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)

Post-mortem brain material from control and Parkinson's disease patients was examined to elucidate further the neurochemistry of this disease and to determine the mechanism of action of L-dopa as a therapeutic agent. The activities of L-aromatic amino acid decarboxylase (dopa D), tyrosine hydroxylase, monoamine oxidase and catechol-O-methyl transferase were examined; in addition the tissue levels of dopa, 3-O-methyldopa, dopamine (DA) and homovanillic acid (HVA) were determined. In the non-dopa-treated Parkinsonian patients, the greatest decreases were detected for striatal DA and dopa D, with homovanillic acid and tyrosine hydroxylase levels showing a lesser change. The activities of monoamine oxidase and catechol-O-methyl transferase in the striatal nuclei were not different from the controls. The putamen was consistently the most severely affected region. Dopa and 3-O-methyldopa were detectable in all brain areas only in those patients treated with L-dopa shortly before death. The mean concentrations of DA in the striatum of these patients were 1) 9 to 15 times higher than those in non-dopa-treated patients, 2) related to the time before death of the last dose of L-dopa and 3) greater in the striatum of patients clinically classified as "good responders" as compared to "poor responders." Although L-dopa therapy increased homovanillic acid levels in all brain areas, a preferential increase was observed in the striatum. It was concluded that L-dopa's principal therapeutic effects in Parkinson's disease are consistent with its transformation to DA in the striatum.
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PMID:The neurochemistry of Parkinson's disease: effect of L-dopa therapy. 0 Apr 89

An open cross-over study of 20 patients with Parkinson's disease performed with two drugs containing L-dopa and a peripheral aromatic amino acid decarboxylase inhibitor (benserazide, carbidopa) confirmed the conclusions reached in other clinical trials that this combined treatment of Parkinson's disease is the most effective form of drug therapy available at present. With both drugs, Madopar or Sinemet, an optimum therapeutic result was obtained with relatively small doses of L-dopa (the reduction in L-dopa dosage amounting to about 80%). A loss of efficacy with both drugs, which has observed during long-term treatment of patients with Parkinson's disease, could be avoided by switching the patients from Sinemet to Madopar and vice versa. Determination of L-dopa in the plasma demonstrated that with either drug similar plasma levels of L-dopa were achieved during clinically effective treatment.
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PMID:[The combined treatment of Parkinson's disease with L-dopa plus decarboxylase inhibitors (carbidopa, benserazide) (author's transl)]. 45 2

Rats with unilateral 6-hydroxydopamine lesions of the substantia nigra (SN) were challenged with L-DOPA (25 mg/kg, i.p.). One hour later, during the peak of rotational behavior, the animals were killed and the striatum and the SN were dissected and assayed for dopamine (DA) and dihydroxyphenylacetic acid (DOPAC) content. While L-DOPA treatment elevated DA levels in the lesioned striatum by only 10%, DA levels in the lesioned SN were completely restored to normal levels. DOPAC levels showed similar changes. In order to establish whether the large DA increase in the lesioned SN contributed to L-DOPA-induced contralateral circling, animals were implanted with chronic in-dwelling cannulas in the lesioned SN. Infusion of the DOPA decarboxylase inhibitor carbidopa (5 micrograms in 1 microliter) 30 min prior to peripheral L-DOPA injection not only reduced contralateral circling but reversed the direction of turning 20 min after the L-DOPA injection. The results are discussed in terms of dopaminergic regulation of the striatonigral pathway, their clinical relevance to Parkinson's disease and the suggestion that the SN is an important site for the action of L-DOPA.
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PMID:Evidence that the substantia nigra is a site of action for L-DOPA. 339 96

The plasma amine oxidase (benzylamine oxidase, BzAO) of patients with Parkinson's disease is sometimes decreased in activity, when compared to normal controls. This is the result of therapy with DOPA decarboxylase inhibitors. The Authors suggest that complications due to prolonged therapy with these drugs may be, at least in part, the result of an interference with BzAO capacity to catabolize circulating amines.
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PMID:Inhibitory effect of drugs used in the treatment of Parkinson's disease on plasma monoamine oxidase activity. 398 25

Human erythrocytes have been found to contain appreciable amounts of DOPA decarboxylase (EC 4.1.1.26) activity. The enzyme activity in erythrocytes from patients with Parkinson's disease who were treated with DOPA was significantly lower than that of untreated patients and of normal individuals. Administration of the drug to mice led to a marked decrease of DOPA decarboxylase in liver and kidney, but not of the brain enzyme. The findings thus indicate that administration of DOPA leads to a decrease in peripheral DOPA decarboxylase, an effect that is expected to be of benefit in DOPA therapy of patients with Parkinson's disease. Peripheral DOPA decarboxylase concentration also decreases in mice after short periods of fasting; the findings suggest that the peripheral enzyme activities may be affected by various nutritional and perhaps hormonal influences, which may be partially responsible for the observed fluctuations in the motor abilities of Parkinsonian patients receiving constant doses of the drug. Study of DOPA decarboxylase activity in erythrocytes may be useful in following changes in patients receiving DOPA therapy and may also be of general interest and value in investigations of catecholamine metabolism in man.
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PMID:Decrease of the 3,4-dihydroxyphenylalanine (DOPA) decarboxylase activities in human erythrocytes and mouse tissues after administration of DOPA. 528 72

Sixteen days after a unilateral lesion of the ventromedial tegmentum (VMT) of the midbrain, adult cats received an intravenous dose of L-DOPA (20 mg/kg), and the caudate nucleus from each hemisphere was removed at various time intervals thereafter. In the caudate nucleus contralateral, to the VMT lesions, DA levels reached 200% of control values within 15 min, and maintained this elevation for at least 2 hours. DA levels in the caudate nucleus ipsilateral to the VMT lesion were much lower than contralateral values; however, they were much higher than those of non-DOPA treated animals with comparable lesions. DA levels in the caudate nucleus of the lesioned hemisphere were directly related to the remaining DOPA decarboxylase activity. The striatal serotonin concentrations were unchanged after L-DOPA, but an increase in 5-hydroxyindoleacetic acid levels was observed. From these results, we conclude that, (i) in cats with nigrostriatal tract lesions after low doses of L-DOPA comparable to those given to patients with Parkinson's disease, the bulk of the newly formed DA in the caudate nucleus is contained in nigrostriatal neurons, and (ii) there exists an inverse relationship between the ability of the caudate to synthesize DA and the severity of the nigrostriatal tract lesion.
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PMID:Kinetics of L-DOPA metabolism in the caudate nucleus of cats with ventrotegmental lesions. 693 23

Recent experimental reports concerning L-dihydroxyphenylalanine (L-DOPA) and aromatic L-amino acid decarboxylase (AADC, L-DOPA decarboxylase) are reviewed in this article. Both in vitro and in vivo data now suggest that L-DOPA is an endogenous neuroactive compound that is released from neurons and acts as a neurotransmitter or neuromodulator in the brain. Administration of exogenous L-DOPA affects dopamine receptor status, AADC activity, and mitochondrial oxidation in experimental animals. The type and severity of these effects depend on the duration of the treatment. These findings may partly explain the limited efficacy of L-DOPA therapy in Parkinson's disease (PD). AADC also plays a controlling role in the central nervous system, being a regulatory enzyme in the synthesis of a putative neuromodulator 2-phenylethylamine and other trace amines. Recent experimental findings on AADC activity and localisation are of importance because they suggest that striatal [18F]DOPA uptake used as an indicator of PD progression in positron emission tomography (PET) studies is likely to overestimate nigrostriatal integrity in advanced PD. Possible new PET tracers of presynaptic dopaminergic function are discussed in this context.
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PMID:L-dihydroxyphenylalanine and its decarboxylase: new ideas on their neuroregulatory roles. 881 39

threo-Dihydroxyphenylserine (DOPS) is a synthetic amino acid which can be decarboxylated by L-aromatic amino acid decarboxylase to yield natural form of norepinephrine (l-NE), a principal neurotransmitter in both central and peripheral (sympathetic) nervous systems. Like L-Dopa as an agent for dopamine precursor therapy, DOPS was expected to have a potential as an agent for NE precursor therapy. Previous studies carried out by several groups in early 1970s, however, reached a negative conclusion that threo-DOPS was not an effective precursor of NE in the brain because of its low NE-increasing activity and weak pharmacological action. Since the latter half of 1970s, on the contrary, three Japanese research groups have successfully shown the possibility of DOPS as a useful NE-precursor. That is, Tanaka (Kobe Univ.) showed that L-threo-DOPS is the real l-NE precursor among four DOPS-enantiomers, and that it has several pharmacological activities such as a slow-onset and long-lasting pressor effect, an inhibitory effect on harmaline-induced tremor and so on. Hayashi and Suzuki (Osaka Univ.) found through the mobility study on familial amyloid polyneuropatchy (FAP) that the progress of the disease develops NE-deficiency (NE-D), that severe orthostatic hypotention in FAP might be due to NE-D, and that L-DOPS has favorable effects on this symptom. Narabayashi (Juntendo Univ.) found that NE-D develops in patients with advanced Parkinson's disease (PD), that a freezing phenomenon in these patients might be associated with NE-D, and that L-DOPS improves the phenomenon. Based on these findings, the development of L-DOPS for registration had been undertaken by Sumitomo Pharmaceuticals Co., and an approval was given to it in 1989 as an agent for the treatment orthostatic hypotention in FAP or Shy-Drager syndrome and freezing phenomenon in PD. Preclinical and clinical studies done in the R&D confirmed that L-DOPS markedly restored NE-D and improved related-syndrome in the NE-deficient animals/patients, and that its actions were slow-onset, long-lasting and gentle. The R & D of L-DOPS described in this paper includes studies on industrial production, efficacy pharmacology (mode of action), metabolism and clinical trial of this agent.
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PMID:[Development of L-threo-DOPS, a norepinephrine precursor amino acid]. 785 46

Aromatic alpha-amino-alpha-methyl acids and alpha-hydrazino-alpha-methyl acids are known aromatic amino acid decarboxylase inhibitors. Specific derivatives such as 2-amino-2-methyl-3-(3,4- dihydroxyphenyl)propanoate, Aldomet, and 2-hydrazino-2-methyl-3-(3,4- dihydroxyphenyl)propanoate, Lodosyn, have been developed as therapeutic agents to treat hypertension and Parkinson's disease, respectively. We recently reported a method for the kinetic resolution of the racemic esters of such compounds using a crude preparation of a novel enzyme catalyst from the yeast Candida lipolytica (Yee, C.; Blythe, T.A., McNabb, T.J.; Walts, A.E. J. Org. Chem. 1992, 57, 3525-3527). Here we report the purification and initial characterization of the active enzyme component, an enzyme given the name Candida lipolytica ester hydrolase (CLEH). CLEH was purified to > 95% homogeneity by chromatography on Matrex Blue B resin. The enzyme was found to be a glycoprotein with M(r) = 80,000-300,000. In addition to esterolytic activity, the enzyme was found to catalyze the hydrolysis of amides, anilides and peptides. Sequence analysis of internal peptides of CLEH revealed striking homology to a number of enzymes belonging to the group of serine carboxypeptidases (E.C. 3.4.16.1). One peptide aligned with the canonical serine carboxypeptidase active site sequence, GESYAG. Based on the structural relationship of CLEH to serine carboxypeptidases, three representative serine carboxypeptidases were evaluated for their utility in resolving racemic alpha-tertiary ester substrates and compared with the activity of CLEH. All enzymes revealed similarly high activity and enantioselectivity towards the alpha-hydrazino-alpha-methyl ester precursor of the Parkinson-drug Carbidopa. However, differences in enantioselectivity were observed with other alpha-tertiary-substituted ester substrates. Serine carboxypeptidase-catalyzed ester resolutions thus offer a new route to many sterically hindered homochiral alpha-amino, alpha-hydrazino and alpha-hydroxy carboxylic acids.
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PMID:Enzymes for the resolution of alpha-tertiary-substituted carboxylic acid esters. 785 60

The effects of D2 dopamine (DA) receptor antagonism or stimulation by systemic haloperidol or quinpirole, respectively, on in vivo DA synthesis in 6-hydroxydopamine (6-OHDA)-lesioned rats and 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-treated black mice were assessed by measuring the rate of dihydroxyphenylalanine (DOPA) accumulation following acute inhibition of L-aromatic amino acid decarboxylase with NSD-1015. 6-OHDA and MPTP caused partial lesions of nigrostriatal input to the striatum. Dopamine synthetic capacity was preserved relative to the severity of nigrostriatal lesion over a broad range of DA depletions. An exponential increase in fractional DA synthesis (the ratio DOPA/DA) was observed with increasing DA depletion, suggesting an elevation of the DA synthetic capacity per surviving DA terminal. In both lesioned rats and mice, haloperidol caused a significant increase in fractional DA synthesis above that induced by the lesion alone, while quinpirole significantly depressed fractional DA synthesis. Our results provide evidence that nigrostriatal terminals acquire increased DA synthetic capacity as nigrostriatal lesions exceed 90%, but that the increase in fractional DA synthesis observed in partially lesioned animals is not due to a loss of autoreceptor function. Pharmacological strategies to stimulate DA synthesis and release in moderately advanced Parkinson's disease should be pursued.
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PMID:Regulation by D2 dopamine receptors of in vivo dopamine synthesis in striata of rats and mice with experimental parkinsonism. 792 42


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