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)

Rats were fed maximally tolerated doses of L-3,4-Dihydroxyphenylalanine (L-DOPA) and carbidopa daily for 120 days in order to achieve a sustained elevation in brain dopamine levels. Some animals were also given buthionine sulfoximine, a gamma-glutamylcysteine synthetase inhibitor, in an unsuccessful effort to reduce brain glutathione contents. L-DOPA- and carbidopa-treated animals displayed no behavioral changes suggestive of nigrostriatal dopaminergic neuronal loss. When sacrificed 60 days after L-DOPA treatment ended, all rats had normal tyrosine hydroxylase activities and dopamine contents in their striata, and cell counts were normal in the substantia nigra. It therefore seems unlikely that a model of Parkinson's disease, suitable for exploring the etiological importance of glutathione deficiency, can be produced in rats merely by administering the largest tolerable doses of L-DOPA.
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PMID:Nigrostriatal dopaminergic neurons remain undamaged in rats given high doses of L-DOPA and carbidopa chronically. 614 92

L-3,4-Dihydroxyphenylalanine (DOPA) and dopamine encapsulated in liposomes have been obtained. These preparations can be used as drugs for Parkinson's disease. The level of encapsulation of the compounds under study in liposomes and their partition coefficients have been determined. The kinetics of DOPA (or dopamine) exit from the liposomes have been studied.
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PMID:[Physico-chemical properties of liposome forms of L-3,4-dihydroxyphenylalanine (DOPA) and dopamine]. 903 44

L-3,4-Dihydroxyphenylalanine (L-dopa) is the mainstay of therapy for patients with Parkinson's disease (PD), and mediates its primary effects through conversion into dopamine by aromatic L-amino acid decarboxylase (AADC). Given the loss of AADC-containing nigrostriatal dopaminergic neurons in PD, however, the location of residual AADC that converts L-dopa into dopamine remains controversial. The first objective of this study was to establish the presence of AADC expression in striatal neurons and glia using reverse transcriptase and PCR. Transcripts for the neuronal but not nonneuronal forms of AADC were detected in striatal tissue, cultured striatal neurons, and glia. We then examined whether this striatal AADC expression represents a physiologically significant source of dopaine production. No dopamine release was detected following incubation of striatal cultures with L-dopa or transduction with adenovirus expressing tyrosine hydoxylase. Our data establish the presence of AADC expression in the striatum both in vivo and in vitro, but suggest that striatal components do not represent a primary source of L-dopa decarboxylation following nigrostriatal denervation in rats. Understanding the source and localization of AADC is important in understanding the complications of L-dopa therapy and in designing rational therapeutic strategies for PD, including cellular transplantation and gene therapy.
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PMID:The localization and functional contribution of striatal aromatic L-amino acid decarboxylase to L-3,4-dihydroxyphenylalanine decarboxylation in rodent parkinsonian models. 1114 54

L-3,4-Dihydroxyphenylalanine (L-DOPA) is a common and effective treatment for Parkinson's disease, but dyskinesia continues to be a serious adverse effect with chronic use. Evidence suggests that L-DOPA induces increases in dopamine, which then binds to supersensitive dopamine receptors, resulting in dyskinesia. We have shown previously that L-DOPA directly causes stereotypy in rats, suggesting that chronic L-DOPA-induced dyskinesia is also caused by L-DOPA itself. This raises the possibility that other L-DOPA metabolites have a role in dyskinesia. We examined the behavioral effects of five L-DOPA metabolites (3-methoxytyramine, 3-MT; 3,4-dihydroxyphenylalanine, DOPAC; dopamine; homovanillic acid, and 3-o-methyl-DOPA) in rats. A unilateral, intracerebroventricular injection of 3-MT (10-200 microg, 40 microl) over 30 min, dose-dependently increased behavioral activity and stereotypy. This effect was suppressed by the dopamine D1/5-receptor antagonist SCH 23390, but not by the dopamine D2/3/4-receptor antagonist sulpiride. Dopamine denervation resulted in behavioral supersensitivity to 3-MT. Neither dopamine nor DOPAC levels increased in the striatum after 3-MT administration, as measured using in vivo voltammetry. The behavioral changes paralleled a rise in 3-MT in the contralateral striatum. DOPAC also caused behavioral changes and stereotypy, but to a smaller degree than 3-MT. Dopamine-denervated rats did not exhibit a supersensitive response to DOPAC, however. Other L-DOPA metabolites did not cause behavioral effects. These data suggest that 3-MT directly induced dopamine-D1/5-receptor-mediated behavioral changes in rats, and that 3-MT may have a role in dyskinesia due to chronic L-DOPA treatment in Parkinson's disease patients.
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PMID:Behavioral activity and stereotypy in rats induced by L-DOPA metabolites: a possible role in the adverse effects of chronic L-DOPA treatment of Parkinson's disease. 1187 3

L-3,4-Dihydroxyphenylalanine (L-DOPA) remains a common treatment for Parkinson's disease; however, side effects (i.e., dyskinesia and hallucinations) also remain problematic. We recently reported that the dopamine metabolite 3-methoxytyramine causes stereotypy in rats via dopamine receptors, raising the possibility that 3-methoxytyramine is involved in the adverse side effects of chronic L-DOPA treatment. Thus, the present study examined the sites of 3-methoxytyramine action in the rat brain. After intracerebroventricular administration of 3-methoxytyramine, significantly more neurones expressed c-Fos in mesocortico-limbic dopamine areas including frontal cortex, medial prefrontal cortex, parietal cortex, piriform cortex, the nucleus accumbens shell, and ventral tegmental area. 3-Methoxytyramine injection into the medial prefrontal cortex specifically resulted in behavioural changes characteristic of those elicited by the more general intracerebroventricular injection of 3-methoxytyramine. This suggests that the medial prefrontal cortex mediates the 3-methoxytyramine-induced behavioural changes and that a reduction of its action there may alleviate the adverse effects of chronic L-DOPA treatment.
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PMID:The medial prefrontal cortex mediates 3-methoxytyramine-induced behavioural changes in rat. 1202 Jun 84

The steroid dehydroepiandrosterone (DHEA) is abundant in men and women and decreases rapidly during aging. Parkinson's disease (PD) is the second most common neurodegenerative disorder just behind Alzheimer. l-3,4-Dihydroxyphenylalanine (l-Dopa) therapy remains the most effective treatment but many patients develop motor complications. This study investigated the acute effect of DHEA alone and with l-Dopa in 12 females monkeys lesioned with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) to model PD. DHEA administration alone improved the mean parkinsonian score at 1, 5 and 15mg/kg in moderately and severely impaired MPTP monkeys and increased blood DHEA concentrations. DHEA with a low dose of l-Dopa increased the l-Dopa effect in moderately and severely impaired MPTP monkeys. DHEA lengthened duration of the effect of the low dose of l-Dopa by 15-45min. DHEA at 1, 5 and 15mg/kg combined with a high dose of l-Dopa did not increase dyskinesias. DHEA could act by reducing inhibitory GABAergic activity in the striatal output pathways. DHEA could also be metabolized into estradiol in the brain and increase acutely dopamine activity.
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PMID:DHEA improves symptomatic treatment of moderately and severely impaired MPTP monkeys. 1625 92

l-3,4-Dihydroxyphenylalanine (L-dopa) remains the most effective pharmacological treatment for relief of the severe motor impairments of Parkinson's disease. It is very effective in controlling parkinsonian symptoms in the initial phase of the disease, but its action wanes with time. Such 'wearing-off' imposes an escalation in the dosage of the drug, which ultimately fails to provide stable control of motor symptoms and results in the appearance of abnormal involuntary movements or dyskinesia. 'Peak-dose'l-dopa-induced dyskinesia (LID) currently represents one of the major challenges in the treatment of Parkinson's disease. Accumulating evidence suggests that LID derives from overstimulation of dopamine receptors located on the GABAergic medium spiny neurons (MSNs) of the dorsal striatum. These neurons form two distinct projection pathways, which exert opposite effects on motor activity: the direct, striatonigral pathway promotes locomotion, whereas the indirect, striatopallidal pathway depresses locomotion. In order to understand the mechanisms underlying LID, it is important to identify molecular adaptations produced by chronic administration of L-dopa, at the level of one or the other of these two neuronal populations. This review summarizes the results of recent studies indicating that LID is associated with abnormal dopamine D1 receptor signaling affecting the MSNs of the direct pathway. The role of this pathological adaptation and of the consequent changes in signaling in the development and expression of LID are discussed.
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PMID:Parkinson's disease: levodopa-induced dyskinesia and signal transduction. 1827 79

L-3,4-Dihydroxyphenylalanine (L-DOPA) is one of the most important drugs for the treatment of Parkinson's disease (PD). Although neurotoxicity of L-DOPA remains controversial, there are many reports suggesting that L-DOPA causes neuronal death. We investigated whether the neurotoxic effect of L-DOPA could be inhibited by the activation of the phosphatidylinositol 3-kinase (PI3K) pathway. Cell counting kit-8, trypan blue staining, and DAPI staining all showed that L-DOPA decreased nPC12 cell viability at high concentrations. However, combined treatment with the PI3K activator and L-DOPA significantly increased the viability of nPC12 cells when compared with treatment with L-DOPA only. Phosphorylated Akt (Ser473), phosphorylated glycogen synthase kinase-3beta (GSK-3beta) (Ser9), and heat shock transcription factor-1, which are survival-related signaling proteins, were decreased in nPC12 cells treated with 200 microM L-DOPA, but were significantly increased with combined treatment with the PI3K activator in a concentration-dependent manner. However, treatment of L-DOPA significantly increased expressions of cytosolic cytochrome c and cleaved caspase-3, which are death-related signaling proteins, in nPC12 cells, but combined treatment with the PI3K activator reduced those expressions. To confirm whether the effect of the PI3K activator is associated with direct activation of PI3K, LY294002, a PI3K inhibitor, was used to pretreat the nPC12 cells prior to combined treatment with the PI3K activator and L-DOPA. The protective effect of the PI3K activator was almost completely blocked. Together, these results suggest that L-DOPA neurotoxicity can be prevented by PI3K activation.
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PMID:L-DOPA-induced neurotoxicity is reduced by the activation of the PI3K signaling pathway. 1978 63

Parkinson's disease (PD) is a neurodegenerative movement disorder affecting about 2% of the human population in old age. L-3,4-Dihydroxyphenylalanine (L-DOPA) in combination with a peripheral aromatic amino acid decarboxylase inhibition has been the most frequently prescribed drug for alleviating symptoms of PD, but a potential contribution of L-DOPA therapy to further neurodegeneration via oxidative stress is still debated. We report that the specific oxidative stress biomarker 8-oxo-7,8-dihydro-2'-deoxyguanosine (8-oxodG) level in peripheral blood lymphocyte DNA was elevated to 8.1 +/- 1.7 8-oxodG/10(6)dG in 17 chronically L-DOPA-treated PD patients, compared to 4.6 +/- 1.2 8-oxodG/10(6)dG in 12 controls. However, the total antioxidative capacity of plasma was increased to 1113 +/- 237 microM in the PD patients compared to 941 +/- 254 microM in controls. The frequency of micronuclei, a subgroup of chromosomal aberrations, in peripheral blood lymphocytes was not elevated compared to healthy age-matched individuals. In vitro, in a cell-free assay, dopamine and its precursor L-DOPA exhibited antioxidative capacity. On the other hand, the 8-oxodG concentration in cultured PC 12 cells was enhanced after dopamine treatment. This elevation may be below a threshold for manifestation as chromosomal damage.
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PMID:No increased chromosomal damage in L-DOPA-treated patients with Parkinson's disease: a pilot study. 2040 31

l-3,4-Dihydroxyphenylalanine (L-DOPA) remains the most effective drug for therapy of Parkinson's disease. However, the current clinical route of L-DOPA administration is variable and unreliable because of problems with drug absorption and first-pass metabolism. Administration of drugs via the nasal passage has been proven an effective alternate route for a number of medicinal substances. Here we examined the acute behavioral and neurochemical effects of intranasally (IN) applied L-DOPA in rats bearing unilateral lesions of the medial forebrain bundle, with severe depletion (97%) of striatal dopamine. Turning behavior in an open field, footslips on a horizontal grid and postural motor asymmetry in a cylinder were assessed following IN L-DOPA or vehicle administration with, or without, benserazide pre-treatment. IN L-DOPA without benserazide pre-treatment mildly decreased ipsilateral turnings and increased contralateral turnings 10-20 min after the treatment. IN L-DOPA with saline pre-treatment reduced contralateral forelimb-slips on the grid while no effects were evident in the cylinder test. These results support the hypothesis that L-DOPA can bypass the blood-brain barrier by the IN route and alleviate behavioral impairments in the hemiparkinsonian animal model.
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PMID:Intranasally applied L-DOPA alleviates parkinsonian symptoms in rats with unilateral nigro-striatal 6-OHDA lesions. 2210 32


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