Disease relevance of L-dopa

• L-Dopa has has been shown to demonstrate enhanced toxicity toward melanoma cells in vitro [1].
• L-Dopa, L-Dopa and dopa-decarboxylase inhibitor, or placebo was given orally for 7 days to 75 cirrhotic patients with hepatic encephalopathy [2].
• L-Dopa has long been the mainstay of therapy for Parkinson's disease but its long-term shortcomings, principally uncoordinated, spasmodic or irregular movements (dyskinesias) and fluctuating control of motor symptoms (on/off fluctuations), are well documented [3].
• L-Dopa decarboxylase activity thus does appear to be a valuabe marker for separating SCC cells from other lung cancer cells in vitro [4].
• It is concluded that, similar to glutathione, the oxidative stress limiting NQO is likely to contribute to the capacity of astroglial cells to protect dopaminergic neurons against L-Dopa, and, hence, may be considered as a potential target for the development of neuroprotective strategies for Parkinson's disease [5].

Psychiatry related information on L-dopa

• A marked reduction of this ratio was found in patients with Huntington's disease (1.38 +/- 0.12; p = 0.0001), no significant changes in untreated parkinsonian patients (1.67 +/- 0.14), but a reduction in L-Dopa-treated cases (1.59 +/- 0.13; p = 0.0014) [6].
• Treatment with reserpine plus L-Dopa (125 mg/kg i.p.) produced an increase in motor activity probably due to stimulation of dopamine receptors since it was not accompanied by an accumulation of noradrenaline and it was not inhibited by phenoxybenzamine [7].
• However, DLB is also different to PD and DAT (less tremor and asymmetry of the motor symptoms, more falls, and less favourable response to L-Dopa than PD; in contrast to DAT marked cognitive fluctuations and phases of reduced alertness, hallucinations and delirium) [8].
• On the contrary, clinical studies demonstrate its excellent efficacy in neuroleptic-induced tardive dyskinesia, L-Dopa-induced dyskinesias, psychomotor agitation in geriatric patients and choreatic movement disorders [9].
• Plasma melatonin was not affected by electroconvulsive therapy, TRH-injection, L-Dopa or bromoergocryptine orally [10].

High impact information on L-dopa

• L-Dopa, then, appears to have an action in animals with selective lesions of the substantia nigra pars compacta produced by MPTP that is distinctly different from its effects in the normal monkey [11].
• We examined the effect of L-Dopa, after peripheral L-amino acid decarboxylase inhibition, on sympathetic nerve activity (SNA) and blood pressure in spontaneously hypertensive rats (SHR) and in normotensive control rats [12].
• To ascertain the source of the catecholamine, we examined postnatal TH-null albino mice that lack tyrosinase, another enzyme that converts tyrosine to L-Dopa but does so during melanin synthesis [13].
• L-Dopa therapy reversed the oculomotor symptoms in these monkeys, as well as the decrease of lCMRGlc in the frontal eye fields and the paralamellar mediodorsal thalamus [14].
• Although the biomarkers L-Dopa decarboxylase, bombesin, carcinoembryonic antigen, and neurotensin were detectable in SCLC-22H, they were undetectable or low in SCLC-21H [15].

Chemical compound and disease context of L-dopa

• Iodine-123-iodobenzamide binding in parkinsonism: reduction by dopamine agonists but not L-Dopa [16].
• The importance of brain noradrenaline synthesis and receptor activation for the hyperkinesia induced by carbidopa plus L-Dopa in reserpine-treated or normal mice was analyzed in four different models [7].
• Thus, noradrenaline receptor activation is of importance for the L-Dopa-induced hyperkinesia, at least after high doses or after monoamine oxidase inhibition [7].
• The results suggest that the stimulation of AADC mRNA by amantadine may be one of its effects on dopamine metabolism that may have relevance for potentiation of L-Dopa therapy in Parkinsonism [17].
• Yet metoclopramide, in anti-emetic doses, has no effect on disability in Parkinson's disease or on the therapeutic benefit of L-Dopa and L-Dopa dyskinesias [18].

Biological context of L-dopa

• CONCLUSIONS: L-Dopa may influence the responsiveness of the parkinsonian brain as assessed by frontal somatosensory evoked potentials [19].
• The main macrophage nitrating agent was shown to be peroxynitrite derived because parasite nitration occurred in the virtual absence of polymorphonuclear cells (monitored as peroxidase activity) and was accompanied by protein hydroxylation (monitored as 3-hydroxytyrosine levels) [20].
• Given the likely importance of Arc in the regulation of cytoskeleton during synaptic plasticity, its upregulation supports the hypothesis that a relationship exists between cytoskeletal modifications and the longlasting action of chronically administrated L-Dopa [21].
• A number of these derivatives effectively prevent the metabolism of L-Dopa prior to and/or during the absorption process, resulting in a significantly better bioavailability of the drug [22].
• In the blood of rats and mice, 1 functions as a prodrug to release L-Dopa by hydrolysis [23].

Anatomical context of L-dopa

• However, subtle changes in prefrontal cortex (PFC) activity are seen following L-Dopa withdrawal in PD during working memory tasks, suggesting that this may be a further site of action for dopamine D2 receptor antagonists [24].
• A new procedure is described for staining Langerhans cells (LCs) based on the ability of anti-S-100 antibody to stain both epidermal LCs and melanocytes, while L-Dopa stains only melanocytes [25].
• L-Dopa (or one of its metabolites) probably acts upon a noradrenergic or a dopaminergic system located in the hypothalamus to alter the release of hypothalamic corticotropin regulatory factor(s) and thereby enhance the release of ACTH [26].
• Human L-Dopa decarboxylase (L-aromatic amino acid decarboxylase, DDC) has been purified from pheochromocytoma tissue, a benign tumor of the catecholamine-synthesizing cells of the adrenal medulla [27].
• L-tyrosine significantly increased (P < 0.01) L-Dopa and norepinephrine (NE) content of lymphocytes [28].

Associations of L-dopa with other chemical compounds

• Papaverine, 150 mg BID for 2 weeks, a dose which produced marked clinical impairment in Parkinsonian patients taking L-Dopa, failed to alter L-Dopa-stimulated GH secretion or L-Dopa inhibited PRL secretion in 6 normal volunteers [29].
• This carbamate codrug provides adequate stability [t(1/2) = 12.1 h (pH 1.2); 1.4 h (pH 5.0); 1.1 h (pH 7.4)] against chemical hydrolysis but rapidly hydrolyzes to L-Dopa and entacapone in liver homogenate (t(1/2) = 7 min; pH 7.4) at 37 degrees C. The therapeutical potential of this novel codrug is discussed [30].
• Simultaneous injection of L-Dopa and metyrapone resulted in a marked increase in plasma ACTH from 93 +/- 18 pg/ml to 432 +/- 80 pg/ml, whereas plasma 11-deoxycortisol increased from 1.5 +/- 0.2 mug/100 ml to 14.6 +/- 1.0 mug/100 ml 90 min after treatment [26].
• The most striking difference was a rise in 8-OHG in PD substantia nigra (p = 0.0002); rises in other base oxidation/deamination products were not evident, showing that elevation in 8-OHG is unlikely to be due to peroxynitrite (ONOO-) or hydroxyl radicals (OH.), or to be a prooxidant effect of treatment with L-Dopa [31].
• Catecholamines (CA) were studied in peripheral human lymphocytes, as well as in the supernatants, after incubation with L-tyrosine and L-dihydroxyphenylalanine (L-Dopa) for 1 h [32].

Gene context of L-dopa

• The effect of selegiline (L-deprenyl) on plasma catecholamines, clinical response, and drug tolerability was studied in 13 patients with Parkinson's disease (PD) treated with L-Dopa/benserazide and entacapone, a peripheral catechol-O-methyltransferase (COMT) inhibitor, in a placebo-controlled double-blind study [33].
• Simultaneous MAO-B and COMT inhibition in L-Dopa-treated patients with Parkinson's disease [33].
• During chronic L-Dopa + carbidopa therapy, the basal PRL levels, evaluated in 21 PP, showed a correlation with the severity of clinical features [34].
• After L-Dopa, 4 patients showed no change in serum GH, 3 exhibited a decrease and in 3 an increase in serum hGH occurred [35].
• L-Dopa decarboxylase (DDC) has been cloned from several species and was shown to undergo alternative splicing within its 5'-untranslated and coding regions [36].

Analytical, diagnostic and therapeutic context of L-dopa

• Although oral administration of L-Dopa remains the best therapy for Parkinson disease, its long-term administration causes the appearance of abnormal involuntary movements such as dyskinesia [21].
• The intravenous injection of L-Dopa (15 mg/kg) to monkeys (Macaca mulatta) failed to alter plasma concentrations of ACTH and of 11-deoxy-cortisol [26].
• Since all six patients had been treated with L-Dopa, we also analyzed the effects of this drug in an animal model of Parkinson's disease [37].
• As an aid in the development of vector systems for use in gene therapy paradigms of central nervous system disorders such as Parkinson's disease, we have developed L-Dopa or dopamine-producing gene cassettes [38].
• In the parkinsonian patients group who were untreated until SPET study and in the group of patients with a sustained response to chronic L-Dopa, striatal [123I]-IBZM uptake did not differ significantly from mean values of the control group [39].

References