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PubMed1983

The protective effect of gamma-glutamyl L-dopa on the glycerol treated rat model of acute renal failure.

gamma-Glutamyl L-dopa, a renal pro-drug for dopamine, was administered to rats before and after injection of glycerol, and to a control group which received water in place of glycerol. A third group of rats was given glycerol but no gamma-glutamyl L-dopa. The plasma creatinine in rats given gamma-glutamyl L-dopa and glycerol was significantly lower than in rats receiving glycerol alone. The fall in urine creatinine excretion, and polyuria, after glycerol was reduced by gamma-glutamyl L-dopa and the natriuresis abolished. gamma-Glutamyl L-dopa given alone caused a 4000-fold increase in urine dopamine excretion, associated with a natriuresis. The administration of gamma-glutamyl L-dopa reduces the severity of renal failure produced by glycerol.

Acute Kidney Injury↗
PubMed2000

Morphogenesis in Aspergillus nidulans requires Dopey (DopA), a member of a novel family of leucine zipper-like proteins conserved from yeast to humans.

DopA is the founding member of a novel protein family required for correct cell morphology and spatiotemporal organization of multicellular structures in the filamentous fungus Aspergillus nidulans. DopA homologues from Saccharomyces cerevisiae (Dop1), Candida albicans, Caenorhabditis elegans, Rattus norvegicus and Homo sapiens have been identified from genome sequencing projects. S. cerevisiae DOP1 is essential for viability and, like DopA, affects cellular morphogenesis. dopA encodes a large protein (207 kDa) containing several putative domains, including three leucine zipper-like domains. Strains with either the temperature-sensitive dopA1(ts) allele, which alters one of the leucine zippers, or the null deltadopA allele, had abnormal morphology of the vegetative hyphae, delayed and asynchronous initiation of asexual development, aberrant morphogenesis of the conidiophore and an early block in the sexual cycle. The expression patterns of key transcriptional regulators of the asexual and sexual cycle (brlA, abaA and steA) are altered in a deltadopA background, suggesting that DopA functions upstream in the developmental pathway. Double mutant analysis showed that dopA interacts genetically with constitutively active and inactive forms of A. nidulans Aras to modulate hyphal morphogenesis and asexual development.

Amino Acid Sequence↗
PubMed1995

L-dopa inhibits complex IV of the electron transport chain in catecholamine-rich human neuroblastoma NB69 cells.

L-3,4-Dihydroxyphenylalanine (L-dopa) is toxic for human neuroblastoma cells NB69 and its toxicity is related to several mechanisms including quinone formation and enhanced production of free radicals related to the metabolism of dopamine via monoamine oxidase type B. We studied the effect of L-DOPA on activities of enzyme complexes in the electron transport chain (ETC) in homogenate preparations from the human neuroblastoma cell line NB69. As a preliminary step we compared the activity of ETC in cellular homogenates with that of purified mitochondria from NB69 cells and rat brain. Specific activities for complex I, complex II-III, and complex IV in NB69 cells were, respectively, 65, 96, and 32% of those in brain mitochondria. Complex I activity was inhibited in a dose-dependent way by 1-methyl-4-phenylpyridinium ion with an EC50 of approximately 150 microM. Treatment with 0.25 mM L-dopa for 5 days reduces complex IV activity to 74% of control values but does not change either complex I or citrate synthase. Ascorbic acid (1 mM), which protects NB69 cells from L-dopa-induced neurotoxicity, increases complex IV activity to 133% of the control and does not change other ETC complexes. Ascorbic acid also reverses L-dopa-induced reduction of complex IV activity in NB69 cells. This observation might indicate that the protection observed with ascorbic acid is related to complex IV activation. In vitro incubation with L-dopa (0.125-4 mM) for 2 min produced a dose-dependent reduction of complex IV without change in complex I and II-III activities.

1-Methyl-4-phenylpyridinium↗
PubMed1997

Effects of wild-type and mutated copper/zinc superoxide dismutase on neuronal survival and L-DOPA-induced toxicity in postnatal midbrain culture.

Mutations in the free radical-scavenging enzyme copper/zinc superoxide dismutase (Cu/Zn-SOD) are associated with neuronal death in humans and mice. Here, we examine the effects of human wild-type (WT SOD) and mutant (Gly93 --> Ala; G93A) Cu/Zn-SOD enzyme on the fate of postnatal midbrain neurons. One-week-old cultures from transgenic mice expressing WT SOD enzyme had significantly more midbrain neurons and fewer necrotic and apoptotic neurons than nontransgenic cultures. In contrast, 1-week-old cultures from transgenic G93A mice expressing mutant SOD enzyme had significantly fewer midbrain neurons and more necrotic and apoptotic neurons than nontransgenic cultures. To subject postnatal midbrain neurons to oxidative stress, cultures were incubated with L-DOPA. L-DOPA at 200 microM caused approximately 50% loss of tyrosine hydroxylase (TH)-positive neurons in nontransgenic cultures and even greater loss in transgenic G93A cultures; no alterations were noted in GABA neuron numbers. In contrast, 200 microM L-DOPA did not cause any significant reductions in TH-positive or GABA neuron numbers in transgenic WT SOD cultures. L-DOPA at 50 microM had opposite effects, in that it significantly increased TH-positive, but not GABA neuron numbers in transgenic WT SOD and G93A and in nontransgenic cultures. These results indicate that increased amounts of WT SOD enzyme promote cell survival and protect against L-DOPA-induced dopaminergic neurotoxicity, whereas increased amounts of mutated Cu/Zn-SOD enzyme have inverse effects. As the spontaneous loss and L-DOPA-induced loss of postnatal dopaminergic midbrain neurons appear to be mediated by free radicals, our study supports the view that mutated Cu/Zn-SOD enzyme kills cells by oxidative stress.

Age Factors↗
PubMed1997

L-DOPA is a substrate for tyrosine hydroxylase.

In the presence of thiols, tyrosine hydroxylase (TH) oxidizes L-dihydroxyphenylalanine (L-DOPA) with a specific activity of up to 140 nmol min(-1) mg(-1) at 37 degrees C and pH 7.0, which is approximately 12-50% of its TH activity under similar experimental conditions. Using assay conditions that are optimal for measuring TH activity, the specific DOPA oxidase activity of human TH is similar to that of mushroom tyrosinase, but the two enzymes are clearly different in terms of substrate specificities, cofactor dependencies, and selectivity with respect to the effects of metal chelators and other inhibitors. In the presence of an excess of dithiothreitol, 2-mercaptoethanol, cysteine, or reduced glutathione, the reaction products of the two enzymes are identical and have been identified tentatively as thioether derivatives of DOPA. Theoretically, the oxidation of L-DOPA by TH may contribute to the formation of neuromelanin (pheomelanin) in catecholaminergic neurons and in the metabolism of DOPA to reactive intermediates that can react with free thiol groups in cellular proteins. The DOPA oxidase activity of TH can lead to errors in the estimation of in vivo or in vitro TH activity, and currently used assay protocols may have to be modified to avoid interference from this activity.

Antioxidants↗
PubMed1989

[The problems of L-dopa therapy in the course of Parkinson syndrome].

UNLABELLED: 101 patients with Parkinson's disease were analyzed in a retrospective study to evaluate the influence of L-Dopa monotherapy, duration of the disease and age at onset on the clinical course of the syndrome. The effects of L-Dopa dosage adjustments after hospitalization were particularly considered. RESULTS: patients with late onset of symptoms showed a more accelerated deterioration as compared to those with early manifestation of the disease who also were less severely affected. Patients treated with L-Dopa for more than five years had a greater neurological deficit score than patients who had not received L-Dopa. Besides a more severe course, these patients also exhibited significantly more dyskinesias and on-off-phenomena. It should be emphasized that in our study, 73% of the 101 patients had been treated inadequately prior to admission to our clinic. The extent of neurological deficit could be improved by L-Dopa dose adjustments in those cases. Only in 11% of cases, an augmentation of the dopa medication was found to be effective in improving the clinical syndrome, whereas in 43%, a substantial reduction of dosage was necessary and resulted in a marked improvement of the clinical syndrome.

Adult↗
PubMed1987

Local cerebral metabolic effects of L-dopa therapy in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-induced parkinsonism in monkeys.

The quantitative 2-deoxy[14C]glucose autoradiographic method was used to map the distribution of alterations in local cerebral glucose utilization that accompanies clinically effective chronic L-dopa therapy of rhesus monkeys made parkinsonian by the administration of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). This pattern of changes was compared to the effects of a similar treatment regimen in normal monkeys. L-Dopa (100 mg with 10 mg carbidopa) was administered orally to normal and parkinsonian monkeys 3 times daily for 60-120 days prior to measurement of local cerebral glucose utilization. In parkinsonian monkeys treated with L-dopa, signs and symptoms of parkinsonism were controlled or suppressed, and widespread increases in glucose utilization were seen throughout the brain. Cerebral metabolic activity was increased both in areas rich in dopaminergic receptors, such as the caudate and putamen, and in nondopaminergic areas involved in motor functions. In many structures the rates of glucose utilization in L-dopa-treated parkinsonian monkeys were increased to levels that far exceeded rates measured in normal monkeys. In sharp contrast, similar treatment with L-dopa in normal monkeys had little if any effect on local cerebral glucose utilization. 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.

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine↗
PubMed1983

Blood pressure and vasopressin in progressive autonomic failure. Response to postural stimulation, L-dopa and naloxone.

UNLABELLED: We showed previously that patients with progressive autonomic failure with multiple system atrophy (MSA) failed to excrete a water load while they were standing, suggesting abnormal postural regulation of vasopressin release. The rise of plasma arginine vasopressin (AVP) with upright posture is modulated by central dopamine and opioid receptors. Patients with MSA may have depletion of brain dopamine and opioid peptides. We measured the plasma levels of AVP in patients with MSA and control subjects during postural stimulation by head-up tilt and the inhibition of this rise in AVP by L-DOPA (dopamine precursor) and naloxone (opiate antagonist). Since L-DOPA and naxolone can alleviate hypotension, we also studied the effects of these agents on orthostatic hypotension. Plasma AVP concentration of normal subjects rose progressively over 90 min of head-up tilt and this postural rise in AVP was abolished by L-DOPA and naloxone. Patients with MSA had similar levels of AVP while horizontal. However, they showed a severely blunted postural AVP response since their levels rose to only 10 per cent of the rise in the normal subjects despite the additional stimulus to AVP secretion of considerable postural hypotension. They also showed no inhibition of AVP secretion by L-DOPA or naloxone. Naloxone did not alter the blood pressure of either group. Although L-DOPA did not change the blood pressure of normal subjects, it lowered it in patients with MSA both while they were horizontal and tilted. IN CONCLUSION: (1) the postural stimulation of AVP release is blunted in MSA; (2) this postural rise in AVP is not inhibited by a dopamine agonist or opioid antagonist in MSA suggesting loss of dopaminergic and opioid pathways involved in AVP release; (3) endogenous opioids do not contribute to orthostatic hypotension in MSA; (4) patients with MSA are supersensitive to the hypotensive effects of an acute L-DOPA infusion.

Aged↗
PubMed2002

Striatal and extrastriatal dysfunction in Parkinson's disease with dementia: a 6-[18F]fluoro-L-dopa PET study.

We investigated the relative differences in dopaminergic function through the whole brain in patients with Parkinson's disease without dementia (PD) and with dementia (PDD) using 6-[18F]fluoro-L-dopa (18F-dopa) PET and a voxel-by-voxel analysis. The 10 PD and 10 PDD patients were equivalently disabled, having mean scores of 3.2 +/- 0.6 and 3.2 +/- 0.7, respectively, on the Hoehn and Yahr rating scale. 18F-dopa influx constant (Ki) images of those patients and 15 normal age-matched subjects were transformed into standard stereotactic space. The significant differences between the groups (expressed in mean regional Ki values) were localized with statistical parametric mapping (SPM) on a voxel-by-voxel basis. Compared with the normal group, SPM localized declines of the 18F-dopa Ki bilaterally in the putamen, the right caudate nucleus and the left ventral midbrain for the PD group (P < 0.01, corrected). Compared with the normal group, the PDD group showed reduced 18F-dopa Ki bilaterally in the striatum, midbrain and anterior cingulate area (P < 0.01, corrected). A relative difference in 18F-dopa uptake between PD and PDD was the bilateral decline in the anterior cingulate area and ventral striatum and in the right caudate nucleus in the PDD group (P < 0.001, corrected). Accordingly, we conclude that dementia in PD is associated with impaired mesolimbic and caudate dopaminergic function.

Aged↗
PubMed2004

Therapeutic doses of L-dopa reverse hypersensitivity of corticostriatal D2-dopamine receptors and glutamatergic overactivity in experimental parkinsonism.

Levodopa (l-dopa) therapy is still considered the gold-standard in the treatment of Parkinson's disease. However, the synaptic and cellular mechanisms involved in the amelioration of motor symptoms during this treatment are still unclear. To address this issue, we analysed the physiological and pharmacological properties of striatal glutamatergic and GABAergic synaptic transmission in an experimental model of Parkinson's disease. Single-cell recordings were performed in sham-operated rats, in 6-hydroxydopamine-lesioned animals and in rats receiving chronic l-dopa treatment following dopamine (DA) denervation. We utilized a dose of l-dopa (10 mg/kg, twice daily for 21 days) able to reverse motor deficits in about half of parkinsonian animals. In the striatum of parkinsonian animals showing therapeutic benefits following l-dopa treatment, we observed a reversal of glutamatergic overactivity and of the hypersensitivity of presynaptic D2 DA receptors controlling glutamate release from corticostriatal terminals. Conversely, no change was detected in the sensitivity of presynaptic D2 DA receptors modulating striatal GABA transmission in both parkinsonian and l-dopa-treated rats. We suggest that the reversal of striatal glutamatergic overactivity and the normalization of hypersensitive D2 DA receptors modulating excitatory transmission might underlie some of the therapeutic actions of l-dopa in Parkinson's disease.

Animals↗
PubMed1992

Induction of social dominance by L-dopa treatment in Arctic charr.

The effect of L-dopa on social dominance was studied in the juvenile Arctic charr (Salvelinus alpinus). L-dopa is the immediate precursor of dopamine, a neurotransmitter that has been connected with aggressive behaviour in fish as well as mammals. Arctic charr were placed in pairs. One individual in each pair was given L-dopa orally, while the other was given vehicle. The results showed that 18 out of 22 fish given 10 mg L-dopa kg-1 became dominant (p = 0.004, binomial test). A higher dose of L-dopa (200 mg kg-1) induced dyskinesia. L-dopa was found to cause a dose-dependent increase in the brain levels of dopamine and 3,4-dihydroxyphenylacetic acid (DOPAC, a major dopamine metabolite), as well as an increase in the DOPAC/dopamine ratio (an index of dopaminergic activity).

Aggression↗
PubMed1996

Glia conditioned medium protects fetal rat midbrain neurones in culture from L-DOPA toxicity.

L-DOPA kills dopamine neurones in culture but is the most effective drug for the treatment of Parkinson's disease, where it exhibits no clear toxicity. While glial cells surround and protect neurones in vivo, neurones are usually cultured in vitro in the absence of glia. We treated fetal midbrain rat neurones with L-DOPA, mesencephalic glia conditioned medium (CM) and L-DOPA + CM. L-DOPA reduced the number of tyrosine hydroxylase-positive (TH+) cells and [3H]DA uptake, and increased quinone levels. L-DOPA + CM restored [3H]DA uptake and quinone levels to normal, and increased the number of TH+ cells and terminals to 170% of control. CM greatly increased the number of TH+ cells and [3H]DA uptake. Mesencephalic glia therefore produced soluble factors which are neurotrophic for dopamine neurones, and which protect these neurones from the toxic effects of L-DOPA.

Animals↗
PubMedDate not supplied

Methylphenidate increases the motor effects of L-Dopa in Parkinson's disease: a pilot study.

We determined whether methylphenidate, a dopamine transporter blocker, modifies motor, cognitive, or affective responses to L-Dopa in Parkinson's disease (PD). Five patients who reported benefit from L-Dopa/carbidopa and motor fluctuations were admitted and withdrawn from their usual antiparkinsonian medications. On 3 consecutive days in a randomized double-blinded fashion, they took 0.2 mg/kg oral methylphenidate or placebo followed 30 minutes later by a 1-hour intravenous L-Dopa (2 mg/kg per h) or placebo infusion. Vital signs, tapping, walking, dyskinesias, mood, anxiety, concentration, and arousal were monitored every 30 minutes. Cognitive testing was performed before and following the infusion. Methylphenidate combined with L-Dopa led to greater peak right-hand tapping speed than either alone. Dyskinesia severity increased most when methylphenidate and L-Dopa were co-administered. There were no differences between conditions on the Stroop test, digit ordering, simple reaction time, or covert orienting of attention validity effect. Methylphenidate alone led to improvement in choice reaction time. Change in self-assessed analogue ratings of mood, anxiety, arousal, or concentration did not differ between conditions. Methylphenidate increased the motor effects of L-Dopa with minimal effects on cognitive or affective functions, suggesting a physiologic role for the dopamine transporter in patients with PD with motor fluctuations.

Aged↗
PubMedDate not supplied

Mirtazapine in L-dopa-induced dyskinesias.

Mirtazapine is a novel antidepressant with a pharmacologic profile (alpha-2 antagonist, 5HT-(1A) agonist, and 5HT-(2) antagonist) that renders it potentially useful for l-dopa-induced dyskinesias. Drugs with 5HT-(1A) agonistic activity, such as buspirone and tandospirone, have been reported to be effective in reducing l-dopa-induced dyskinesias. Furthermore, 5HT-(2) antagonism may, by reducing substantia nigra pars reticulata hyperactivity, play a role in the improvement of Parkinsonian symptoms and l-dopa-induced dyskinesias, as has been observed with ritanserin, a 5HT-(2) antagonist. Alpha-2 antagonists, such as idazoxan, have recently also been reported to improve l-dopa-induced dyskinesias. The authors investigated the antidyskinetic properties of mirtazapine by designing an open-label study of 20 Parkinsonian patients with l-dopa-induced dyskinesias. Mirtazapine proved to be moderately effective in reducing l-dopa-induced dyskinesias, either alone or in association with amantadine. Mirtazapine may be of use in patients who do not respond or are intolerant to amantadine.

Aged↗
PubMed2002

Mitogenic effect of L-dopa on human periodontal ligament fibroblast cells.

In cases of tooth avulsion, immediate replantation is the treatment of choice. In the event of any problem, the tooth should be stored in a medium that supports the periodontal ligament cell viability. Theoretically, mitotic promoting agents may be of use to preserve cell viability. It has previously been reported that levodopa (L-dopa) accelerates healing by increasing the growth hormone level. In this study, the direct effect of L-dopa was investigated on human periodontal ligament fibroblast (HPLF) cells. Cell culture methods were used to assess the potential mitogenic effect of L-dopa. Results show that in low concentrations of L-dopa (1 microgram/microl in this study), the number of HPLF cells were remarkably higher than the control group, and the number of viable cells were not affected by increasing the L-dopa concentration in the range of the study. These results suggest that L-dopa can also have a direct local effect on the growth of HPLF cells. These results may be of use clinically to increase the viability of HPLF cells in cases of an avulsed tooth preserved in storing medium.

Cells, Cultured↗
PubMed2003

Evaluation of the serum L-dopa/L-tyrosine ratio as a melanoma marker.

A wide range of molecules have been investigated as tumour markers in melanoma, most of which are not suitable for use by clinical oncologists for the detection of fast and unpredictable metastatic dissemination. We have already shown that the serum L-dopa/L-tyrosine ratio (an index of tyrosinase functional activity) correlates with the tumour burden and in some cases predicted disease progression in metastatic melanoma patients. We examined the potential value of this ratio for the follow-up, therapy monitoring and prognosis in melanoma compared with a reference marker (S100B, a melanoma-associated antigen). Sixty melanoma patients (24 stage I-II, 18 stage III, 18 stage IV, American Joint Committee on Cancer staging) were entered into the study, sampled two to eight times (before and after therapy) and were followed for up to 30 months. Serum L-dopa and L-tyrosine were determined by high performance liquid chromatography and S100B by an immunoluminometric assay. In stage III patients with elevated marker concentration, lymph node dissection decreased the S100B level (from 0.27 to < 0.13 microg/l, P=0.008), but not the L-dopa/L-tyrosine ratio. Chemotherapy decreased the L-dopa/L-tyrosine ratio by 38% (P =0.04) and the S100B level by 45% (P = 0.02) in stage IV responders. During follow-up, patients with marker levels within normal limits (n=19) had stable disease, except for two stage II patients. In patients with progressive disease (n=20), an increase in one or both markers was observed. Stage IV patients with high L-Dopa/L-Tyrosine ratio (above 20 x 10-5) at inclusion had shorter survival (3 months), while patients with low levels had longer survival (15 months). Levels of S100B had no impact on survival, as all stage IV patients (with levels below or above 0.38 microg/l) had the same survival (5 months). The serum L-dopa/L-tyrosine ratio may be influenced by successful therapy and levels at inclusion may correlate with prognosis in stage IV patients. Levels of these two markers in other biological fluids such as cerebrospinal fluid and tumour exudates may be useful diagnostically and prognostically in difficult cases.

Adult↗
PubMed1975

Inability of murine melanoma melanosomal "tyrosinase" (L-dopa oxidase) to oxidize tyrosine to melanin in polyacrylamide gel systems.

Melanosomal "tyrosinase" (L-dopa) was isolated from trypsin digest of B-16 mouse melanoma melanosomes, using polyacrylamide gel disc electrophoresis. The enzyme was represented by a single band, having characteristics similar to the T1 dopa-positive band observed when using supernatants of crude melanoma homogenates as the source. When gels with this band were incubated in solutions containing tyrosine and dopa in varying ratios , there was no enhancement of melanin formation by tyrosine when compared with incubations in corresponding concentrations of dopa alone. These data further support previous studies in our laboratory demonstrating an inability of so-called mamalian "tyrosinase" to convert tyrosine to melanin; since this enzyme readily converts L-dopa to melanin, it seems more reasonable to term this enzyme an L-dopa oxidase.

Animals↗
PubMed1980

Evaluation of two inhibitory tests (nomifensine and L-dopa + carbidopa) for the diagnosis of hyperprolactinaemic states.

It has been reported that administration of nomifensine (Nom) or of L-dopa + carbidopa (L-dopa + Carb) potentiates central dopaminergic tonus, resulting in decreased prolactin (PRL) secretion. It has been proposed that these drugs would help to discriminate patients with PRL-secreting pituitary tumours from those with so-called 'functional' hyperprolactinaemia. In this study, oral Nom (200 mg) was given to forty-three hyperprolactinaemic patients and L-dopa + Carb (50 mg Carb every 6 h for four doses followed by L-dopa 100 mg and Carb 35 mg) to thirty of them and both treatment to ten normal subjects. The hyperprolactinaemic patients were divided into four clinical groups. Group A, twenty patients with proven PRL-secreting pituitary tumours; Group B, thirteen women with elevated PRL levels (less than 100 ng/ml) without any radiological evidence of a pituitary tumour (hyperprolactinaemia of unknown aetiology or 'functional' hyperprolactinaemia); Group C, four women with polycystic ovarian disease and mildly elevated serum PRL; Group D, six patients with various other disorders associated with hyperprolactinaemia. PRL levels decreased in the normal controls below the basal values by 61.3% +/- 6.2 (SEM) after Nom and 77.6% +/- 4.2 after L-dopa + Carb. Decreases in serum PRL of at least 50% (in three consecutive determinations) were found in group A in 20% of patients after Nom and in 25% after L-dopa + Carb; in group B in 15% and 40% of cases; in most of the hyperprolactinaemic women in group C; and some in group D. In conclusion, these two treatments did not discriminate between tumorous and non-tumorous cases of PRL hypersecretion.

Adenoma↗