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PubMed1987

Impaired T-dependent immune response in L-dopa treated BALB/c mice.

Various neurotransmitters and neuropharmacological agents can affect lymphocyte responses. The purpose of the present study was to investigate the potential immunological effects of L-dihydroxyphenylalanine (L-dopa), the direct precursor of dopamine, by examining the influence of the in vivo administration of the drug on different functional and phenotypic parameters in BALB/c mice. L-dopa at the dose of 100 mg/kg/day altered T-dependent immune responses. The antibody response to sheep red blood cells (SRBC) was abolished by the drug. The delayed-type hypersensitivity reaction to SRBC was also depressed. Lymphocyte proliferation and generation of cytotoxic T cells in response to allogeneic stimulator cells in vitro were decreased by L-dopa treatment. These suppressive effects were correlated with a decrease in spleen T cells number. However, the proliferative response of spleen cells to concanavalin A was greatly enhanced by the L-dopa treatment. Conversely, there was no evidence for alteration of T-independent immune responses by L-dopa. Hence, the antibody response to TNP-Ficoll, and the proliferation of B spleen cells induced by E. coli lipopolysaccharide were unchanged. Altogether, these results showed that L-dopa which is converted to dopamine in the organism, could selectively affect T-dependent immune responses. The integration of these findings in the immune-neuroendocrine interactions, and the possible sites and mechanisms of action are discussed.

Animals↗

PubMed1988

Augmentation by L-dopa of growth inhibition and melanin formation of X-irradiated Harding-Passey melanoma cells in culture.

Treatment of exponentially proliferating melanogenic Harding-Passey melanoma cells in monolayer culture (HPM-73 line) with a single dose of X-irradiation (up to 8 Gy) or continuously (for several weeks) with L-3,4-dihydroxyphenylalanine (L-Dopa) up to 5 X 10(-4) M resulted in a dose-dependent inhibition of cell proliferation, but not in death of all cells. Actually, 8 Gy-irradiated or L-Dopa (2 X 10(-4) M)-treated cultures finally reached the cell number and cell density of controls. However, a combination of a single dose of radiation (8 Gy) followed by L-Dopa (2 X 10(-4) M)-treatment resulted in destruction of all cells. Melanin formation was stimulated by L-dopa-treatment or X-irradiation, and was further elevated by the combined application of radiation and L-Dopa-exposure. Whether the effects of exogenously applied L-Dopa, an intermediary metabolite of melanin synthesis, are due to the conversion to growth-inhibitory metabolites (quinones, radicals, etc.) inside or outside the cell, was discussed. The latter might result from release (due to membrane damage or cell disintegration) of tyrosinase or/and melanosomes into the culture medium with the consequence of extracellular synthesis of potentially cytotoxic metabolites from medium substrates. Further, endocytosis of exogenous melanosomes and tyrosinase with potentially harmful effects is feasible. An application of such a combination therapy of melanoma to clinical medicine should be considered.

Animals↗

PubMed1979

Short- and long-term effects of graduated doses of DL-6-OH-DOPA upon marsh mice.

The lethal effects in Marsh mice for a range of DL-6-OH-DOPA levels were ascertained and exceeded those previously reported for 6-OH-DA under comparable conditions. The addition of vitamin "C" to the 6-OH-DOPA solution given intraperitoneally increased the lethal effect, as did the intraperitionel route of injection over that of the subcutaneous. Increased water consumption developed the fourth day for those surviving toxic levels of 6-OH-DOPA given subcutaneously as compared with controls. For all mice initially surviving administration of 6-OH-DOPA, tumorigenesis and long-term survival were of the same order as that of the controls. The toxicity of 6-OH-DOPA relating to ferric heme formation more likely involves metmyoglobin than methemoglobin. The combination of direct damage to sympathetic adrenergic cardiac innervation and metmyoglobin formation appears sufficient to account for the lethal effects of 6-OH-DOPA.

Age Factors↗

PubMed1983

Effect of stress and cholinergic stimulation on ACTH release in alpha-methyl-dopa pretreated rats.

Pituitary-adrenocortical function and the changes of hypothalamic catecholamine content were studied following alpha-methyl-dopa treatment in rats. After three-day administration of alpha-methyl-dopa the plasma corticosterone concentration increased significantly and at the same time ether stress failed to elicit a pituitary-adrenocortical response. Moreover, the alpha-methyl-dopa pretreatment prevented the facilitatory effect of physostigmine on pituitary-adrenocortical activation. As the result of alpha-methyl-dopa treatment the norepinephrine content decreased significantly and the amount of compounds measured as dopamine (dopamine, alpha-methyl-dopamine and alpha-methyl-dopa) increased in the hypothalamus. It is concluded that the impaired metabolism of catecholamines may inhibit the pituitary-adrenocortical activation to stimulation, and that not only norepinephrine and dopamine, but other phenylalanine derivatives and alpha-methyl-dopa may also influence the responsiveness of pituitary-adrenocortical function.

Adrenocorticotropic Hormone↗

PubMed1981

The site of dopamine formation in rat striatum after L-dopa administration.

Unilateral nigrostriatal lesions produced by injecting 6-hydroxydopamine stereotaxically into both the substantia nigra and the medial forebrain bundle reduced striatal tyrosine hydroxylase activity and dopamine (DA) concentrations by 95% (compared with the intact, contralateral striata) but lowered dopa decarboxylase (DDC) activity by only 80%. L-Dopa administration increased DA concentrations in both lesioned and unlesioned sides; absolute increases were higher in control striata and pretreatment with carbidopa (an inhibitor of peripheral DDC) amplified the increases on both sides. Animals given both of the above lesions plus intrastriatal kainic acid injections exhibited a further reduction in DDC activity, i.e., to only 6% of the activity measured in intact, contralateral striata. Kainic acid lesions alone reduced striatal DDC activity by 20%, without affecting striatal tyrosine hydroxylase activity or DA concentrations, and diminished DA formation from exogenous L-dopa. These observations indicate that DA formation from exogenous L-dopa within the striatum occurs mainly, but not exclusively, within DA terminals. Some DA formation persists after most DA neurons have been destroyed; it may occur within kainic acid-sensitive striatal interneurons or efferent neurons. The DA formed outside DA neurons is apparently able to stimulate postsynaptic DA receptors and to mediate some of the behavioral effects of L-dopa, since L-dopa continued to induce circling behavior in animals with unilateral nigrostriatal lesions, even when these lesions approached totality.

Animals↗

PubMed1977

Patterns of dystonia ("I-D-I" and "D-I-D-") in response to l-dopa therapy for Parkinson's disease.

The clinical, biochemical, and pharmacologic responses to L-dopa were studied in 87 patients with Parkinson's disease. Eleven of the 87 patients had a long-duration response, 39 had a short-duration response, and 37 had a combination of both. Thirty-four of the 39 patients with short-duration response to L-dopa experienced a consistent and reproducible sequence of clinical and biochemical events after each dose, characterized by improvement of parkinsonism and a single phase of dystonia occurring during or shortly after the peak of dopa concentration in plasma and during maximal clinical improvement. We have called this the I-D-I- response, for Parkinsonism-Improvement-Dystonia-Improvement-Parkinsonism. The remaining five patients all had the onset of the disease at an unusually young age and showed a distinctly different response pattern consisting of a first phase of dystonia, before there was any improvement, followed by a phase of improvement without dystonia and then by a second phase of dystonia before the abrupt return of parkinsonism. We have called this the D-I-D response, for Parkinsonism-Dystonia-Improvement-Dystonia-Parkinsonsim. Dystonia occurs in the D-I-D- response when the concentration of dopa in plasma passes through a critical but relatively low level, whereas it remains absent as long as the concentration of dopa remains above that level. In the I-D-I- response, dystonia is avoided by keeping the plasma concentration of dopa low, in the D-I-D- response by keeping it high. It is postulated that in the D-I-D response postsynaptic depolarization blockade due to supramaximal stimulation of the neuronal system mediating dystonia occurs, whereas in the I-D-I response the postsynaptic members of the same neuronal population respond with excitation but not with depolarization blockade.

Dose-Response Relationship, Drug↗

PubMed1977

Mediation of enhanced reflex vagal bradycardia by L-dopa via central dopamine formation in dogs.

L-Dopa (5 mg/kg i.v.) decreased blood pressure and heart rate after extracerebral decarboxylase inhibition with MK-486 (25 mg/kg i.v.) in anesthetize MAO-inhibited dogs. In addition, reflex bradycardia caused by injected norepinephrine was significantly enhanced by L-dopa, DL-Threo-dihydroxyphenylserine had no effect on blood pressure, heart rate or reflex responses to norepinephrine. FLA-63, a dopamine-beta-oxidase inhibitor, did not have any effect on the hypotension, bradycardia or reflex-enhancing effect of L-dopa. Pimozide did not affect the actions of L-dopa on blood pressure and heart rate but completely blocked the enhancement of reflexes. Removal of the carotid sinuses caused an elevation blood pressure and heart rate and abolished the negative chronotropic effect of norepinephrine. However, L-dopa restored the bradycardia caused by norepinephrine in addition to decreasing blood pressure and heart rate. 5-HTP (5 mg/kg i.v.) decreased blood pressure and heart rate and decreased the reflex bradycardia to norepinephrine. It is concluded that L-dopa enhances reflex bradycardia through central alpha-receptor stimulation. Furthermore, the effects are mediated through dopamine rather than norepinephrine and do not require the carotid sinus baroreceptors.

Animals↗

PubMed1997

Interactions between a novel cholinergic ion channel agonist, SIB-1765F and L-DOPA in the reserpine model of Parkinson's disease in rats.

SIB-1765F, a novel nicotinic acetylcholine receptor agonist, was tested for its efficacy in attenuating reserpine-induced hypolocomotion in rats. SIB-1765F was administered alone or in combination with L-DOPA and its effects were compared to those of nicotine, d-amphetamine and amantadine in the same conditions. Consistent with previous reports, reserpine-induced hypolocomotion was reversed by L-DOPA (plus benserazide), d-amphetamine and amantadine in a dose-dependent manner and the effect of L-DOPA in reserpine-treated rats was potentiated by amantadine. SIB-1765F also increased the locomotor activity of reserpine-treated rats and potentiated the effect of L-DOPA on reserpine-induced hypolocomotion. The onset of potentiation of L-DOPA by SIB-1765F was rapid (< 5 min) compared to the onset of potentiation by amantadine (> 105 min). Interestingly, nicotine did not attenuate reserpine-induced hypolocomotion nor did it affect the action of L-DOPA on reserpine-treated rats. Biochemical analysis of levels of dopamine and its metabolites, dihydroxyphenylacetic and homovanillic acid, indicated that, in contrast to amphetamine, SIB-1765F did not inhibit dopamine reuptake. The effect of SIB-1765F in reserpine-treated rats was attenuated by alpha-methyl-p-tyrosine, implying that SIB-1765F acts by releasing dopamine from both reserpine-insensitive and reserpine-sensitive pools. Our findings demonstrate that nicotinic acetylcholine receptor agonists may offer a new therapeutic approach to the symptomatic treatment of the motor deficits in patients with Parkinson's disease.

Amantadine↗

PubMed1998

L-DOPA-induced dyskinesia in the rat is associated with striatal overexpression of prodynorphin- and glutamic acid decarboxylase mRNA.

Rats sustaining unilateral near-complete 6-hydroxydopamine lesions of the mesostriatal dopamine pathway received daily injections of 3, 4 dihydroxyphenyl-l-alanine (L-DOPA, 8 mg/kg plus 15 mg/kg benserazide) for 3 weeks. During this period, about 50% of the rats gradually developed abnormal involuntary movements, lasting for 2-3 h following each L-DOPA dose. Rats were killed 3 days after the last L-DOPA injection, and sections through the striatum were processed for in situ hybridization histochemistry. Within the L-DOPA-treated group, levels of preproenkephalin (PPE) mRNA, glutamic acid decarboxylase (GAD67) mRNA, and prodynorphin (PDyn) mRNA in the dopamine-denervated caudate-putamen, as well as GAD67 mRNA expression in the globus pallidus ipsilateral to the 6-hydroxydopamine (6-OHDA) lesion, were higher in dyskinetic than non-dyskinetic animals, and positively correlated with the rats' dyskinesia scores. By contrast, striatal preprotachykinin mRNA expression and D2 receptor-radioligand binding were not significantly associated with dyskinesia. Among all these markers, PDyn mRNA levels showed the most pronounced treatment-dependence (three times higher in the L-DOPA-treated group than in saline-injected lesion-only controls), and the strongest correlation with the rats' dyskinesia scores (r2 = 0.82). However, a multiple regression equation including the three factors, GAD67 mRNA levels in the GP, GAD67 mRNA in the lateral CPu, and striatal PDyn mRNA, gave a better fit for dyskinesia scores than PDyn mRNA alone (r2 = 0.92). The results show that L-DOPA-induced dyskinesia is associated with overexpression of PDyn and GAD67 mRNA in the striatal projection neurons, and GAD67 mRNA levels in the globus pallidus. Due to its treatment-dependent expression, and strong correlation with the associated dyskinetic symptoms, striatal PDyn mRNA, in particular, may play a role in the mechanisms of behavioural sensitization brought about by the drug.

Animals↗

PubMed1980

Nonaminergic striatal neurons convert exogenous L-dopa to dopamine in parkinsonism.

In intact striatum, the enzyme dopa decarboxylase is localized predominantly in dopaminergic nerve terminals. In Parkinson disease, loss of dopaminergic neurons is associated with massive depletion of striatal decarboxylase activity. Nevertheless, efficacy of exogenous L-dopa in parkinsonism is generally believed to result from its enzymatic decarboxylation to dopamine in the corpus striatum. It has previously been suggested that, after degeneration of nigrostriatal pathways, decarboxylation of administered L-dopa may occur mainly at such striatal sites as surviving dopaminergic terminals, serotonergic neurons, or capillaries; but currently available data do not favor these hypotheses. Recent experimental studies indicate that a substantial amount of decarboxylase activity is localized in striatal interneurons or efferent neurons that may not normally synthesize monoamines. We propose that after depletion of dopaminergic terminals, these nonaminergic striatal neurons may contain a large fraction of residual dopa decarboxylase activity and may represent an important locus for conversion of administered dopa to functional dopamine in the parkinsonian corpus striatum.

Corpus Striatum↗

PubMed2001

Acute neuroleptic stimulates DOPA decarboxylase in porcine brain in vivo.

The activity of DOPA decarboxylase measured in homogenates from rat striatum, or calculated from the rate of tracer decarboxylation measured ex vivo, is stimulated following acute treatment with antagonists of dopamine D2-like receptors. We used compartmental kinetics to test the hypothesis that utilization of the DOPA decarboxylase substrate [(18)F]fluorodopa is potentiated in living striatum following acute treatment with a typical neuroleptic. The kinetics of the tracer uptake were determined in eight anesthetized female pigs (40 kg) and in three animals receiving an infusion of haloperidol (75 microg kg(-1) h(-1)) for 1 h prior to tracer administration and throughout the 2-h positron emission recording. The relative activity of DOPA decarboxylase in striatum was increased threefold by the treatment. This potentiation of DOPA decarboxylation after pharmacological blockade of dopamine D2-like receptors may be used to optimize the utilization of exogenous DOPA in the treatment of Parkinson's disease.

Animals↗

PubMed1990

Purification of dopa decarboxylase from bovine striatum.

Pyridoxal phosphate-dependent DOPA decarboxylase has been purified from bovine striatum to a specific activity of 1.6 U/mg protein. After ammonium sulfate precipitation (30-60%) it was purified by DEAE-Sephacel, Sephacryl S-200, and TSK Phenyl 5 PW chromatography. The purified enzyme showed a single silver straining band with polyacrylamide gel electrophoresis under both denaturing and non-denaturing conditions. The bovine striatal DOPA decarboxylase is a dimer (subunit Mr = 56,000 by SDS-PAGE) with a native Mr of 106,000 as judged by chromatography on Sephacryl S-200 and by sedimentation analysis. Similar to the DOPA decarboxylase purified from non-CNS tissues, the bovine striatal enzyme requires free sulfhydryl groups for activity, is strongly inhibited by heavy metal ions, and can decarboxylate 5-hydroxytryptophan as well. It should be noted, however, that the final enzyme preparation is enriched in DOPA decarboxylase activity. The distribution of the DOPA decarboxylase and 5-HTP decarboxylase activities also varies among several bovine brain regions. In addition, heat treatment of the enzyme preparation inactivated the two decarboxylation activities at different rates.

5-Hydroxytryptophan↗

PubMed1990

Purification and characterization of L-dopa decarboxylase from human kidney.

L-dopa decarboxylase has been purified to homogeneity from post mortem removed human kidneys. Homogeneity was examined by polyacrylamide gel electrophoresis (PAGE) analysis both in the presence and absence of SDS. The enzyme has a molecular weight of 100,000 daltons estimated by gel filtration and 50,000 daltons determined after SDS-PAGE. Human L-dopa decarboxylase therefore is a dimer. Polyclonal antibodies produced against human L-dopa decarboxylase react with the 50,000 daltons enzyme subunit after immuno-blotting and also precipitates enzyme activity. Activity against L-dopa is partially inhibited by 5-hydroxytryptophan (5-HTP). The effect of various cations on L-dopa decarboxylase activity has also been tested.

Adolescent↗

PubMed1987

The alpha methyl dopa hypersensitive gene, 1(2)amd, and two adjacent genes in Drosophila melanogaster: physical location and direct effects of amd on catecholamine metabolism.

The dopa decarboxylase gene (Ddc) is located in a very dense cluster of genes many of whose functions appear to be related to the physiological role of dopa decarboxylase (DDC) in catecholamine metabolism. In Drosophila melanogaster catecholamine metabolism is involved in the production of neurotransmitters and in the synthesis of cross-linking agents for cuticular sclerotization. In this report we consider three loci near Ddc that affect cuticle formation. The alpha methyl dopa hypersensitive gene, 1(2)amd, is definitively assigned to a transcriptional unit 2 kb distal to Ddc. The assignment of 1(2) 37 Bd and 1(2)37 Cc to coding regions in the immediate vicinity of amd and Ddc is examined. amd+ gene activity performs a vital function essential for the formation of insect cuticle and also determines the level of sensitivity to the DDC analogue inhibitor, alpha methyl dopa. We present data that provide direct evidence that the amd+ gene product is required for a step in the metabolism of dopa to one or more novel catecholamines involved in the colorless sclerotization of cuticle.

Animals↗

PubMed1985

Roles of dopa decarboxylase and phenoloxidase in the melanization of the tobacco hornworm and their control by 20-hydroxyecdysone.

When Manduca sexta larvae are allatectomized 5 h before head capsule slippage (HCS) in the final larval molt, the new larval cuticle contains granules that melanize 3 h before ecdysis when the ecdysteroid titer falls (Curtis et al. 1984). In both the epidermis and hemolymph of these allatectomized larvae dopamine was higher than dopa prior to and at the time of melanization. Dopamine also increased in the new cuticle as melanization began. Dopa decarboxylase (DDC) activity increased in the epidermis, cuticle, and fat body beginning 16 h after HCS, with a two-fold greater increase in the epidermis of allatectomized larvae. Both alpha-MDH and alpha-fluoromethyl-dopa inhibited epidermal DDC activity and inhibited melanization in vitro when dopa was used as a precursor. Addition of dopamine to the medium allowed melanization in the presence of the inhibitors. All these results indicate that dopamine is likely the primary precursor of cuticular melanin. The diphenoloxidase in the premelanin granules was activated in vivo between 19 and 21 h after HCS and was found to prefer dopamine to dopa and not to convert tyrosine to melanin. The activation of the prophenoloxidase was inhibited by 20-hydroxyecdysone (20-HE), both in vivo and in vitro, if hormone was given by 16 h after HCS. Infusion of 1.2 microgram/ml 20-HE into allatectomized larvae for 24 h from HCS prevented both the increase in DDC activity and the activation of the premelanin granules. Although the larvae ecdysed after a 15 h delay, melanization never occurred.

Animals↗

PubMed1983

Evidence of dopa in the nerves of sea anemones.

An analysis of the presence of catechol-derivatives in the sea anemones Metridium senile and Tealia felina, made with the aid of high-pressure liquid chromatography (HPLC), established the presence of dopa, 5-OH-dopa, and 5-S-cysteinyldopa. In addition, 2-S-cysteinyldopa and 2.5-diSS-cysteinyldopa occurred in Metridium. Two unknown substances were found to be present in the tentacles of Metridium and in the tentacles of some specimens of Tealia. Neither catecholamines nor serotonin could be traced in detectable amounts. No dopa-decarboxylase could be demonstrated by the assay performed in this investigation. 6-OH-dopa, 6-OH-dopamine and reserpine had no effect on the formaldehyde-induced fluorescence of the subepithelial tentacular nerve net of Tealia. It is concluded that the tentacular nerve net of sea anemones contains dopa, but neither catecholamines nor serotonin. The localization of the other compounds is not yet established.

Animals↗

PubMed1986

A kinetic analysis of Drosophila melanogaster dopa decarboxylase.

The kinetic mechanism of dopa decarboxylase (3,4-dihydroxy-L-phenylalanine carboxy-lyase, EC 4.1.1.28) was investigated in Drosophila melanogaster. Based on initial velocity and product inhibition studies, an ordered reaction is proposed for dopa decarboxylase. This kinetic mechanism is interpreted in the context of measured enzyme activities and the catecholamine pools in Drosophila. The 1(2)amd gene is immediately adjacent to the gene coding for dopa decarboxylase (Ddc) and determines hypersensitivity to alpha-methyldopa in Drosophila. Dopa decarboxylase does not decarboxylate alpha-methyldopa and hence does not generate a toxic product capable of inhibiting 1(2)amd gene function. We propose that the 1(2)amd gene is involved with an unknown catecholamine pathway involving dopa but not dopamine.

Animals↗

PubMed1973

3,4-Dihydroxyphenylalanine (dopa) decarboxylase activity in the arthropod nervous system.

1. When homogenates of brains from mature adult locusts (Locusta migratoria) were incubated with l-3-(3,4-dihydroxyphenyl)[3-(14)C]alanine the major radioactive metabolite was dopamine, suggesting the presence of a dopa (3,4-dihydroxyphenylalanine) decarboxylase. 2. Decarboxylation of l-dopa by this tissue, measured under optimum conditions by a radiochemical method, was 21mumol of CO(2)/h per g wet wt. Apparent decarboxylation of l-tyrosine proceeded at 0.34mumol of CO(2)/h per g wet wt. There was no detectable decarboxylation of l-tryptophan, l-histidine or l-phenylalanine. 3. Dopa decarboxylase activity was found in all major regions of the ventral nerve cord of the mature locust (range: 4-7mumol of CO(2)/h per g wet wt.) but was low or absent in thoracic peripheral nerve. 4. Marked decarboxylation of l-dopa was found in homogenates of brains of four other species of insects, and in brain and ventral nerve cord, but not in the claw nerve, of the crayfish. 5. The activity of the locust brain enzyme may be slightly lower at the time of imaginal ecdysis than during the mature period. By contrast, the dopa decarboxylase that produces dopamine as an intermediate in cuticle biosynthesis is known to be high in activity at the time of ecdysis and low in activity during the intermoult stages.

Animals↗