Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0030567 (Parkinson's disease)
 63,064 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Gene transfer techniques have been explored as therapeutic modalities and neurobiologic tools to understand the role of various genes in animal models of Parkinson's disease. The gene for tyrosine hydroxylase, the rate-limiting step of dopamine synthesis, has been transferred into animal models by viral vectors or by implantable cells that have been modified by retrovirus vectors. The role of additional genes such as GTP cyclohydrolase 1 and aromatic L-amino acid decarboxylase in optimal delivery of dopamine in animal models is reviewed. Gene therapy also allows goals beyond replacement of dopamine. Neurotrophic factors such as brain-derived neurotrophic factor and glial cell line-derived neurotrophic factor can be introduced to promote sprouting of neurites and protect the dopaminergic neurons from degeneration. Genes involved in apoptosis, free radical scavenger pathway, or other cell death mechanism could also be used to prevent the degeneration of the neurons. Current technology of gene therapy is limited in its long-term expression and ability to regulate the gene expression. However, recent developments provide better understanding of these limitations and suggest potential solutions to these technical hurdles.
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PMID:Potential of gene therapy for Parkinson's disease: neurobiologic issues and new developments in gene transfer methodologies. 961 21

Striatal dopamine deficiency in Parkinson's disease (PD), first described in 1960, was a key event that led to the era of levodopa therapy. In 1961, levodopa was first tried in PD patients, but throughout most of the 1960s the results were inconsistent. In 1967, questions about the effectiveness of levodopa in PD were finally set aside when Cotzias and colleagues reported dramatic improvement in PD patients with oral administration of levodopa in increasing amounts over long periods. The major side effects of levodopa administration, i.e., dyskinesias and motor fluctuations, also became apparent at this time. In the early 1970s, the advantages of adding a dopa decarboxylase inhibitor to treatment were discovered--reducing side effects and gaining better symptom control--and the first levodopa combination, carbidopa/levodopa, became commercially available in 1975. Since then, PD researchers have attempted to overcome complications with such techniques as continuous levodopa infusion and, most recently, long-acting levodopa combinations. A dopamine agonist, apomorphine, was used in 1970 as a means to overcome side effects and loss of levodopa efficacy. However, side effects and difficulty of administration limited its use. Dopamine agonists began to find a place in routine treatment of PD after the discovery of bromocriptine's benefits in PD in 1974. Since then, new approaches have been tried, such as dopamine agonist monotherapy and early therapy in combination with levodopa. The development of new dopamine agonists has led to characterization of dopamine receptor subtypes and agonists targeted to stimulation of specific receptors.
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PMID:History of levodopa and dopamine agonists in Parkinson's disease treatment. 963 79

In this study, we investigated the presence, possible synthesis, and release of catecholamines (CA) by monkey amniotic epithelial cells (MAEC) using different methods. Immunocytochemical techniques demonstrated the presence of tyrosine hydroxylase (TH), aromatic L-amino acid decarboxylase (AADC), dopamine-beta-hydroxylase (DBH), and dopamine (DA) immunoreactivities, suggesting the capability of these cells to synthesize CA. Further evidence from high performance liquid chromatography (HPLC) studies indicated the presence of norepinephrine (NE), DA, and its metabolite 3,4-dihydroxyphenylacetic acid (DOPAC) in the cell extracts of cultured MAEC. Incubation of MAEC for various time intervals in medium supplemented with L-tyrosine and tetrahydrobiopterin significantly increased the production of CA, thus confirming active synthesis of CA by MAEC and that increasing the incubation time increases this synthesis. In contrast, pharmacological inhibition of TH by alpha-methyl-p-tyrosine significantly reduced CA production, further confirming CA synthesis by MAEC. Catecholamines were also detected in the cell incubation media, suggesting the ability of MAEC to spontaneously secrete CA. Moreover, depolarization with high concentration of K+ increased the amount of CA released into the incubation media. Additionally, the detection of DOPAC, a primary metabolite of DA, in MAEC strongly indicates that these cells contain DA metabolizing enzymes. These results demonstrate the presence of CA in MAEC and that these cells can synthesize and release CA. Further extensive studies are needed to fully explore MAEC so that it may serve as a model to study the aspects of catecholaminergic activity in primate cells and may be a possible candidate for allotransplantation therapy of monkey model of Parkinson's disease.
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PMID:Synthesis and release of catecholamines by cultured monkey amniotic epithelial cells. 967 Sep 97

Tolcapone is a potent, reversible catechol-O-methyltransferase (COMT) inhibitor with both peripheral and central activity. It has been demonstrated to improve motor function and allow levodopa dose reductions in Parkinson's disease (PD) patients who are experiencing either a stable response or motor fluctuations while on levodopa/dopa decarboxylase inhibitor therapy. Because striatal dopamine is metabolized by COMT and monoamine oxidase (MAO), central COMT inhibition alone or in combination with MAO inhibition might provide symptomatic benefit for patients not receiving levodopa. We conducted a pilot study to evaluate the tolerability, safety, and efficacy of tolcapone alone and in combination with oral selegiline in early untreated PD patients. Patients were randomized to receive 200 mg tolcapone three times a day or placebo for the 8 weeks of the study. Open-label oral selegiline (5 mg in the morning and midday) was administered to all patients during the second 4 weeks of the study. There was no difference between treatment groups according to the investigator's assessment of tolerability at week 4. Ninety-five percent of tolcapone-treated patients and 98% of placebo-treated patients experienced excellent or good tolerability during the first 4 weeks (95% confidence interval [CI]: -10.3, 5.7; p = 0.57). A decrease in tolerability occurred in the tolcapone group during the second 4 weeks of the study following the addition of selegiline. The most commonly reported side effects were diarrhea (31% tolcapone, 7% placebo), nausea (21% tolcapone, 2% placebo), urine discoloration (12% tolcapone, 0% placebo), dizziness (12% tolcapone, 5% placebo), headaches (12% tolcapone, 10% placebo), and abdominal pain (10% tolcapone, 5% placebo). We did not identify symptomatic benefit associated with tolcapone alone or in combination with oral selegiline in this group of otherwise untreated PD patients.
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PMID:A pilot evaluation of the tolerability, safety, and efficacy of tolcapone alone and in combination with oral selegiline in untreated Parkinson's disease patients. Tolcapone De Novo Study Group. 968 68

An adeno-associated virus (AAV) vector, expressing genes for human tyrosine hydroxylase (TH) and aromatic amino acid decarboxylase (AADC), demonstrated significantly increased production of dopamine in 293 (human embryonic kidney) cells. This bicistronic vector was used to transduce striatal cells of six asymptomatic but dopamine-depleted monkeys which had been treated with the neurotoxin MPTP. Striatal cells were immunoreactive for the vector-encoded TH after stereotactic injection for periods up to 134 days, with biochemical effects consistent with dopamine biosynthetic enzyme expression. A subsequent experiment was carried out in six more severely depleted and parkinsonian monkeys. Several TH/aadc-treated monkeys showed elevated levels of dopamine near injection tracts after 2.5 months. Two monkeys that received a beta-galactosidase expressing vector showed no change in striatal dopamine. Behavioral changes could not be statistically related to the vector treatment groups. Toxicity was limited to transient fever in several animals and severe hyperactivity in one animal in the first days after injection with no associated histological evidence of inflammation. This study shows the successful transfection of primate neurons over a period up to 2.5 months with suggestive evidence of biochemical phenotypic effects and without significant toxicity. While supporting the idea of an in vivo gene therapy for Parkinson's disease, more consistent and longer lasting biochemical and behavioral effects will be necessary to establish the feasibility of this appraoch in a primate model of parkinsonism.
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PMID:In vivo expression of therapeutic human genes for dopamine production in the caudates of MPTP-treated monkeys using an AAV vector. 974 62

Catechol-O-methyltransferase inhibitors have been newly introduced as adjunct drugs to the levodopa/dopa decarboxylase inhibitor therapy in Parkinson's disease. When given alone, catechol-O-methyltransferase inhibitors seem to affect behaviour. We wanted to determine whether the concentrations of free amine would be increased by catechol-O-methyltransferase inhibition with tolcapone and underpin the positive behavioural effects. To this end, dopamine and noradrenaline levels were analyzed in the microdialysis perfusion fluid collected from several brain regions in chloral hydrate anaesthetized rats. We also analyzed the turnover rate of catecholamines in the brain after single doses of tolcapone and entacapone using the alpha-methyl-p-tyrosine method. On their own, tolcapone (at 10 or 30 mg/kg) did not elevate dopamine or noradrenaline levels in any brain region studied although the formation of catechol-O-methyltransferase-dependent metabolites was strongly reduced. Neither tolcapone nor entacapone (at 30 mg/kg) affected the turnover rate of catecholamines. It seems that catechol-O-methyltransferase inhibitors do not alter behaviour by elevating extracellular levels of free catecholamines levels but other explanations are needed.
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PMID:No change of brain extracellular catecholamine levels after acute catechol-O-methyltransferase inhibition: a microdialysis study in anaesthetized rats. 977 42

The present study examined the effects of the antiparkinsonian drug budipine on dopamine synthesis and release from L-DOPA in the substantia nigra of reserpine-treated rats. Budipine (at 100 microM, but not 10 microM) applied by reverse dialysis to the nigra caused a small and significant rise in dopamine recovery in normal rats, but not in rats pretreated with reserpine (4 mg/kg i.p. for 18 hours) and alpha-methyl-p-tyrosine (alpha-MPT; 200 mg/kg i.p. for 1 hour to limit dopamine synthesis to L-DOPA). L-DOPA applied to the nigra by reverse dialysis in reserpine + alpha-MPT-treated rats, increased the recovery of dopamine when applied at 5 or 10 microM, but not at 2 microM. Coadministration of budipine (10 microM) significantly enhanced L-DOPA-induced dopamine (and DOPAC) release with 5 microM L-DOPA, but not with 2 or 10 microM L-DOPA. This potentiation was even more pronounced when the budipine concentration was raised to 100 microM (equivalent to approximately 10 microM extracellularly). Pretreating rats with budipine (5, 12.5, or 20 mg/kg i.p.) for 1 hour significantly raised the activity of the enzyme L-aromatic amino acid decarboxylase in the striata and nigras of intact rats, as well as in rats pretreated with reserpine alone (5 mg/kg i.p.), without altering tissue levels of dopamine or its metabolites. It is suggested that the beneficial effects of budipine, when used as an adjunct to L-DOPA therapy of Parkinson's disease, may be due to an increase in the bioconversion of L-DOPA with a consequent rise in synaptic dopamine. These actions of budipine may be related to its weak NMDA receptor antagonist property.
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PMID:The antiparkinsonian drug budipine stimulates the activity of aromatic L-amino acid decarboxylase and enhances L-DOPA-induced dopamine release in rat substantia nigra. 977 34

The efficacy of levo-DOPA in the treatment of Parkinson's disease is potentiated by blockade of its peripheral metabolism with inhibitors of catechol-O-methyltransferase (COMT). Some COMT inhibitors may act entirely in the periphery (nitecapone, OR-462), while others may also have some activity in brain (entacapone, OR-611). We used positron emission tomography (PET) to test the effects of these two COMT inhibitors on the plasma kinetics and brain metabolism of the levo-DOPA analog 6-[18F]fluoro-L-dopa (FDOPA) in cynomolgus monkeys, employing a compartmental model for the assay of DOPA decarboxylase activity in living brain. Four monkeys each underwent two PET scans in the baseline condition, one PET scan after treatment with OR-462 (15 mg/kg, i.v.), and one PET scan after treatment with OR-611 (15 mg/kg, i.v.). Pharmacokinetic analysis of FDOPA metabolism in plasma indicated that these compounds blocked peripheral COMT activity by 80% for at least 60 minutes. Both COMT inhibitors increased the net availability of FDOPA in circulation, and increased the ratio of the radioactivity concentrations in striatum and occipital cortex, suggesting that [18F]fluorodopamine synthesis in striatum was potentiated. However, OR-611 treatment reduced the unidirectional (K1D) and net (Ki) blood-brain clearances of FDOPA, and also inhibited the rate of decarboxylation (k3D) of FDOPA in striatum. These observations suggest that high doses of OR-611 may partially antagonize the cerebral utilization of levo-DOPA. We used the present data to test the sensitivity of the compartmental model to the physiological constraint that the blood-brain permeabilities of the O-methylated plasma metabolite and FDOPA have a fixed ratio. In the groups with COMT inhibition, the estimates of k3D were insensitive to the magnitude of the permeability ratio. In the control group, the estimate of k3D increased by 40% as the magnitude of the constrained permeability ratio increased in the range of published estimates.
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PMID:Effect of catechol-O-methyltransferase inhibition on brain uptake of [18F]fluorodopa: implications for compartmental modelling and clinical usefulness. 982 27

Parkinson's disease (PD) is characterized by the progressive loss of the dopaminergic neurons in the substantia nigra and a severe decrease in dopamine in the striatum. A promising approach to the gene therapy of PD is intrastriatal expression of enzymes in the biosynthetic pathway for dopamine. Tyrosine hydroxylase (TH) catalyzes the synthesis of L-dopa, which must be converted to dopamine by aromatic L-amino acid decarboxylase (AADC). Since the endogenous AADC activity in the striatum is considered to be low, coexpression of both TH and AADC in the same striatal cells would increase the dopamine production and thereby augment the therapeutic effects. In the present study, the TH gene and also the AADC gene were simultaneously transduced into rat striatal cells, using two separate adeno-associated virus (AAV) vectors, AAV-TH and AAV-AADC. Immunostaining showed that TH and AADC were coexpressed efficiently in the same striatal cells in vitro and in vivo. Moreover, cotransduction with these two AAV vectors resulted in more effective dopamine production and more remarkable behavioral recovery in 6-hydroxydopamine (6-OHDA)-lesioned rats, compared with rats receiving AAV-TH alone (p < 0.01). These findings suggest an alternative strategy for gene therapy of PD and indicate that the simultaneous transduction with two AAV vectors can extend their utility for potential gene therapy applications.
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PMID:Behavioral recovery in 6-hydroxydopamine-lesioned rats by cotransduction of striatum with tyrosine hydroxylase and aromatic L-amino acid decarboxylase genes using two separate adeno-associated virus vectors. 985 19

This study examines the hypothesis that glutamate tonically suppresses the activity of the enzyme aromatic L-amino acid decarboxylase (AADC), and hence the biosynthesis of dopamine, to explain how antagonists of glutamate receptors might potentiale the motor actions of L-DOPA in animal models of Parkinson's disease. A variety of glutamate antagonists were therefore administered acutely to normal rats, which were sacrificed 30-60 min later and AADC activity assayed in the substantia nigra pars reticulata (SNr) and corpus striatum (CS). The NMDA receptor-ion channel antagonists MK 801, budipine, amantadine, memantine and dextromethorphan all caused a pronounced in creased in AADC activity, more especially in the SNr than CS. The NMDA glycine site antagonist (R)-HA 966 produced a modest increase in AADC activity in the CS but not SNr, whilst the NMDA polyamine site antagonist eliprodil, the NMDA competitive antagonist CGP 40116 and the AMPA antagonist NBQX were without effect. The results suggest that an increase in dopamine synthesis might contribute to the L-DOPA-facilitating actions of some glutamate antagonists.
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PMID:Effects of glutamate antagonists on the activity of aromatic L-amino acid decarboxylase. 987 40


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