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PubMed1980

Larvicidal activity of inhibitors of DOPA decarboxylase on the Australian sheep blowfly, Lucilia cuprina.

Inhibitors of DOPA decarboxylase, the key enzyme in the formation of the sclerotizing agent (N-acetyl dopamine) of the blowfly cuticle, have been tested for larvicidal activity against L. cuprina. A significant level of DOPA decarboxylase activity has been shown to be present throughout larval life in this species. Four potent in vitro inhibitors of L. cuprina larval DOPA decarboxylase (carbidopa, benserazide, methyl tyrosine and methyl DOPA) have been shown to be effective larvicides when fed to first- or second-instar larvae. However, no correlation is seen between the apparent Ki and LD50 values for these compounds. Treated larvae are observed to die at the next moult but death can be averted by the addition of N-acetyl dopamine to the food. Thus the toxic effects of the DOPA decarboxylase inhibitors appear to result from an inhibition of the formation of the sclerotizing agent in the cuticles of treated larvae.

Animals↗
PubMed1998

Regulation of dopa decarboxylase expression during colour pattern formation in wild-type and melanic tiger swallowtail butterflies.

The eastern tiger swallowtail butterfly Papilio glaucus shows a striking example of Batesian mimicry. In this species, females are either wild type (yellow and black) or melanic (where most of the yellow colour is replaced by black). In order to understand how these different colour patterns are regulated, we examined the temporal order of wing pigment synthesis via precursor incorporation studies, enzyme assays, and in situ hybridisation to mRNA encoding a key enzyme, dopa decarboxylase. We show that dopa decarboxylase provides dopamine to both of the two major colour pigments, papiliochrome (yellow) and melanin (black). Interestingly, however, dopa decarboxylase activity is spatially and temporally regulated, being utilised early in presumptive yellow tissues and later in black. Further, in melanic females, both dopa decarboxylase activity and early papiliochrome synthesis are suppressed in the central forewing and this normally yellow area is later melanised. These results show that the regulation of enzyme synthesis observed in the yellow/black pattern of a single wing, is similar to that involved in melanism. We infer that dopa decarboxylase activity must be regulated in concert with downstream enzymes of either the melanin and/or the papiliochrome specific pathways, forming part of a developmental switch between yellow or black. This modification of multiple enzyme activities in concert is consistent with a model of melanisation involving coordinate regulation of the underlying synthetic pathways by a single Y-linked (female) factor.

Animals↗
PubMed2000

Reaction of dopa decarboxylase with L-aromatic amino acids under aerobic and anaerobic conditions.

Analysis of the reaction of dopa decarboxylase (DDC) with L-dopa reveals that loss of decarboxylase activity with time is observed at enzyme concentrations approximately equal to the binding constant, K(d), of the enzyme for pyridoxal 5'-phosphate (PLP). Instead, at enzyme concentrations higher than K(d) the course of product formation proceeds linearly until complete consumption of the substrate. Evidence is provided that under both experimental conditions no pyridoxamine 5'-phosphate (PMP) is formed during the reaction and that dissociation of coenzyme occurs at low enzyme concentration, leading to the formation of a PLP-L-dopa Pictet-Spengler cyclic adduct. Taken together, these results indicate that decarboxylation-dependent transamination does not accompany the decarboxylation of L-dopa proposed previously [O'Leary and Baughn (1977) J. Biol. Chem. 252, 7168-7173]. Nevertheless, when the reaction of DDC with L-dopa is studied under anaerobic conditions at an enzyme concentration higher than K(d), we observe that (1) the enzyme is gradually inactivated and inactivation is associated with PMP formation and (2) the initial velocity of decarboxylation is approximately half of that in the presence of O(2). Similar behaviour is observed by comparing the reaction with L-5-hydroxytryptophan occurring in aerobiosis or in anaerobiosis. Therefore the reaction of DDC with L-aromatic amino acids seems to be under O(2) control. In contrast, the reactivity of the enzyme with L-aromatic amino acids does not change in the presence or absence of O(2). These and other results, together with previous results on the effect exerted by O(2) on reaction specificity of DDC towards aromatic amines [Bertoldi, Frigeri, Paci and Borri Voltattorni (1999) J. Biol. Chem. 274, 5514-5521], suggest a productive effect of O(2) on an intermediate complex of the reaction of the enzyme with L-aromatic amino acids or aromatic amines.

5-Hydroxytryptophan↗
PubMed2000

Surface-enhanced Raman spectroscopy of DOPA-containing peptides related to adhesive protein of marine mussel, Mytilus edulis.

The common blue marine mussel adheres to underwater surfaces using an adhesive protein (Mefp-1) extruded from its foot. This highly hydroxylated protein contains a number of unusual amino acids, including 3,4-dihydroxyphenylalanine (DOPA), which is thought to contribute to the crosslinking of the extruded threads and adhesion to the substratum. Mefp-1 adheres to a wide variety of surfaces and is ultimately biodegradable. In this study we use surface-enhanced Raman spectroscopy (SERS) to characterize the adsorption of DOPA-containing peptides on colloidal gold. The peptides are simplified fragments of the Mefp-1 consensus decapeptide repeat, Ala-Lys-Pro-Ser-Tyr-DHP-Hyp-Thr-DOPA-Lys. Our results show that the peptides TDeltaKA, PTDeltaKA, and PPTDeltaKA (where Delta represents DOPA) coordinate to the gold surface through the catechol oxygens of the DOPA residue and through primary amine groups. The diproline sequence introduces conformational constraints that influence the conformations of the adsorbed peptides. These findings lay the groundwork for developing synthetic adhesives for underwater and medical applications.

Adhesives↗
PubMed2000

Beneficial effects of amantadine on L-dopa-induced dyskinesias in Parkinson's disease.

L-Dopa-induced dyskinesias constitute a challenge to the management of advanced Parkinson's disease. According to recent reports, treatment with the NMDA receptor antagonist amantadine may significantly diminish L-dopa-induced dyskinesias. In the present study, the effect of amantadine on L-dopa-induced dykinesias was assessed in a 5-week, double-blind crossover trial. Dyskinesia severity as assessed following oral L-dopa challenges and by self-scoring dyskinesia diaries were reduced approximately 50% after amantadine treatment compared with baseline or placebo phases. Similarly, dyskinesia assessments on the Unified Parkinson's Disease Rating Scale, part IV (items 32 and 33) also revealed significant improvement after treatment with amantadine. The magnitude of the L-dopa motor response to oral challenges was not different after amantadine or placebo treatment, and there was no significant reduction of daily off-time when patients received active treatment. These results confirm previous observations concerning the antidyskinetic potential of amantadine.

Aged↗
PubMed1986

Pigment cell pattern formation in amphibian embryos: a reexamination of the dopa technique.

Neural crest-derived melanophores form species-specific patterns in the dermis of amphibian embryos. Melanophore patterns may be generated by one of two general mechanisms: pigment cell precursors disperse throughout the embryo, with melanophores differentiating in certain regions due to environmental cues, or melanoblasts may localize in different regions as a result of a hierarchy of tissue affinities. Both of these mechanisms have been proposed to be responsible for the dorso-ventral patterning of melanophores in Xenopus laevis. We have reexamined the distribution of melanoblasts in X. laevis and Taricha torosa using the dopa (3,4-dihydroxyphenyl-alanine)-staining technique. We have found that many of the dopa-positive cells identified as melanoblasts by some researchers are actually not derived from the neural crest: dopa-positive cells in T. torosa were identified in the transmission electron microscope to be either leukocytes or erythrocytes, in X. laevis dopa-positive cells are found between the ectoderm and somites where neural crest cells are not found, and X. laevis embryos surgically depleted of neural crest have dopa-staining patterns identical to control embryos. Melanoblasts are apparently not found in the ventralmost regions of early T. torosa and X. laevis embryos, providing additional evidence for the role of differential tissue affinities in directing the formation of embryonic pigment cell patterns.

Animals↗
PubMed2005

Sydney Multicenter Study of Parkinson's disease: non-L-dopa-responsive problems dominate at 15 years.

One-third of the 149 people recruited 15 to 18 years ago in the Sydney Multicenter Study of Parkinson's disease have survived. The original study compared low-dose levodopa with low-dose bromocriptine. We now report the problems experienced by people who survive 15 years from diagnosis. The standardized mortality ratio is significantly elevated at 1.86 and is not significantly different between treatment arms. Falls occur in 81% of patients, and 23% sustained fractures. Cognitive decline is present in 84%, and 48% fulfill the criteria for dementia. Hallucinations and depression are experienced by 50%. Choking has occurred in 50%, symptomatic postural hypotension in 35%, and urinary incontinence in 41%. No patient is still employed, and 40% of patients live in aged care facilities. Although approximately 95% have experienced L-dopa-induced dyskinesia/dystonia and end of dose failure of medication, in the majority, these symptoms are not disabling. Dyskinesia and dystonia were delayed by early use of bromocriptine, but end-of-dose failure appeared at a similar time once L-dopa was added. The rate of disease progression is similar in both arms of the study. We conclude that the most disabling long-term problems of Parkinson's disease relate to the emergence of symptoms that are not improved by L-dopa. Neuroprotective interventions in Parkinson's disease should be judged by their ability to improve non-L-dopa-responsive aspects of the disease, rather than just by their capacity to delay the introduction of L-dopa or reduce its associated side effects.

Aged↗
PubMed1988

Comparison between L-dopa and lisuride intravenous infusions: a clinical study.

L-Dopa is still the most effective drug for the treatment of Parkinson's Disease, but after 5 years or more of therapy fluctuations in motor performance and abnormal involuntary movements commonly appear. Continuous intravenous infusions of L-Dopa abolish or strikingly reduce such fluctuations. Unfortunately, this is not suitable for daily treatment because of the low solubility of L-Dopa. Lisuride is a potent dopamine agonist and is very soluble in water. In this study the clinical effects of L-Dopa and lisuride continuous intravenous infusions were compared in a group of 20 fluctuating parkinsonian patients. L-Dopa controlled fluctuations in almost all the subjects, whereas only seven patients were continuously mobile while taking lisuride. Another seven patients showed a fluctuating response and the remaining six did not satisfactorily respond to lisuride. Dyskinesias were present in all patients during "on" phases, with both levodopa and lisuride treatment.

Adult↗
PubMed1993

Single-dose L-dopa response in early Parkinson's disease: measurements with optoelectronic recording technique.

Twenty-five patients with suspected Parkinson's disease were submitted to optoelectronic movement analysis with the Posturo-Locomotor-Manual (PLM) test before and 60 min after a single dose of L-Dopa. They were then examined clinically for diagnosis. Two patients were excluded due to L-Dopa intolerance. Seventeen of the remaining patients were classified as having Parkinson's disease. The movement time (MT) in the PLM test was increased for all these patients, and they improved their performance after L-Dopa. The degree of improvement was roughly proportional to the pretreatment augmentation of MT in comparison to healthy subjects of the same age. The PLM phase analysis showed a specific disability profile for each individual. Six patients were given diagnoses other than PD. Some improvement was found in one patient with suspected olivopontocerebellar atrophy and one patient with multiple brain injury. Two patients with progressive supranuclear palsy, one with suspected striatonigral degeneration, and one with functional disturbance deteriorated after L-Dopa. In conclusion, truly objective and fully reproducible evaluation of the motor performance before and after a single L-Dopa dose is easily accomplished with computer-assisted modern optoelectronic recording equipment. The technique is a valuable tool for the quantitative measurement of treatment effects and contributes to the differential diagnosis.

Adult↗
PubMed1993

Suppressive effect of L-dopa on dopamine cells remaining in the ventral tegmental area of rats previously exposed to the neurotoxin 6-hydroxydopamine.

Ever since the introduction of levo-3,4-dihydroxyphenylalanine (L-dopa) for the treatment of Parkinson's disease, there has been concern that it might accelerate the degeneration of dopamine neurones. Using rats with a unilateral 6-hydroxydopamine (6-OHDA) lesion of the medial forebrain bundle (MFB), we have studied the effect of chronic L-dopa treatment on the survival of dopamine cells which remain in the ventral tegmental area (VTA) ipsilateral to a 6-OHDA lesion. Following lesion surgery, rats were treated with L-dopa and carbidopa administered in the drinking water for 27 weeks. At the end of the treatment period, the number of dopamine cells remaining in each of the lesioned and intact substantia nigra (SN) and VTA were assessed, using tyrosine hydroxylase immunohistochemistry. Chronic L-dopa treatment resulted in an apparent reduction in the number of dopamine neurones remaining in the VTA ipsilateral to the lesion, whereas it had no effect on the number of dopamine cells remaining in the intact SN and VTA. This finding suggests a possible suppressive effect in vivo of L-dopa on dopamine cells in the midbrain of adult animals that have been previously exposed to 6-OHDA.

Animals↗
PubMed1998

Asymmetry of basal ganglia glucose metabolism and dopa responsiveness in parkinsonism.

We investigated, by positron emission tomography (PET) with [18F]fluoro-2-deoxy-d-glucose (FDG) (FDG-PET), brain glucose metabolism in 19 patients with parkinsonian features. We compared local pattern of FDG uptake and asymmetry indexes in patients with therapeutic response to levodopa (L-dopa) (group 1, presumed Parkinson's disease, n = 9) and patients without L-dopa therapeutic response (group 2, presumed striatonigral degeneration, n = 10). Limb dystonia was present in 11% of patients in group 1 and in 40% of patients in group 2. Asymmetry in basal ganglia metabolism was distributed differently in the two groups (analysis of variance, p < 0.04). In superior and inferior putamen, superior and middle caudate, ventral striatum, and inferior thalamus, relative reduction in metabolism on the side contralateral to predominant parkinsonian signs was associated with L-dopa unresponsiveness. On the contrary, in middle caudate, ventral striatum, and inferior thalamus, a relative increase in metabolism on the side contralateral to the predominant side, parkinsonian signs were found in L-dopa-responsive patients. Our FDG-PET study using simple statistical procedures demonstrates inverse asymmetry of basal ganglia glucose metabolism in parkinsonian patients grouped on the sole basis of L-dopa responsiveness.

Adult↗
PubMed1980

DOPA metabolism in neuroblastoma.

Blood plasma samples from 60 neuroblastoma patients prior to, during, and following treatment were studied for their content of circulating DOPA using a radioenzymatic assay. Normal values were established from children who were tumor-free or had other nonneurogenic tumors. The highest plasma DOPA concentration in tumor-free or nonneuroblastoma controls was 5.3 ng/ml with a mean of 2.15 ng/ml. Most neuroblastoma patients (28/31) with active disease had DOPA values above this level. Only one out of 30 "successfully" treated patients without evidence of disease was encountered with an abnormally high level. In treated patients, elevated values forewarned of impending clinical recurrence or persistent tumor. Cerebrospinal fluid DOPA levels in one patient with cerebral neuroblastoma were extraordinarily high and suggests that this assay may prove useful to distinguish neuroblastoma from other central neuroectodermal or metastatic tumors. Plasma DOPA appears to be a reliable predictive and diagnostic test for neuroblastoma.

Adolescent↗
PubMed2002

18F-dopa PET evidence that tolcapone acts as a central COMT inhibitor in Parkinson's disease.

Tolcapone is a potent, selective, and reversible inhibitor of cathecol-O-methyl-transferase (COMT). This enzyme plays a crucial role in the extraneural inactivation of catecholamine neurotransmitters. Tolcapone's ability to inhibit central COMT in humans at therapeutic concentrations is not yet clear. The aim was to determine the effect of tolcapone on central COMT activity in Parkinson's disease (PD) using (18)F-dopa positron emission tomography (PET). The study was a randomized two-way crossover study. Twelve PD patients were recruited. On the treatment days patients were given either tolcapone (200 mg) or placebo together with levodopa/carbidopa (100/125 mg) 1 h before the injection of (18)F-dopa. Data were acquired in 25 frames over 94 min for the first PET scan period. At the end of this period the patients were removed from the scanner for 90 min and subsequently repositioned and data acquired in six 10-min time frames over 60 min. Influx constants (Ki) were computed using a graphical approach with a plasma input function. Mean (18)F-dopa putamen Ki's for the first 30-90 min, primarily reflecting central dopa decarboxylase (DDC) activity, were similar in PD patients whether tolcapone was present (0.0078 +/- 0.0031 min(-1)) or absent (0.0078 +/- 0.0030 min(-1)). Mean putamen Ki values calculated 180-240 min after injection of (18)F-dopa, reflecting both central DDC and COMT activity, were unchanged from 30-90' values in the presence of tolcapone (0.0079 +/- 0.0030), implying blockade of central COMT, but were significantly reduced (0.0059 +/- 0.0028) in the absence of this drug. These findings are compatible with clinical doses of tolcapone having a significant blocking effect on peripheral and central COMT but not DDC activity in PD.

Aged↗
PubMed2004

Upregulation of striatal adenosine A2A receptor mRNA in 6-hydroxydopamine-lesioned rats intermittently treated with L-DOPA.

To determine whether the adenosine A2A receptor might play a role in L-DOPA-induced dyskinesia in Parkinson's disease, we analyzed changes in the expression of A2A receptor mRNA in response to intermittent treatment with L-DOPA in rats with dopaminergic denervation by 6-hydroxydopamine (OHDA) infusion into the medial forebrain bundle. Intermittent treatment with L-DOPA increased A2A receptor mRNA levels in the dopamine-depleted striatum of 6-OHDA-lesioned rats exhibiting behavioral sensitization to L-DOPA. These results suggest that A2A receptor activation is associated with the development of motor complications induced by L-DOPA treatment.

Animals↗
PubMed2000

Effect of acute L-Dopa pretreatment on apomorphine-induced rotational behavior in a rat model of Parkinson's disease.

Currently, reduction of apomorphine-induced rotational behavior in the 6-hydroxydopamine (6-OHDA) lesioned rat is the most utilized drug-induced paradigm for assessing functional efficacy in a rat model of Parkinson's disease (PD). Any clinically predictive animal model of PD should include a positive response to l-dopa, the standard pharmacotherapy for PD. However, the acute interaction between L-dopa and apomorphine has never been studied to determine if L-dopa pretreatment could reduce apomorphine-induced rotational behavior in a 6-OHDA lesioned rat. The present study was designed to explore whether, indeed, pretreatment with subrotational doses of L-dopa could inhibit apomorphine-induced rotations. The data indicate that L-dopa significantly reduced apomorphine-induced rotational behavior only at one dose (5.0 mg/kg) for 12 min. Based on these and other data, it is concluded that although the apomorphine-induced rotational paradigm may continue to be utilized as one additional indicator of efficacy in the 6-OHDA rat model of PD, it is not in itself a completely valid functional assay.

Animals↗
PubMed2000

The expression of the calcium binding protein calretinin in the rat striatum: effects of dopamine depletion and L-DOPA treatment.

The activity of the striatum is regulated by glutamate and dopamine neurotransmission. Consequent to striatal dopamine depletion the corticostriatal excitatory input is increased, which in turn can raise intracellular calcium levels. We investigated changes in the neuronal expression of the calcium binding protein calretinin related to dopamine depletion and l-DOPA administration. Immunohistochemical methods were used to assess calretinin in the striatum of rats with unilateral lesions of the nigrostriatal system. In these animals we observed a loss of the patchy distribution of calretinin fibers. Moreover, after dopaminergic depletion we detected two new, not previously described, calretinin cell types, the presence of which could be related to morphological changes induced by loss of a dopaminergic input. We also found an increase in the number of calretinin-labeled cells in the striatum ipsilateral to the lesion compared to the contralateral striatum or to the striatum of normal rats. This increase was mostly evident at 3 weeks postlesion and tended to decrease toward normal levels at 6, 10, and 18 weeks postlesion. In unlesioned animals, l-DOPA administration did not induce changes in the expression of calretinin. In unilaterally lesioned animals, l-DOPA reversed the increase in the number of calretinin-positive cells induced by the lesion. However, chronic l-DOPA administration was less effective than acute l-DOPA in reversing the effect of the lesion. The present data suggests that striatal calretinin neurons are sensitive to dopamine depletion. Increased expression of calretinin in striatal cells may be consequent to enhanced striatal excitatory input.

Animals↗
PubMed2001

Alterations in cortical and basal ganglia levels of opioid receptor binding in a rat model of l-DOPA-induced dyskinesia.

Opioid receptor-binding autoradiography was used as a way to map sites of altered opioid transmission in a rat model of l-DOPA-induced dyskinesia. Rats with unilateral 6-hydroxydopamine lesions of the nigrostriatal pathways sustained a 3-week treatment with l-DOPA (6 mg/kg/day, combined with 12 mg/kg/day benserazide), causing about half of them to develop dyskinetic-like movements on the side of the body contralateral to the lesion. Autoradiographic analysis of mu-, delta-, and kappa-opioid binding sites was carried out in the caudate-putamen (CPu), the globus pallidus (GP), the substantia nigra (SN), the primary motor area, and the premotor-cingulate cortex. The dopamine-denervating lesion alone caused an ipsilateral reduction in opioid radioligand binding in the CPu, GP, and SN, but not in the cerebral cortex. Chronic l-DOPA treatment affected opioid receptor binding in both the basal ganglia and the cerebral cortex, producing changes that were both structure- and receptor-type specific, and closely related to the motor response elicited by the treatment. In the basal ganglia, the most clear-cut differences between dyskinetic and nondyskinetic rats pertained to kappa opioid sites. On the lesioned side, both striatal and nigral levels of kappa binding densities were significantly lower in the dyskinetic group, showing a negative correlation with the rats' dyskinesia scores on one hand and with the striatal expression of opioid precursor mRNAs on the other hand. In the cerebral cortex, levels of mu and delta binding site densities were bilaterally elevated in the dyskinetic group, whereas kappa radioligand binding was specifically increased in the nondyskinetic cases and showed a negative correlation with the rats' dyskinesia scores. These data demonstrate that bilateral changes in cortical opioid transmission are closely associated with l-DOPA-induced dyskinesia in the rat. Moreover, the fact that dyskinetic and nondyskinetic animals often show opposite changes in opioid radioligand binding suggests that the motor response to l-DOPA is determined, at least in part, by compensatory adjustments of brain opioid receptors.

Animals↗
PubMed2002

L-DOPA-induced dyskinesia in the intrastriatal 6-hydroxydopamine model of parkinson's disease: relation to motor and cellular parameters of nigrostriatal function.

In order to assess the role of striatal dopamine (DA) afferents in L-DOPA-induced dyskinesia, we have studied a large series of rats sustaining 2, 3, or 4 unilateral injections of 6-hydroxydopamine (6-OHDA) in the lateral striatum. This type of lesion produced a dose-dependent depletion of DA fibers in the caudate-putamen, which was most pronounced in the lateral aspects of this structure. An additional group of rats was injected with 6-OHDA in the medial forebrain bundle to obtain complete DA denervation on one side of the brain. During a course of chronic L-DOPA treatment, rats with intrastriatal 6-OHDA lesions developed abnormal involuntary movements (AIMs), which mapped onto striatal domains exhibiting at least approximately 90% denervation, as judged by DA transporter autoradiography. The denervated areas showed local upregulation of preproenkephalin and prodynorphin mRNA, and FosB-like immunoreactivity, which were highly correlated with the rats' AIM scores. When compared to completely DA-denervated animals, the rats with intrastriatal 6-OHDA lesions showed an overall lower incidence, lower severity and different topographic distribution of AIMs. The involvement of proximal limb and axial muscles in the abnormal movements was proportional to the spreading of the lesion from lateral towards medial aspects of the caudate-putamen. Locomotive AIMs were only seen in rats with complete lesions, but not in any of the animals with intrastriatal 6-OHDA (which showed > 5% DA fiber sparing in the medial striatum). Intrastriatally 6-OHDA-lesioned rats had a larger therapeutic window for L-DOPA than did rats with complete bundle lesions, since they exhibited an overall lower predisposition to dyskinesia but a similar degree of drug-induced motor improvement in a test of forelimb stepping. Our results are the first to demonstrate that selective and partial DA denervation in the sensorimotor part of the striatum can confer cellular and behavioral supersensitivity to L-DOPA, and that the phenomenology of L-DOPA-induced rat AIMs can be accounted for by the topography of DA denervation within the caudate-putamen.

Afferent Pathways↗