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ACS Chemical Neuroscience Dec 2014Levodopa was the first and most successful breakthrough in the treatment of Parkinson's disease (PD). It is estimated that PD affects approximately 1 million people in... (Review)
Review
Levodopa was the first and most successful breakthrough in the treatment of Parkinson's disease (PD). It is estimated that PD affects approximately 1 million people in the United States alone. Although PD was discovered in 1817, prior to levodopa's discovery there was not an effective treatment for managing its symptoms. In 1961, Hornykiewicz pioneered the use of levodopa to enhance dopamine levels in the striatum, significantly improving symptoms in many patients. With the addition of carbidopa in 1974, the frequency of gastrointestinal adverse drug reactions (ADRs) was significantly reduced, leading to the modern treatment of PD. Although levodopa treatment is more than 50 years old, it remains the "gold standard" for PD treatment. This Review describes in detail the synthesis, metabolism, pharmacology, ADRs, and importance of levodopa therapy to neuroscience in the past and present.
Topics: Animals; Antiparkinson Agents; History, 19th Century; History, 20th Century; Humans; Levodopa; Neurosciences; Parkinson Disease
PubMed: 25270271
DOI: 10.1021/cn5001759 -
The Journal of Pharmacology and... Jul 1978gamma-Glutamyl derivatives of amino acids and peptides are selectively accumulated in the kidney and introduced into the metabolism of kidney cells. gamma-Glutamyl...
gamma-Glutamyl derivatives of amino acids and peptides are selectively accumulated in the kidney and introduced into the metabolism of kidney cells. gamma-Glutamyl L-3,4-dihydroxyphenylalanine (gamma-glutamyl dopa) was synthesized both chemically and enzymatically. Injection of this derivative into mice led to a selective generation of dopamine in the kidney as a consequence of the sequential action of gamma-glutamyl transpeptidase and aromatic L-amino acid decarboxylase, two enzymes which are highly concentrated in the kidney. The concentration of dopamine in the kidney after gamma-glutamyl dopa was almost 5 times higher than that after an equivalent dose of L-dopa. Infusion of 10 nmol/g/30 min of gamma-glutamyl dopa to rats produced a 60% increase in renal plasma flow. By contrast the same dose of L-dopa had no effect on renal plasma flow. Only a small pressor effect was observed after the infusion dose of gamma-glutamyl dopa was increased 20-fold indicating that the systemic effects of this pro-drug slight. The results suggest that the pro-drug gamma-glutamyl dopa can be used as a specific renal vasodilator.
Topics: Animals; Blood Pressure; Dihydroxyphenylalanine; Dopamine; Female; Glutamates; Kidney; Levodopa; Male; Mice; Rats; Regional Blood Flow
PubMed: 660553
DOI: No ID Found -
Journal of Neural Transmission.... 2000L-DOPA therapy for Parkinson's disease is one of the major achievements of twentieth century neurology; Parkinson's disease was the first in which specific neurochemical...
L-DOPA therapy for Parkinson's disease is one of the major achievements of twentieth century neurology; Parkinson's disease was the first in which specific neurochemical deficits in defined brain regions were identified, and thus for which a rational, chemical therapy could be developed, ushering in the era of clinical neurochemistry. The contributions of Birkmayer and Hornykiewicz (Vienna), Barbeau and Sourkes (Montreal) and of Cotzias (New York) to this story are well-known. Almost completely forgotten, on the other hand, is a paper presented by the Japanese neurologist Isamu Sano in 1960 which reported what is probably the first attempt to treat Parkinson's disease patients with DOPA. This is all the more remarkable as the author was also responsible for one of the key papers which led to the use of DOPA in Parkinson's disease by other workers. Despite the negative outcome of his experience with L-DOPA, Sano deserves to be remembered as one of the pioneers in catecholamine research, having been the first to map dopamine levels in the human brain, and identified the reduction of dopamine levels in the substantia nigra and striatum in Parkinson's disease.
Topics: Animals; Antiparkinson Agents; History, 20th Century; Humans; Japan; Levodopa; Parkinson Disease
PubMed: 11205132
DOI: 10.1007/978-3-7091-6301-6_1 -
Soins; La Revue de Reference Infirmiere Oct 1980
Topics: Adult; Drug Interactions; Humans; Levodopa; Parkinson Disease
PubMed: 6910139
DOI: No ID Found -
Neurology Feb 1984We measured decarboxylation of oral L-dopa in patients chronically treated with L-dopa, and in untreated controls. Chronic L-dopa and carbidopa administration did not...
We measured decarboxylation of oral L-dopa in patients chronically treated with L-dopa, and in untreated controls. Chronic L-dopa and carbidopa administration did not affect the extent of whole-body decarboxylation, and it is therefore unlikely that on-off fluctuations are related to chronic changes in the activity of L-aromatic amino acid decarboxylase. The observed duration of action and dose-response properties of carbidopa suggested that current empirically based dose schedules are optimal and supported the concept that decarboxylase inhibitors enhance the clinical effect of L-dopa largely by reducing the extent of first-pass metabolism rather than through an action on the decarboxylase enzyme in cerebral capillaries.
Topics: Adult; Carbidopa; Chemistry, Organic; Decarboxylation; Dose-Response Relationship, Drug; Female; Humans; Levodopa; Male; Organic Chemistry Phenomena; Parkinson Disease; Time Factors
PubMed: 6538008
DOI: 10.1212/wnl.34.2.198 -
Brain Research Feb 1988In the intact rat, intragastric administration of D-dihydroxyphenylalanine (D-DOPA) together with carbidopa (alpha-methyldopa hydrazine, a peripheral dopadecarboxylase... (Comparative Study)
Comparative Study
In the intact rat, intragastric administration of D-dihydroxyphenylalanine (D-DOPA) together with carbidopa (alpha-methyldopa hydrazine, a peripheral dopadecarboxylase inhibitor) increased striatal dopamine concentration to the same extent as a similar treatment with L-DOPA plus carbidopa. In rats with unilateral 6-hydroxydopamine-induced lesions of their substantia nigra, both stereoisomers of DOPA produced significant increases in dopamine and its metabolites in the intact striata. Although dopamine concentrations in the lesioned striata did not change, a significant increase in dopamine metabolites was observed, indicating some extraneuronal formation of dopamine. These results suggest that D-DOPA can be converted to dopamine in the normal striatum as well as in the striatum devoid of dopamine nerve terminals. D- and L-DOPA produced turning behavior in unilaterally lesioned rats with a similar efficacy. The onset of turning after D-DOPA was delayed compared with L-DOPA. Turning behavior elicited by these amino acids was attributed to stimulation of supersensitive dopamine receptors in the lesioned striata by the extraneuronally formed dopamine. Preliminary results suggest that D-DOPA is converted to dopamine via transamination and/or D-amino acid oxidation to 3,4-dihydroxyphenylpyruvic acid which upon further transamination gives rise to L-DOPA and hence dopamine. The relatively fast and slow onset of stimulation of dopamine receptors L-DOPA and D-DOPA respectively suggests that the use of the racemic mixture of DOPA combined with a peripheral dopadecarboxylase inhibitor may prove useful in the treatment of parkinsonism.
Topics: 3,4-Dihydroxyphenylacetic Acid; Animals; Brain; Carbidopa; Cerebral Ventricles; Dihydroxyphenylalanine; Dopamine; Homovanillic Acid; Levodopa; Male; Rats; Rats, Inbred Strains; Stereotyped Behavior; Structure-Activity Relationship
PubMed: 3129126
DOI: 10.1016/0006-8993(88)91176-6 -
Movement Disorders : Official Journal... Jun 2015
Topics: Antiparkinson Agents; Humans; Levodopa; Parkinson Disease
PubMed: 25880230
DOI: 10.1002/mds.26242 -
Cell and Tissue Research Apr 2020We have tested whether the lack of chromogranins (Cgs) A and B could provoke CNS disorders when combined with an excess of dopamine. We chronically treated (over...
We have tested whether the lack of chromogranins (Cgs) A and B could provoke CNS disorders when combined with an excess of dopamine. We chronically treated (over 6 months) mice lacking both chromogranins A and B (Cgs-KO) with a low oral dosage of L-DOPA/benserazide (10/2.5 mg/kg). Motor performance in the rota-rod test, open field activity, and metabolic cages indicated a progressive impairment in motor coordination in these mice, and an increase in rearing behavior, which was accompanied by an increase in DA within the substantia nigra. We conclude that mild chronic L-DOPA treatment does not produce nigro-striatal toxicity that could be associated with parkinsonism, neither in control nor Cgs-KO mice. Rather, Cgs-KO mice exhibit behaviors compatible with an amphetamine-like effect, probably caused by the excess of catecholamines in the CNS.
Topics: Animals; Chromogranins; Dopamine Agents; Levodopa; Male; Mice; Motor Activity
PubMed: 31900665
DOI: 10.1007/s00441-019-03159-8 -
Annales Pharmaceutiques Francaises 1993Since 25 years ago, it was postulated that the antiparkinsonian activity of L-DOPA was due to the activation of the synthesis and the release of dopamine that it could... (Review)
Review
Since 25 years ago, it was postulated that the antiparkinsonian activity of L-DOPA was due to the activation of the synthesis and the release of dopamine that it could trigger in the dopaminergic terminals preserved during the Parkinson's disease. Recent experimental data, presented in this paper could show that L-DOPA, far from activate the nigro-striatal dopaminergic neurons, would rather inhibit them and that its antiparkinsonian action could be attributed to the antiglutamatergic activity that L-DOPA, converted to dopamine, could exert by acting on the D2 receptors of the striatal glutamatergic afferences. This antiglutamatergic action of L-DOPA would concern the NMDA as well as the non-NMDA receptors and it is therefore unlikely that the NMDA antagonists could be good anti-parkinsonian drugs (unless they would be coadministered with non-NMDA antagonists). Dopaminergic (D2) agonists could be interesting antiparkinsonian drugs all the more they could be devoid of the potentially neurotoxic properties of L-DOPA.
Topics: Animals; Corpus Striatum; Dopamine; Excitatory Amino Acid Antagonists; Levodopa; Neurons; Rats
PubMed: 8215122
DOI: No ID Found -
International Journal of Biological... Jun 2017In spite of the fact that amyloid related neurodegenerative illnesses and non-neuropathic systemic amyloidosis have allured the research endeavors, as no cure has been...
In spite of the fact that amyloid related neurodegenerative illnesses and non-neuropathic systemic amyloidosis have allured the research endeavors, as no cure has been announced yet apart from symptomatic treatment. Therapeutic agents which can reduce or disaggregate those toxic oligomers and fibrillar species have been studied with more compounds are on their way. The current research work describes comprehensive biophysical, computational and microscopic studies which reveal that L-3, 4-dihydroxyphenylalanine (L-Dopa) have indisputable efficacy to hinder the heat induced amyloid fibrillation of the human lysozyme (HL) and also preserve the fibril disaggregating potential. The IC value of L-Dopa is calculated to be 63.0±0.09μM. L-Dopa intervenes in the process of amyloid fibrillogenesis through hydrophobic interaction and hydrogen bond formation with the amino acid residues found in the amyloid fibril forming prone region of HL as clarified by molecular simulation data. L-Dopa also disaggregates the mature amyloid fibrils into some unorganized species and the DC value was estimated to be 19.95±0.063μM. Hence, L-Dopa and related compounds can act as effective inhibitors in the therapeutic development to combat systemic amyloidosis.
Topics: Amyloidosis; Cell Line, Tumor; Cell Survival; Humans; Hydrogen Bonding; Hydrophobic and Hydrophilic Interactions; Inhibitory Concentration 50; Levodopa; Molecular Docking Simulation; Muramidase; Parkinsonian Disorders; Protein Multimerization; Protein Structure, Secondary
PubMed: 28283460
DOI: 10.1016/j.ijbiomac.2017.03.028