoral bed. The arteriovenous decrement of plasma dopa concentrations in the kidney was preserved, and the arteriovenous increment in the adrenal bed was decreased by about half. Arterial plasma dopa levels fell by 41%. 4. Regional extraction percentages of I-[3H]dopa were used to estimate the clearances and rates of appearance (spillovers) of dopa in plasma. Dopa spillover was detected in the femoral, renal, splanchnic and adrenal beds, with skeletal muscle accounting for about 44% and the kidneys accounting for about 18% of dopa in arterial plasma. Whereas chemical sympathectomy decreased the femoral and renal spillover of dopa by 90% or more, arterial dopa levels and estimated dopa spillover into arterial plasma were decreased by only about 45%. 5. The kidneys accounted for 22% of dopa clearance from arterial plasma. From the renal extraction of I-[3H]dopa and the urinary excretion of [3H]dopamine, it was estimated that 77% of dopa removed in the kidneys was excreted as dopamine in intact animals and 69% was excreted as dopamine in sympathectomized animals. Conversely, about 80% of urinary endogenous dopamine was derived from plasma dopa, regardless of 6-hydroxydopamine treatment. 6. The results indicate that endogenous dopa in arterial plasma is derived substantially but not exclusively from sympathetic nerve endings that are destroyed by 6-hydroxydopamine, especially in skeletal muscle and the kidneys. Regional dopa spillover therefore probably reflects regional catecholamine biosynthesis. In rats, urinary dopamine is derived mainly from renal decarboxylation of circulating dopa.
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Cao, Wenhui, Shaodong Liang, Yindong Yang, Chuanzhen Zhu, Li Sun, and Liming Zhang. "Fisetin Ameliorates Levodopa-Induced Dyskinesia in Experimental Model Parkinson's Disease: Role of Mitochondrial Activities and Monoamines Turnover." Natural Product Communications 17, no. 11 (November 2022): 1934578X2211366. http://dx.doi.org/10.1177/1934578x221136674.
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Background: Levodopa (or l-DOPA) is the current standard of care for the management of Parkinson's disease (PD), but its chronic administration has been associated with the development of LID (l-DOPA-induced dyskinesia). Fisetin is a dietary flavonoid known for its neuroprotective efficacy. Aim: To determine the neuroprotective potential of fisetin in 6-hydroxydopamine (6-OHDA)-lesioned LID animals. Methods: 6-OHDA (12 µg and L-ascorbic acid [10 µL]) was injected in a substantial nigra of Sprague-Dawley rat to develop PD followed by l-DOPA (20 mg/kg and benserazide HCl [5 mg/kg], 42 days) to induce LID. Rats were concomitantly administered with vehicle or amantadine (40 mg/kg), or fisetin (5, 10, and 25 mg/kg, p.o.) for 42 days with l-DOPA. Results: Chronic l-DOPA administration resulted in progressive abnormal involuntary movements (AIMs viz. axial, forelimb, and orolingual), akinesia (forelimb adjusting steps, FAS), muscular rigidity (catalepsy bar test), muscular coordination, and neurological impairments. Fisetin at doses of 10 and 25 mg/kg effectively reduced ( P < .05) these LID-induced AIMs and behavioral changes. Furthermore, fisetin treatment markedly ( P < .05) attenuated LID-induced diminished striatal mitochondrial complex activities, striatal monoamines (serotonin [5-HT] and dopamine [DA]), elevated monoamines turnover (DA: DOPAC and 5-HT: 5-HIAA). In addition, fisetin treatment effectively ( P < .05) reversed the upregulated expressions of striatal cFOS, FosB, Homer, Nurr-77, Parkin, and Pdyn. Conclusion: Our study demonstrated that fisetin offered neuroprotection via amelioration of striatum mitochondrial dysfunction and monoamine (5-HT and DA) turnover to halt further development of abnormal involuntary movement and dyskinesia.
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Kura, Aminu Umar, Samer Hasan Hussein-Al-Ali, Mohd Zobir Hussein, and Sharida Fakurazi. "Preparation of Tween 80-Zn/Al-Levodopa-Layered Double Hydroxides Nanocomposite for Drug Delivery System." Scientific World Journal 2014 (2014): 1–10. http://dx.doi.org/10.1155/2014/104246.
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We incorporated anti-Parkinsonian drug, levodopa (dopa), in Zn/Al-LDH by coprecipitation method to form dopa-LDH nanocomposite. Further coating of Tween-80 on the external surfaces of dopa-LDH nanocomposite was achieved through the oxygen of C=O group of Tween-80 with the layer of dopa-LDH nanocomposite. The final product is called Tween-dopa-LDH nanocomposite. The X-ray diffraction indicates that the Tween-dopa-LDH nanocomposite was formed by aggregation structure. From the TGA data, the Tween-80 loading on the surface of LDH and dopa-LDH was 8.6 and 7.4%, respectively. The effect of coating process on the dopa release from Tween-dopa-LDH nanocomposite was also studied. The release from Tween-dopa-LDH nanocomposite shows slower release compared to the release of the drug from dopa-LDH nanocomposite as done previously in our study, presumably due to the retarding shielding effect. The cell viability study using PC12 showed improved viability with Tween-80 coating on dopa-LDH nanocomposite as studied by mitochondrial dehydrogenase activity (MTT assay).
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Carstam, R., C. Hansson, H. Rorsman, and E. Rosengren. "Oxidation of dopa in the skin of black and albino mice." Acta Dermato-Venereologica 66, no. 5 (September 1, 1986): 369–74. http://dx.doi.org/10.2340/0001555566369374.
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The dopa oxidase activity of tyrosinase in the skin from albino and black mice was assayed using a technique based on the formation of two diastereomers of 5-S-cysteinyldopa when incubating tissue extracts with both L-dopa and D-dopa as substrates in the presence of cysteine. The amounts of 5-S-L-cysteinyl-L-dopa and 5-S-L-cysteinyl-D-dopa formed were then determined. In the extract from black mouse skin the L-L-diastereomer was produced in more than ten times the amount of the L-D-diastereomer. This stereospecific dopa-oxidation is indicative of the presence of tyrosinase and corresponds well with earlier determinations of the rates of oxidation for human tyrosinase, using L-dopa and D-dopa as substrates. Stereospecific dopa oxidation was absent in albino skin, and the nonspecific dopa-oxidation was two orders of magnitude less than the dopa oxidation in black skin. The study demonstrates the lack of tyrosinase activity in albino skin, and quantifies the non-specific dopa oxidation. The lack of tyrosinase activity in the eluates from albinotic skin was found not to be due to the presence of a tyrosinase inhibitor.
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Daiwile, Atul P., Patricia Sullivan, Subramaniam Jayanthi, David S. Goldstein, and Jean Lud Cadet. "Sex-Specific Alterations in Dopamine Metabolism in the Brain after Methamphetamine Self-Administration." International Journal of Molecular Sciences 23, no. 8 (April 14, 2022): 4353. http://dx.doi.org/10.3390/ijms23084353.
Full textAbstract:
Methamphetamine (METH) use disorder affects both sexes, with sex differences occurring in behavioral, structural, and biochemical consequences. The molecular mechanisms underlying these differences are unclear. Herein, we used a rat model to identify potential sex differences in the effects of METH on brain dopaminergic systems. Rats were trained to self-administer METH for 20 days, and a cue-induced drug-seeking test was performed on withdrawal days 3 and 30. Dopamine and its metabolites were measured in the prefrontal cortex (PFC), nucleus accumbens (NAc), dorsal striatum (dSTR), and hippocampus (HIP). Irrespective of conditions, in comparison to females, male rats showed increased 3,4-dihydroxyphenylalanine (DOPA) in the PFC, dSTR, and HIP; increased cys-dopamine in NAc; and increased 3,4-dihydroxyphenylethanol (DOPET) and 3,4-dihydroxyphenylacetic acid (DOPAC) in dSTR. Males also showed METH-associated decreases in DA levels in the HIP but increases in the NAc. Female rats showed METH-associated decreases in DA, DOPAL, and DOPAC levels in the PFC but increases in DOPET and DOPAC levels in the HIP. Both sexes showed METH-associated decreases in NAc DA metabolites. Together, these data document sex differences in METH SA-induced changes in DA metabolism. These observations provide further support for using sex as an essential variable when discussing therapeutic approaches against METH use disorder in humans.
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Taira, Shu, Akari Ikeda, Yuki Sugiura, Hitomi Shikano, Shoko Kobayashi, Tsutomu Terauchi, and Jun Yokoyama. "Pyrylium based derivatization imaging mass spectrometer revealed the localization of L-DOPA." PLOS ONE 17, no. 8 (August 2, 2022): e0271697. http://dx.doi.org/10.1371/journal.pone.0271697.
Full textAbstract:
Simultaneous imaging of l-dihydroxyphenylalanine (l-DOPA), dopamine (DA) and norepinephrine (NE) in the catecholamine metabolic pathway is particularly useful because l-DOPA is a neurophysiologically important metabolic intermediate. In this study, we found that 2,4,6-trimethylpyrillium tetrafluoroborate (TMPy) can selectively and efficiently react with target catecholamine molecules. Specifically, simultaneous visualization of DA and NE as metabolites of l-DOPA with high steric hinderance was achieved by derivatized-imaging mass spectrometry (IMS). Interestingly, l-DOPA showed strong localization in the brainstem, in contrast to the pattern of DA and NE, which co-localized with tyrosine hydroxylase (TH). In addition, to identify whether the detected molecules were endogenous or exogenous l-DOPA, mice were injected with l-DOPA deuterated in three positions (D3-l-DOPA), which was identifiable by a mass shift of 3Da. TMPy-labeled l-DOPA, DA and NE were detected at m/z 302.1, 258.1 and 274.1, while their D3 versions were detected at 305.0, 261.1 and 277.1 in mouse brain, respectively. l-DOPA and D3-l-DOPA were localized in the BS. DA and NE, and D3-DA and D3-NE, all of which are metabolites of L-DOPA and D3-l-DOPA, were localized in the striatum (STR) and locus coeruleus (LC). These findings suggest a mechanism in the brainstem that allows l-DOPA to accumulate without being metabolized to monoamines downstream of the metabolic pathway.
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Dimic, Dusan, Dejan Milenkovic, Zoran Markovic, and Jasmina Dimitric-Markovic. "The reactivity of dopamine precursors and metabolites towards ABTS•-: An experimental and theoretical study." Journal of the Serbian Chemical Society 84, no. 8 (2019): 877–89. http://dx.doi.org/10.2298/jsc190430050d.
Full textAbstract:
The antiradical activity of L-3,4-dihydroxyphenylalanine (L-DOPA), dihydroxyphenylacetic acid (DOPAC), homovanillic acid and tyrosine towards 2,2?-azino-bis(3-ethylbenzothiazoline-6-sulphonic acid) diammonium salt radical (ABTS?-) was investigated experimentally and theoretically by UV?Vis spectroscopy and the DFT theory. The importance of the catechol moiety for this reaction was proven due to the formation of intramolecular hydrogen bond in the formed anions and radicals. The results indicated L-DOPA and DOPAC were more potent radical scavengers than homovanillic acid and tyrosine just because of intramolecular hydrogen bond formation. Based on experimental spectra, it was proved that electron transfer led to the reduction of ABTS?-. The values of thermodynamic parameters were used to predict the preferred mechanism. The reaction rates were calculated for the electron transfer processes and it was shown that these were both kinetically and thermodynamically driven processes. Based on the reaction rate values, thermodynamic parameters, and present species, as determined by electronic spectra, it was concluded that single proton loss electron transfer (SPLET) is the dominant reaction mechanism in the investigated system.
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Falck, B., L. Andersson, A. Mikulowska, and G. Ronquist. "alpha/Amino/n/butyric acid methyl ester induces concentrative uptake of L/dopa in human Langerhans' cells normally not operative for L/dopa transport." Acta Dermato-Venereologica 73, no. 3 (June 1, 1993): 197–99. http://dx.doi.org/10.2340/0001555573197199.
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We recently reported the existence of two kinds of human epidermal Langerhans' cells (LC), one which can take up and accumulate L/dopa and one which cannot. The dopa(+) LC take up L/dopa by carrier/mediated exchange diffusion, that is, the influx of L/dopa and the outflow of an intracellular substance are linked via the same carrier. The nature of the fundamental difference between L/dopa(+) and L/dopa(/) cells has not been clarified. We have now found that alpha/amino/n/butyric acid methyl ester (ABA/OME) penetrates into intracellular compartments, perhaps endosomes or lysosomes, of all LC, where hydrolysis results in the accumulation of the free amino acid (ABA). This accumulation causes a considerable increase in osmotic pressure of the membrane/limited organelle, leading to influx of water and swelling. Co/incubation with L/dopa revealed an influx of L/dopa into LC which normally cannot take up this amino acid. It is suggested that these LC lack the capacity to synthesize and/or store the counterpart which allows L/dopa to enter the dopa(+) LC, but that ABA in the L/dopa(/) LC can function as an equivalent counterpart.
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Alemayehu, Biniyam, Abenet Tafesse, and Yared Zenebe. "Early onset peak-dose L-dopa induced dyskinesia in 55-year-old Ethiopian Parkinson’s disease patient." Ethiopian Pharmaceutical Journal 34, no. 1 (June 19, 2019): 73–74. http://dx.doi.org/10.4314/epj.v34i1.7.
Full textAbstract:
A case study of a 55-year-old newly diagnosed Parkinson’s disease patient naïve to L-dopa, who develop disabling early onset L-dopa induced dyskinesia (LID), which occurs immediately following L-dopa administration is presented. It is recommend to start with low dose L-dopa and to escalate slowly to avoid L-dopa included dyskinesia in dopamine naïve Parkinson’s disease patients.Keywords: Parkinson’s disease, L-dopa, peak-dose induced dyskinesia, 55-year-old male, Ethiopian
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MORIN, Bénédicte, J. Michael DAVIES, and T. Roger DEAN. "The protein oxidation product 3,4-dihydroxyphenylalanine (DOPA) mediates oxidative DNA damage." Biochemical Journal 330, no. 3 (March 15, 1998): 1059–67. http://dx.doi.org/10.1042/bj3301059.
Full textAbstract:
A major product of hydroxy-radical addition to tyrosine is 3,4-dihydroxyphenylalanine (DOPA) which has reducing properties. Protein-bound DOPA (PB-DOPA) has been shown to be a major component of the stable reducing species formed during protein oxidation under several conditions. The aim of the present work was to investigate whether DOPA, and especially PB-DOPA, can mediate oxidative damage to DNA. We chose to generate PB-DOPA using mushroom tyrosinase, which catalyses the hydroxylation of tyrosine residues in protein. This permitted us to study the reactions of PB-DOPA in the virtual absence of other protein-bound oxidation products. The formation of two oxidation products of DNA, 8-oxo-7,8-dihydro-2ʹ-deoxyguanosine (8oxodG) and 5-hydroxy-2ʹ-deoxycytidine (5OHdC), were studied with a novel HPLC using gradient elution and an electrochemical detection method, which allowed the detection of both DNA modifications in a single experiment. We found that exposure of calf thymus DNA to DOPA or PB-DOPA resulted in the formation of 8oxodG and 5OHdC, with the former predominating. The formation of these DNA oxidation products by either DOPA or PB-DOPA depended on the presence of oxygen, and also on the presence and on the concentration of transition metal ions, with copper being more effective than iron. The yields of 8oxodG and 5OHdC increased with DOPA concentration in proteins. Thus PB-DOPA was able to promote further radical-generating events, which then transferred damage to other biomolecules such as DNA.
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van Laar, Teus, and Ad Hovestadt. "Continuous Drug Delivery with Levodopa/Carbidopa Infusion: Review and First Data of a Dutch Cohort." CNS Spectrums 13, S7 (April 2008): 11–14. http://dx.doi.org/10.1017/s1092852900017363.
Full textAbstract:
A duodenal levodopa (L-dopa) and carbidopa infusion has been developed to stabilize plasma levels of L-dopa, in order to reduce existing motor response fluctuations. Stable plasma levels have been shown to reduce these fluctuations significantly. A constant duodenal infusion with an L-dopa solution can improve response fluctuations, however L-dopa has very poor solubility. Only in an acidic environment can L-dopa be dissolved in large volumes. To supply 1 day of infusion with the conventional L-dopa solution, ∼4–5 liters are necessary, an inconvenience to most patients. With L-dopa/carbidopa infusion, L-dopa and carbidopa are concentrated in a water-based gel-like suspension to 20 mg/mL, which has reduced the infusion volumes to <100 mL/day.
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Goldstein, David S., Robin Stull, Graeme Eisenhofer, and John R. Gill. "Urinary excretion of dihydroxyphenylalanine and dopamine during alterations of dietary salt intake in humans." Clinical Science 76, no. 5 (May 1, 1989): 517–22. http://dx.doi.org/10.1042/cs0760517.
Full textAbstract:
1. Urinary excretion of dopamine (DA) increases during dietary salt loading. The majority of urinary DA is derived from circulating dihydroxyphenylalanine (dopa). Whether the increase in urinary DA excretion during salt loading results from increased efficiency of uptake of dopa by proximal tubular cells of the kidney, facilitation of intracellular conversion of dopa to DA, or increased delivery of dopa to tubular uptake sites, has been unknown. 2. In 10 inpatient normal volunteers on a constant diet, daily excretion of dopa and DA was assessed during normal sodium intake (109 mmol/day) for 1 week, low sodium intake (9 mmol/day) for 1 week and high sodium intake (249 mmol/day) for 1 week. 3. Urinary DA excretion exceeded urinary dopa excretion by about tenfold, and the excretion of both DA and dopa increased by about twofold between the low and high salt diets, with similar proportionate changes. Plasma dopa was unchanged by dietary salt manipulation. 4. The results indicate that increases in urinary DA excretion during dietary salt loading can be accounted for by increased delivery of dopa to sites of uptake by proximal tubular cells. Since dopa is released into the bloodstream by sympathetic nerve endings and by the brain, and since interference with decarboxylation of dopa attenuates natriuretic responses, dopa may function indirectly as a neurohormone involved in homoeostatic regulation of sodium balance.
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Dethy, Sophie, Marie Aline Laute, Nadège Van Blercom, Philippe Damhaut, Serge Goldman, and Jerzy Hildebrand. "Microdialysis-HPLC for plasma levodopa and metabolites monitoring in parkinsonian patients." Clinical Chemistry 43, no. 5 (May 1, 1997): 740–44. http://dx.doi.org/10.1093/clinchem/43.5.740.
Full textAbstract:
Abstract We used in vitro microdialysis-HPLC to determine l-3,4-dihydroxyphenylalanine (l-DOPA) and its metabolites in plasma of patients with advanced Parkinson disease. Blood samples and clinical evaluations were obtained 0, 30, 60, 90, 120, and 150 min after oral administration of carbidopa/l-DOPA (25/100 mg, 12.5/125 mg, and 50/200 mg). In vitro recoveries for l-DOPA and metabolites ranged from 22% to 36%. Linear correlation was found between metabolite concentrations in the dialysate and in the surrounding medium. There was a significant positive correlation between l-DOPA dose and plasma concentration of l-DOPA and homovanillic acid (P <0.04). Clinical response was maximum 60 min after l-DOPA administration. Threshold l-DOPA plasma concentration averaged 7.74 ± 3.3 μmol/L. Motor effect is longer with the highest l-DOPA peak concentration (P <0.01). Microdialysis-HPLC is readily applicable, reproducible, and allows monitoring of plasma l-DOPA and metabolites in parkinsonian patients.
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Grossman, Ehud, Aaron Hoffman, Peter C. Chang, Harry R. Keiser, and David S. Goldstein. "Increased spillover of dopa into arterial blood during dietary salt loading." Clinical Science 78, no. 4 (April 1, 1990): 423–29. http://dx.doi.org/10.1042/cs0780423.
Full textAbstract:
1. We measured urinary excretion rates of dopamine (3,4-dihydroxyphenethylamine) and dopa (3,4-dihydroxyphenylalanine) and the spillover rate of dopa into arterial blood during dietary salt loading in conscious Dahl salt-sensitive and salt-resistant rats with intact or denervated kidneys. 2. Dopa spillover was calculated from the steady-state clearance of intravenously infused l-[3H]dopa and arterial levels of endogenous dopa. 3. Daily excretion rates of dopa and dopamine increased by about sixfold during salt loading in both rat strains. Bilateral renal denervation delayed these increases and the natriuretic responses. 4. During dietary salt loading, dopa spillover increased to approximately the same extent as simultaneously measured dopamine excretion. 5. The results suggest that increases in urinary excretion of dopamine during dietary salt loading can be accounted for by increases in the release of dopa into the bloodstream and that the renal nerves contribute to the dopa and dopamine excretory responses.
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Campbell, Roderick R. A., Brian Hasinoff, Gary Chernenko, James Barrowman, and Norman R. C. Campbell. "The effect of ferrous sulfate and pH on L-dopa absorption." Canadian Journal of Physiology and Pharmacology 68, no. 5 (May 1, 1990): 603–7. http://dx.doi.org/10.1139/y90-087.
Full textAbstract:
Ferrous sulfate decreases L-dopa bioavailability in humans probably as a result of binding of L-dopa by iron in the gastrointestinal tract. This study was conducted to determine if iron by binding L-dopa decreases L-dopa absorption and to investigate the effect of different pH buffers on intestinal absorption of L-dopa in the presence and absence of ferrous sulfate. A rat model developed to examine drug absorption was used. Control animals had buffered [14C]L-dopa solutions injected into two in vivo closed segments of intestine; a 5-cm duodenal and a 5-cm proximal jejunal segment. These studies were conducted using solutions buffered at pH 5.5, 6.5, 7.5, and 8.5. An identical procedure was followed for experimental animals except ferrous sulfate was injected with the buffered L-dopa solutions. Ferrous sulfate resulted in a reduction in L-dopa absorption in the buffers at all pHs in both the duodenum and jejunum. The average reduction in L-dopa absorption in the presence of iron was 22.6% in the duodenum and 23.9% in the jejunum. There was a tendency for ferrous sulfate to cause a greater reduction in L-dopa absorption as the buffer pH increased. There was also a decrease in L-dopa absorption in the higher pH buffers in the absence of iron. Despite this latter result, in the jejunum there was an increase in the percent reduction in L-dopa absorption associated with ferrous sulfate as pH increased. Although this tendency was not as consistent in the duodenum as the jejunum, the combined results are compatible with the chemical model of increased L-dopa–iron binding as pH increases.Key words: L-dopa, ferrous sulfate, complex formation, chelation, drug absorption.
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Hu, Shuyang, Qiuyan Shuai, Yulong Lin, Yan Fu, and Meng Li. "Chiral Fe x Cu y Se nanoparticles as peroxidase mimics for colorimetric detection of 3, 4-dihydroxy-phenylalanine enantiomers." Nanotechnology 33, no. 13 (January 5, 2022): 135503. http://dx.doi.org/10.1088/1361-6528/ac4306.
Full textAbstract:
Abstract L-3,4-dihydroxy-phenylalanine (L-dopa) is the most widely used drug in Parkinson’s disease treatment. However, development of cost-effective and high-throughput sensors to accurate enantioselective discrimination of L-dopa and D-dopa remains challenging to date. Herein, on the basis of the peroxidase-mimic activity of chiral Fe x Cu y Se nanoparticles, we demonstrated a novel colorimetric sensor for determination of chiral dopa. The surface chiral ligand, L/D-histidine (L/D-His), endowed the nanozymes with enantioselectivity in catalyzing the oxidation of dopa enantiomers. According to the values of k cat/K m, the efficiency of L-His modified nanoparticles (L-Fe x Cu y Se NPs) towards L-dopa was 1.56 times higher than that of D-dopa. While, D-His can facilely reverse the preference of the nanozyme to D-dopa. On the basis of high catalytic activity and enantioselectivity of L-Fe x Cu y Se NPs in oxidation of L-dopa, the L-Fe x Cu y Se NPs-based system can be utilized for detection of L-dopa. The linear ranges for L-dopa determination were 5 μM–0.125 mM and 0.125 mM–1 mM with a detection limit of 1.02 μM. Critically, the developed sensor has been successfully applied in the quality control of clinical used L-dopa tablets. Our work sheds light on developing simple and sensitive chiral nanomaterials-based sensors for drug analysis.
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Gori, Sadakatali S., Ajit G. Thomas, Arindom Pal, Robyn Wiseman, Dana V. Ferraris, Run-duo Gao, Ying Wu, et al. "D-DOPA Is a Potent, Orally Bioavailable, Allosteric Inhibitor of Glutamate Carboxypeptidase II." Pharmaceutics 14, no. 10 (September 23, 2022): 2018. http://dx.doi.org/10.3390/pharmaceutics14102018.
Full textAbstract:
Glutamate carboxypeptidase-II (GCPII) is a zinc-dependent metalloenzyme implicated in numerous neurological disorders. The pharmacophoric requirements of active-site GCPII inhibitors makes them highly charged, manifesting poor pharmacokinetic (PK) properties. Herein, we describe the discovery and characterization of catechol-based inhibitors including L-DOPA, D-DOPA, and caffeic acid, with sub-micromolar potencies. Of these, D-DOPA emerged as the most promising compound, with good metabolic stability, and excellent PK properties. Orally administered D-DOPA yielded high plasma exposures (AUCplasma = 72.7 nmol·h/mL) and an absolute oral bioavailability of 47.7%. Unfortunately, D-DOPA brain exposures were low with AUCbrain = 2.42 nmol/g and AUCbrain/plasma ratio of 0.03. Given reports of isomeric inversion of D-DOPA to L-DOPA via D-amino acid oxidase (DAAO), we evaluated D-DOPA PK in combination with the DAAO inhibitor sodium benzoate and observed a >200% enhancement in both plasma and brain exposures (AUCplasma = 185 nmol·h/mL; AUCbrain = 5.48 nmol·h/g). Further, we demonstrated GCPII target engagement; orally administered D-DOPA with or without sodium benzoate caused significant inhibition of GCPII activity. Lastly, mode of inhibition studies revealed D-DOPA to be a noncompetitive, allosteric inhibitor of GCPII. To our knowledge, this is the first report of D-DOPA as a distinct scaffold for GCPII inhibition, laying the groundwork for future optimization to obtain clinically viable candidates.
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SUIKO, Masahito, Yoichi SAKAKIBARA, Hiroshi NAKAJIMA, Hiroshi SAKAIDA, and Ming-Cheh LIU. "Enzymic sulphation of dopa and tyrosine isomers by HepG2 human hepatoma cells: stereoselectivity and stimulation by Mn2+." Biochemical Journal 314, no. 1 (February 15, 1996): 151–58. http://dx.doi.org/10.1042/bj3140151.
Full textAbstract:
HepG2 human hepatoma cells, labelled with [35S]sulphate in media containing L-3,4-dihydroxyphenylalanine (L-dopa), (D-dopa), DL-m-tyrosine or D-p-tyrosine, were found to produce the [35S]sulphated forms of these compounds. Addition to the labelling media of m-hydroxybenzylhydrazine, an aromatic amino acid decarboxylase inhibitor, greatly enhanced the production of L-dopa O-[35S]sulphate and Dl-m-tyrosine O-[35S]sulphate, with a concomitant decrease in the formation of dopamine O-[35S]sulphate and m-tyramine O-[35S]sulphate. With 3´-phosphoadenosine 5´-phospho[35S]sulphate as the sulphate donor, HepG2-cell cytosol was shown to contain enzymic activity catalysing the sulphation of L-dopa, D-dopa, L-m-tyrosine, D-m-tyrosine, L-p-tyrosine and D-p-tyrosine. The pH optimum of the enzyme, designated dopa/tyrosine sulphotransferase, was determined to be 8.75 with D-m-tyrosine as the substrate. The enzyme exhibited stereoselectivity for the D-form of dopa or tyrosine isomers. Addition of 10 mM MnCl2 to the reaction mixture resulted in a remarkable stimulation of dopa/tyrosine sulphotransferase activity, being as high as 267.8 times with D-p-tyrosine as the substrate. Quantitative assays revealed L-dopa, D-dopa and D-m-tyrosine to be better substrates than L-p-tyrosine. When the HepG2-cell cytosol was subjected to DEAE Bio-Gel and hydroxyapatite column chromatography, dopa/tyrosine sulphotransferase was co-eluted with the thermolabile ‘M-form’ phenol sulphotransferase. Furthermore dopa/tyrosine sulphotransferase displayed properties similar to that of the M-form phenol sulphotransferase with respect to thermostability and sensitivity to 2,6-dichloro-4-nitrophenol. Whether the M-form phenol sulphotransferase is truly (solely) responsible for the dopa/tyrosine sulphotransferase activity present in HepG2 cells remains to be clarified.
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Quiñones, Henry, Roberto Collazo, and Orson W. Moe. "The dopamine precursor l-dihydroxyphenylalanine is transported by the amino acid transporters rBAT and LAT2 in renal cortex." American Journal of Physiology-Renal Physiology 287, no. 1 (July 2004): F74—F80. http://dx.doi.org/10.1152/ajprenal.00237.2003.
Full textAbstract:
The intrarenal autocrine-paracrine dopamine (DA) system is critical for Na+ homeostasis. l-Dihydroxyphenylalanine (l-DOPA) uptake from the glomerular filtrate and plasma provides the substrate for DA generation by the renal proximal tubule. The transporter(s) responsible for proximal tubule l-DOPA uptake has not been characterized. Renal cortical poly-A+ RNA injected into Xenopus laevis oocytes induced l-DOPA uptake in a time- and dose-dependent fashion with biphasic Kms in the millimolar and micromolar range and independent of inward Na+, K+, or H+ gradients, suggesting the presence of low- and high-affinity l-DOPA carriers. Complementary RNA from two amino acid transporters yielded l-DOPA uptake significantly above water-injected controls the rBAT/b0,+AT dimer (rBAT) and the LAT2/4F2 dimer (LAT2). In contradistinction to renal cortical poly-A+, l-DOPA kinetics of rBAT and LAT2 showed classic Michaelis-Menton kinetics with Kms in the micromolar and millimolar range, respectively. Sequence-specific antisense oligonucleotides to rBAT or LAT2 (AS) caused inhibition of rBAT and LAT2 cRNA-induced l-DOPA transport and cortical poly-A+-induced arginine and phenylalanine transport. However, the same ASs only partially blocked poly-A+-induced l-DOPA transport. In cultured kidney cells, silencing inhibitory RNA (siRNA) to rBAT significantly inhibited l-DOPA uptake. We conclude that rBAT and LAT2 can mediate apical and basolateral l-DOPA uptake into the proximal tubule, respectively. Additional l-DOPA transport mechanisms exist in the renal cortex that remain to be identified.
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Elabi, Osama F., Elena Espa, Katrine Skovgård, Silvia Fanni, and Maria Angela Cenci. "Ropinirole Cotreatment Prevents Perivascular Glial Recruitment in a Rat Model of L-DOPA-Induced Dyskinesia." Cells 12, no. 14 (July 14, 2023): 1859. http://dx.doi.org/10.3390/cells12141859.
Full textAbstract:
Dopamine replacement therapy for Parkinson’s disease is achieved using L-DOPA or dopamine D2/3 agonists, such as ropinirole. Here, we compare the effects of L-DOPA and ropinirole, alone or in combination, on patterns of glial and microvascular reactivity in the striatum. Rats with unilateral 6-hydroxydopamine lesions were treated with therapeutic-like doses of L-DOPA (6 mg/kg), an equipotent L-DOPA-ropinirole combination (L-DOPA 3 mg/kg plus ropinirole 0.5 mg/kg), or ropinirole alone. Immunohistochemistry was used to examine the reactivity of microglia (ionized calcium-binding adapter molecule 1, IBA-1) and astroglia (glial fibrillary acidic protein, GFAP), as well as blood vessel density (rat endothelial cell antigen 1, RECA-1) and albumin extravasation. L-DOPA monotreatment and L-DOPA–ropinirole cotreatment induced moderate-severe dyskinesia, whereas ropinirole alone had negligible dyskinetic effects. Despite similar dyskinesia severity, striking differences in perivascular microglia and astroglial reactivity were found between animals treated with L-DOPA vs. L-DOPA–ropinirole. The former exhibited a marked upregulation of perivascular IBA-1 cells (in part CD68-positive) and IBA-1–RECA-1 contact points, along with an increased microvessel density and strong perivascular GFAP expression. None of these markers were significantly upregulated in animals treated with L-DOPA–ropinirole or ropinirole alone. In summary, although ropinirole cotreatment does not prevent L-DOPA-induced dyskinesia, it protects from maladaptive gliovascular changes otherwise associated with this disorder, with potential long-term benefits to striatal tissue homeostasis.
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Tesoro, Carmen, Filomena Lelario, Rosanna Ciriello, Giuliana Bianco, Angela Di Capua, and Maria Assunta Acquavia. "An Overview of Methods for L-Dopa Extraction and Analytical Determination in Plant Matrices." Separations 9, no. 8 (August 17, 2022): 224. http://dx.doi.org/10.3390/separations9080224.
Full textAbstract:
L-dopa is a precursor of dopamine used as the most effective symptomatic drug treatment for Parkinson’s disease. Most of the L-dopa isolated is either synthesized chemically or from natural sources, but only some plants belonging to the Fabaceae family contain significant amounts of L-dopa. Due to its low stability, the unambiguous determination of L-dopa in plant matrices requires appropriate technologies. Several analytical methods have been developed for the determination of L-dopa in different plants. The most used for quantification of L-dopa are mainly based on capillary electrophoresis or chromatographic methods, i.e., high-performance liquid chromatography (HPLC), coupled to ultraviolet-visible or mass spectrometric detection. HPLC is most often used. This paper aims to give information on the latest developments in the chemical study of L-dopa, emphasizing the extraction, separation and characterization of this compound by chromatographic, electrochemical and spectral techniques. This study can help select the best possible strategy for determining L-dopa in plant matrices using advanced analytical methods.
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Fridjonsdottir, Elva, Reza Shariatgorji, Anna Nilsson, Theodosia Vallianatou, Luke R. Odell, Luke S. Schembri, Per Svenningsson, et al. "Mass spectrometry imaging identifies abnormally elevated brain l-DOPA levels and extrastriatal monoaminergic dysregulation in l-DOPA–induced dyskinesia." Science Advances 7, no. 2 (January 2021): eabe5948. http://dx.doi.org/10.1126/sciadv.abe5948.
Full textAbstract:
l-DOPA treatment for Parkinson’s disease frequently leads to dyskinesias, the pathophysiology of which is poorly understood. We used MALDI-MSI to map the distribution of l-DOPA and monoaminergic pathways in brains of dyskinetic and nondyskinetic primates. We report elevated levels of l-DOPA, and its metabolite 3-O-methyldopa, in all measured brain regions of dyskinetic animals and increases in dopamine and metabolites in all regions analyzed except the striatum. In dyskinesia, dopamine levels correlated well with l-DOPA levels in extrastriatal regions, such as hippocampus, amygdala, bed nucleus of the stria terminalis, and cortical areas, but not in the striatum. Our results demonstrate that l-DOPA–induced dyskinesia is linked to a dysregulation of l-DOPA metabolism throughout the brain. The inability of extrastriatal brain areas to regulate the formation of dopamine during l-DOPA treatment introduces the potential of dopamine or even l-DOPA itself to modulate neuronal signaling widely across the brain, resulting in unwanted side effects.
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Zimlichman, Reuven, Paul D. Levinson, Gerald Kelly, Robin Stull, Harry R. Keiser, and David S. Goldstein. "Derivation of urinary dopamine from plasma dopa." Clinical Science 75, no. 5 (November 1, 1988): 515–20. http://dx.doi.org/10.1042/cs0750515.
Full textAbstract:
1. We estimated the extent to which circulating dopa (3,4-dihydroxyphenylalanine) is the source of urinary dopamine (DA; 3,4-dihydroxyphenethylamine). Tritiated dopa ([3H]dopa) was infused for 90 min into the left renal artery of seven anaesthetized foxhounds, and levels of labelled and unlabelled dopa and DA were measured in the ureteral urine and in the femoral arterial and left renal venous plasma. 2. Only a small percentage of [3H]dopa delivered to the kidneys was excreted as [3H]DA (0.59% from the left kidney, 0.68% from the right); however, the arterial concentration of endogenous dopa (1220 pg/ml) and the renal plasma flows (144 and 141 ml/min by p-aminohippurate clearances) were such that all of the urinary excretion of endogenous DA (about 1 ng/min from each kidney) could be accounted for by uptake and decarboxylation of circulating endogenous dopa. 3. Plasma dopa is the main source of urinary DA.
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Shinde, Sagar, Athoiba Singh, Shekhar Shinde, and Jagtap Suresh. "Emerging Perspectives on Plant-Based L-Dopa Sources for the Treatment of Parkinson’s disease." Ecology, Environment and Conservation 30, no. 02 (2024): 944–52. http://dx.doi.org/10.53550/eec.2024.v30i02.087.
Full textAbstract:
L-DOPA (L-3, 4-dihydroxyphenylalanine) is a crucial pharmacological agent in the treatment of Parkinson’s disease (PD). As a precursor to dopamine, its administration serves to address the dopamine deficiency. Dopamine is a neurotransmitter and plays a prominent role for motor control and coordination is severely depleted in PD patients, leading to debilitating motor symptoms. L-DOPA crosses the blood-brain barrier, where it is converted into dopamine, While L-DOPA remains the gold standard for PD management, and this review will focus on plant-based L- DOPA sources as an alternative to synthetic L-DOPA in treatment of Parkinson’s disease. While synthetic L-DOPA which can be associated with various side effects. Plantbased L-DOPA, derived from natural sources such as Mucuna pruriens, Vicia faba and along with other plants offer a promising alternative for the management of Parkinson’s disease. Different studies have demonstrated the effectiveness of Mucuna pruriens and other L-DOPA containing plants to alleviating motor symptoms in Parkinson’s. Furthermore, the use of natural plant-based L-DOPA may offer advantages in terms of reduced cost and increased availability, particularly in regions where conventional pharmaceutical L-DOPA preparations may be less accessible collectively, the evidence to date suggests a promising future for plant-based L- DOPA sources in the management of Parkinson disease. However, additional research is required to address issues such as the optimal quality and duration of intake as well as potential mechanisms. Studies in the above areas will help formulate optimum dosage. Overall, plant-based L-DOPA holds promise as a complementary approach to conventional therapy, offering potential benefits for those living with Parkinson’s disease.
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Inyushin, M. Y., A. Huertas, Y. V. Kucheryavykh, L. Y. Kucheryavykh, V. Tsydzik, P. Sanabria, M. J. Eaton, S. N. Skatchkov, L. V. Rojas, and W. D. Wessinger. "L-DOPA Uptake in Astrocytic Endfeet Enwrapping Blood Vessels in Rat Brain." Parkinson's Disease 2012 (2012): 1–8. http://dx.doi.org/10.1155/2012/321406.
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Astrocyte endfeet surround brain blood vessels and can play a role in the delivery of therapeutic drugs for Parkinson’s disease. However, there is no previous evidence of the presence of LAT transporter forL-DOPA in brain astrocytes except in culture. Using systemicL-DOPA administration and a combination of patch clamp, histochemistry and confocal microscopy we found thatL-DOPA is accumulated mainly in astrocyte cell bodies, astrocytic endfeet surrounding blood vessels, and pericytes. In brain slices: (1) astrocytes were exposed to ASP+, a fluorescent monoamine analog of MPP+; (2) ASP+taken up by astrocytes was colocalized withL-DOPA fluorescence in (3) glial somata and in the endfeet attached to blood vessels; (4) these astrocytes have an electrogenic transporter current elicited by ASP+, but intriguingly not byL-DOPA, suggesting a different pathway for monoamines andL-DOPA via astrocytic membrane. (5) The pattern of monoamine oxidase (MAO type B) allocation in pericytes and astrocytic endfeet was similar to that ofL-DOPA accumulation. We conclude that astrocytes controlL-DOPA uptake and metabolism and, therefore, may play a key role in regulating brain dopamine level during dopamine-associated diseases. These data also suggest that different transporter mechanisms may exist for monoamines andL-DOPA.
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Kuo, Tung-Tai, Yuan-Hao Chen, Vicki Wang, Eagle Yi-Kung Huang, Kuo-Hsing Ma, Nigel H. Greig, Jin Jung, et al. "PT320, a Sustained-Release GLP-1 Receptor Agonist, Ameliorates L-DOPA-Induced Dyskinesia in a Mouse Model of Parkinson’s Disease." International Journal of Molecular Sciences 24, no. 5 (February 28, 2023): 4687. http://dx.doi.org/10.3390/ijms24054687.
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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.
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Fang, Lu, Hangxu Ren, Xiyu Mao, Shanshan Zhang, Yu Cai, Shiyi Xu, Yi Zhang, Lihua Li, Xuesong Ye, and Bo Liang. "Differential Amperometric Microneedle Biosensor for Wearable Levodopa Monitoring of Parkinson’s Disease." Biosensors 12, no. 2 (February 7, 2022): 102. http://dx.doi.org/10.3390/bios12020102.
Full textAbstract:
Levodopa (L-Dopa) is considered to be one of the most effective therapies available for Parkinson’s disease (PD) treatment. The therapeutic window of L-Dopa is narrow due to its short half-life, and long-time L-Dopa treatment will cause some side effects such as dyskinesias, psychosis, and orthostatic hypotension. Therefore, it is of great significance to monitor the dynamic concentration of L-Dopa for PD patients with wearable biosensors to reduce the risk of complications. However, the high concentration of interferents in the body brings great challenges to the in vivo monitoring of L-Dopa. To address this issue, we proposed a minimal-invasive L-Dopa biosensor based on a flexible differential microneedle array (FDMA). One working electrode responded to L-Dopa and interfering substances, while the other working electrode only responded to electroactive interferences. The differential current response of these two electrodes was related to the concentration of L-Dopa by eliminating the common mode interference. The differential structure provided the sensor with excellent anti-interference performance and improved the sensor’s accuracy. This novel flexible microneedle sensor exhibited favorable analytical performance of a wide linear dynamic range (0–20 μM), high sensitivity (12.618 nA μM−1 cm−2) as well as long-term stability (two weeks). Ultimately, the L-Dopa sensor displayed a fast response to in vivo L-Dopa dynamically with considerable anti-interference ability. All these attractive performances indicated the feasibility of this FDMA for minimal invasive and continuous monitoring of L-Dopa dynamic concentration for Parkinson’s disease.
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Seri, I., B. C. Kone, S. R. Gullans, A. Aperia, B. M. Brenner, and B. J. Ballermann. "Locally formed dopamine inhibits Na+-K+-ATPase activity in rat renal cortical tubule cells." American Journal of Physiology-Renal Physiology 255, no. 4 (October 1, 1988): F666—F673. http://dx.doi.org/10.1152/ajprenal.1988.255.4.f666.
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Dopamine, generated locally from L-dopa, inhibits Na+-K+-ATPase in permeabilized rat proximal tubules under maximum transport rate conditions for sodium. To determine whether locally formed dopamine inhibits Na+-K+-ATPase activity in intact cortical tubule cells we studied the effect of L-dopa on ouabain-sensitive oxygen consumption rate (QO2) and 86Rb uptake in renal cortical tubule cell suspensions. L-Dopa (10(-4) M) did not affect ouabain-insensitive QO2 or mitochondrial respiration. However, L-dopa inhibited ouabain-sensitive QO2 in a concentration-dependent manner, with half-maximal inhibition (K0.5) of 5 x 10(-7) M and a maximal inhibition of 14.1 +/- 1.5% at 10(-4) M (P less than 0.05). L-Dopa also blunted the nystatin-stimulated QO2 in a concentration-dependent manner, with a K0.5 of 5 x 10(-8) M and a maximal inhibition of 21.8 +/- 1.2% at 10(-5) M (P less than 0.05), indicating that L-dopa directly inhibits Na+-K+-ATPase activity and not sodium entry. Ouabain-sensitive 86Rb uptake was also inhibited by L-dopa (16.0 +/- 2.4%, P less than 0.05). Carbidopa (10(-4) M), an inhibitor of the conversion of L-dopa to dopamine, eliminated the effect of L-dopa on ouabain-sensitive QO2 and 86Rb uptake, indicating that dopamine rather than L-dopa was the active agent. The finding that the L-dopa concentration-response curve was shifted to the left by one order of magnitude in the presence of nystatin suggests that the inhibitory effect is enhanced when the intracellular sodium concentration is increased.(ABSTRACT TRUNCATED AT 250 WORDS)
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Iriarte, Carmen E., and Ian G. Macreadie. "Comparison of Cytocidal Activities of L-DOPA and Dopamine in S. cerevisiae and C. glabrata." Current Bioactive Compounds 16, no. 1 (February 20, 2020): 90–93. http://dx.doi.org/10.2174/1573407214666180108144216.
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Background: Parkinson's Disease results from a loss of dopaminergic neurons, and reduced levels of the neurotransmitter dopamine. Parkinson's Disease treatments involve increasing dopamine levels through administration of L-DOPA, which can cross the blood brain barrier and be converted to dopamine in the brain. The toxicity of dopamine has previously studied but there has been little study of L-DOPA toxicity. Methods: We have compared the toxicity of dopamine and L-DOPA in the yeasts, Saccharomyces cerevisiae and Candida glabrata by cell viability assays, measuring colony forming units. Results: L-DOPA and dopamine caused time-dependent cell killing in Candida glabrata while only dopamine caused such effects in Saccharomyces cerevisiae. The toxicity of L-DOPA is much lower than dopamine. Conclusion: Candida glabrata exhibits high sensitivity to L-DOPA and may have advantages for studying the cytotoxicity of L-DOPA.
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Schwinn, Kathy E. "The dope on l -DOPA formation for betalain pigments." New Phytologist 210, no. 1 (February 25, 2016): 6–9. http://dx.doi.org/10.1111/nph.13901.
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Miller, Dusty R., Jamie E. Spahn, and J. Herbert Waite. "The staying power of adhesion-associated antioxidant activity in Mytilus californianus." Journal of The Royal Society Interface 12, no. 111 (October 2015): 20150614. http://dx.doi.org/10.1098/rsif.2015.0614.
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The California mussel, Mytilus californianus , adheres in the highly oxidizing intertidal zone with a fibrous holdfast called the byssus using 3, 4-dihydroxyphenyl- l -alanine (DOPA)-containing adhesive proteins. DOPA is susceptible to oxidation in seawater and, upon oxidation, loses adhesion. Successful mussel adhesion thus depends critically on controlling oxidation and reduction. To explore how mussels regulate redox during their functional adhesive lifetime, we tracked extractable protein concentration, DOPA content and antioxidant activity in byssal plaques over time. In seawater, DOPA content and antioxidant activity in the byssus persisted much longer than expected—50% of extractable DOPA and 30% of extractable antioxidant activity remained after 20 days. Antioxidant activity was located at the plaque–substrate interface, demonstrating that antioxidant activity keeps DOPA reduced for durable and dynamic adhesion. We also correlated antioxidant activity to cysteine and DOPA side chains of mussel foot proteins (mfps), suggesting that mussels use both cysteine and DOPA redox reservoirs for controlling interfacial chemistry. These data are discussed in the context of the biomaterial structure and properties of the marine mussel byssus.
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Fiebrich, H., A. H. Brouwers, M. N. Kerstens, M. E. Pijl, I. P. Kema, J. R. de Jong, J. E. van der Wal, W. J. Sluiter, E. G. de Vries, and T. P. Links. "Sensitivity of 6-[F-18]fluoro-L-dihydroxyphenylalanine positron emission tomography for localizing tumors causing catecholamine excess." Journal of Clinical Oncology 27, no. 15_suppl (May 20, 2009): 11064. http://dx.doi.org/10.1200/jco.2009.27.15_suppl.11064.
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11064 Background: Positron emission tomography (PET) using the catecholamine precursor 6-[F-18]fluoro-L-dihydroxyphenylalanine (18F-DOPA) has emerged as promising technique to localize tumors with catecholamine excess. This study investigated the sensitivity of 18F-DOPA PET, compared to 123I-metaiodobenzylguanidine (123I-MIBG) scintigraphy and computer tomography (CT)/ magnetic resonance imaging (MRI) in patients with catecholamine excess. Methods: In a single center prospective study 18F-DOPA PET was compared to 123I-MIBG and CT/MRI in patients with catecholamine excess. The performance of each imaging modality was analyzed for individual patients and individual lesions. 18F-DOPA PET, 123I-MIBG, and CT/MRI were compared using a composite reference standard derived from all available imaging, clinical and histological information. Sensitivities were calculated and discordance between imaging techniques was compared. 18F-DOPA PET uptake was measured to determine whole body metabolic burden. Correlations between 18F-DOPA PET imaging and biochemical data were evaluated. Results: 48 patients were included. The tumor localization was found in 45 patients, 43 with 18F-DOPA PET, 31 with 123I-MIBG and 32 with CT/MRI, resulting with surgery in final diagnosis of pheochromocytoma in 40, adrenal hyperplasia in 2, paraganglioma in 2, ganglioneuroma in 1 and 3 unknown (as yet no lesion detected). Per patient based analysis showed sensitivities for 18F-DOPA PET, 123I-MIBG and CT/MRI of 90, 65 and 67% (P<.01 18F-DOPA PET vs 123I-MIBG, P<.01 18F-DOPA PET vs CT/MRI, P=1.0 123I-MIBG vs CT/MRI). Corresponding sensitivities in the lesion based analysis were 73, 48 and 44%, respectively (P<.001 for both 18F-DOPA PET vs 123I-MIBG and vs CT/MRI, P=.51 123I-MIBG vs CT/MRI). The 8F-DOPA PET+CT/MRI combination was superior to 123I-MIBG+CT/MRI (93 vs 76%, P<.001) Whole body metabolic burden measured with 18F-DOPA PET correlated with plasma free normetanephrine (r=.82) and 24h urinary total normetanephrine (r=.84) and metanephrine (r=.57). Conclusions: The sensitivity of 18F-DOPA PET to localize tumors with catecholamine excess is superior to either 123I-MIBG scintigraphy or CT/MRI. No significant financial relationships to disclose.
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Winarni, Sri, and Yudhy Dharmawan. "KANDUNGAN L-DOPA DALAM VARIASI PERENDAMAN DAN PEREBUSAN DALAM PROSES PEMBUATAN TEMPE BENGUK." Jurnal Kesehatan Masyarakat 11, no. 2 (February 24, 2016): 155. http://dx.doi.org/10.15294/kemas.v11i2.3489.
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<p>Abstrak</p><p>L-Dopa biji koro benguk sebesar 14,7%, berbeda dengan tempe benguk. Tujuan penelitian adalah menguji L-Dopa dalam 4 pengolahan tempe benguk yang berbeda. Penelitian tahun 2015 ini menggunakan teknik pengumpulan data dengan mengamati proses pengolahan tempe benguk dan menguji L-Dopa dalam fraksi tempe benguk dengan HPLC. Populasi penelitian adalah seluruh pemilik industri tempe benguk. Sampel penelitian diambil dengan metode purposif sampling, menentukan 4 industri tempe benguk yang sering digunakan. Proses pertama dengan satu rebusan 1-1,5 jam dan satu rendaman (2 hari) mengandung L-Dopa 8425,00 ppm. Proses kedua yaitu rebusan dua kali 1-1,5 jam dan ulangan rendaman tiga kali (setiap rendaman 1 hari 1 malam) mengandung L-Dopa 389,42 ppm. Proses ketiga yaitu ulangan rebusan dua kali (1,5-2 jam) dan rendaman satu kali mengandung L-Dopa 2163,37 ppm. Proses keempat rebusan satu kali (< 1 jam) dan rendaman satu kali (dua hari) mengandung L-Dopa tertinggi yaitu 9781,55 ppm.</p><p>Kata kunci : Tempe benguk; Perendaman Perebusan; L-Dopa</p><p> </p><p><em><strong>Abtract</strong></em></p><p><em>L-Dopa of koro benguk seed is around 14,7%, different with benguk tempeh. The objective of this study is to test L-Dopa in 4 different ways. Data were collected in 2015 by observing benguk tempeh processing and testing L-Dopa in benguk tempeh (HPLC). The population of this study are all owners of benguk tempeh industries. The sample was taken by using purposive sampling, determining 4 benguk tempeh industries that mostly used. The first process with one boiling 1-1,5 hours and one immersion (2 days) contain L-Dopa 8425,00 ppm. The second process with two boiling 1-1,5 hours and repetition immersion three times (each immersion 1 day 1 night) contains L-Dopa 389,42 ppm. The third process is twice re-boiling once (< 1 hour) and immersion once again (2 days) contain the high L-Dopa that is 9781,55 ppm.</em></p><p><em>Keyword : Benguk tempeh; Soaking-boiling; L-Dopa</em></p>
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Sampaio-Maia, B., M. P. Serrão, and P. Soares-da-Silva. "Regulatory pathways and uptake ofl-DOPA by capillary cerebral endothelial cells, astrocytes, and neuronal cells." American Journal of Physiology-Cell Physiology 280, no. 2 (February 1, 2001): C333—C342. http://dx.doi.org/10.1152/ajpcell.2001.280.2.c333.
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We examined the nature and regulation of the inwardl-3,4-dihydroxyphenylalanine (l-DOPA) transporter in rat capillary cerebral endothelial (RBE4) cells, type 1 astrocytes (DI TNC1), and Neuro-2a neuroblastoma cells. In all three cell types, the inward transfer of l-DOPA was largely promoted through the 2-aminobicyclo-(2,2,1)-heptane-2-carboxylic acid-sensitive and sodium-independent L-type amino acid transporter. Only in DI TNC1 cells was the effect of maneuvers that increase intracellular cAMP levels accompanied by increases inl-DOPA uptake. Also, only in DI TNC1 cells was the effect of the guanylyl cyclase inhibitor LY-83583 accompanied by a 65% increase in l-DOPA accumulation, whereas the nitric oxide donor sodium nitroprusside produced a 25% decrease inl-DOPA accumulation. In all three cell types, the Ca2+/calmodulin inhibitors calmidazolium and trifluoperazine inhibited l-DOPA uptake in a noncompetitive manner. Thapsigargin (1 and 3 μM) and A-23187 (1 and 3 μM) failed to alter l-DOPA accumulation in RBE4 and Neuro-2a cells but markedly increased l-DOPA uptake in DI TNC1cells. We concluded that l-DOPA in RBE4, DI TNC1, and Neuro-2a cells is transported through the L-type amino acid transporter and appears to be under the control of Ca2+/calmodulin-mediated pathways. Astrocytes, however, are endowed with other processes that appear to regulate the accumulation of l-DOPA, responding positively to increases in intracellular Ca2+ and cAMP and to decreases in cGMP.
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Salarinejad, Alireza, Khadije Esmaeilpour, Mohammad Shabani, Saeideh Jafarinejad-Farsangi, Abbas Pardakhty, Majid Asadi-Shekaari, and Meysam Ahmadi-Zeidabadi. "Effect of l-Dopa in acute temozolomide-induced cognitive impairment in male mice: a possible antineuroinflammatory role." Behavioural Pharmacology 34, no. 5 (June 24, 2023): 263–74. http://dx.doi.org/10.1097/fbp.0000000000000733.
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Temozolomide is used commonly in the treatment of some types of cancers, but it may also result in cognitive impairments such as memory deficits. l-Dopa, a well known medicine for the central nervous system, has been shown to have positive effects on some cognitive disorders. Here we sought to investigate the effect of l-Dopa on temozolomide-induced cognitive impairments. BALB/c mice were subjected to 3-days temozolomide and 6-days concomitant l-Dopa/benserazide administration in six groups (control, l-Dopa 25 mg/kg, l-Dopa 75 mg/kg, temozolomide, temozolomide + l-Dopa 25 mg/kg, and temozolomide + l-Dopa 75 mg/kg). Open field test, object location recognition, novel object recognition test, and shuttle-box test were carried out to determine the locomotor, anxiety-like behavior, and memory function of subjects. TNF-α and brain-derived neurotrophic factor (BDNF) gene expression in the hippocampus was measured by real-time PCR. Mice treated with temozolomide showed recognition memory impairment, along with hippocampal TNF-α and BDNF mRNA expression level raise, and detection of histological insults in hematoxylin and eosin hippocampal slides. Mice that received temozolomide + l-Dopa showed normal behavioral function and lower TNF-α and BDNF hippocampal mRNA expression levels, and histologically normal hippocampal CA1 region in comparison with mice in the temozolomide group. Our results provide evidence that l-Dopa prevents temozolomide-induced recognition memory deficit in mice at the acute phase probably via l-Dopa antineuroinflammatory effects.
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Altwal, Feras, Connor Moon, Anthony R. West, and Heinz Steiner. "The Multimodal Serotonergic Agent Vilazodone Inhibits L-DOPA-Induced Gene Regulation in Striatal Projection Neurons and Associated Dyskinesia in an Animal Model of Parkinson’s Disease." Cells 9, no. 10 (October 9, 2020): 2265. http://dx.doi.org/10.3390/cells9102265.
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Levodopa (L-DOPA) treatment in Parkinson’s disease is limited by the emergence of L-DOPA-induced dyskinesia. Such dyskinesia is associated with aberrant gene regulation in neurons of the striatum, which is caused by abnormal dopamine release from serotonin terminals. Previous work showed that modulating the striatal serotonin innervation with selective serotonin reuptake inhibitors (SSRIs) or 5-HT1A receptor agonists could attenuate L-DOPA-induced dyskinesia. We investigated the effects of a novel serotonergic agent, vilazodone, which combines SSRI and 5-HT1A partial agonist properties, on L-DOPA-induced behavior and gene regulation in the striatum in an animal model of Parkinson’s disease. After unilateral dopamine depletion by 6-hydroxydopamine (6-OHDA), rats received repeated L-DOPA treatment (5 mg/kg) alone or in combination with vilazodone (10 mg/kg) for 3 weeks. Gene regulation was then mapped throughout the striatum using in situ hybridization histochemistry. Vilazodone suppressed the development of L-DOPA-induced dyskinesia and turning behavior but did not interfere with the prokinetic effects of L-DOPA (forelimb stepping). L-DOPA treatment drastically increased the expression of dynorphin (direct pathway), 5-HT1B, and zif268 mRNA in the striatum ipsilateral to the lesion. These effects were inhibited by vilazodone. In contrast, vilazodone had no effect on enkephalin expression (indirect pathway) or on gene expression in the intact striatum. Thus, vilazodone inhibited L-DOPA-induced gene regulation selectively in the direct pathway of the dopamine-depleted striatum, molecular changes that are considered critical for L-DOPA-induced dyskinesia. These findings position vilazodone, an approved antidepressant, as a potential adjunct medication for the treatment of L-DOPA-induced motor side effects.