Metabolic Modification of Parkinson's Disease and of Chronic Manganese Poisoning

Cotzias, George C.; Papavasiliou, Paul S.; Ginos, James Z.; Steck, and A; Düby, Simone E.

doi:10.1146/annurev.me.22.020171.001513

Cited by 118 publications

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“…The progressive decrease in the liver enzyme, without a concomitant decrease in the brain enzyme, should make more -dopa available to the brain and thereby yield more dopamine and norepinephrine in the central nervous system. These results are consistent with observations of enhanced therapeutic efficacy and the reduction in the necessary maintenance dose after prolonged treatment with L-dopa (12,13).…”

Section: Resultssupporting

confidence: 92%

“…However, several observations with parkinsonian patients on -dopa therapy suggested that this agent may, with time, induce alterations in its own metabolism, possibly at the decarboxylation step. It is known that the therapeutic efficacy of L-dopa increases with continued therapy (12,13). Another finding is that administration of pyridoxine, the vitamin analog of pyridoxal phosphate, antagonizes the theraAbbreviation: Dopa, 3,4-dihydroxyphenylalanine.…”

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confidence: 99%

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Decrease in Liver Aromatic L-Amino-Acid Decarboxylase Produced by Chronic Administration of L-Dopa

Dairman

Christenson

Udenfriend

1971

Proc. Natl. Acad. Sci. U.S.A.

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L-Dopa, an intermediate in the biosynthesis of catecholamines, is now widely used in the treatment of parkinsonism. A number of clinical observations suggested that L-dopa may induce changes in its own metabolism during the course of therapy. In the present study, it was found that when L-dopa was administered to rats, the activity of liver aromatic L-amino-acid decarboxylase, the enzyme which catalyzes the conversion of dopa to dopamine, was reduced by as much as 50%. There were no corresponding changes in enzyme activity in heart, adrenals, kidneys, and brain. Decarboxylase activity in the liver continued to decrease for at least 5 days after the last dose of L-dopa. The reduction of enzyme activity in the liver occurred when L-dopa was administered either subcutaneously or orally at doses comparable to those used clinically. In vitro and in vivo experiments indicated that this action of L-dopa is not due to some effect on the cofactor, pyridoxal phosphate. Immunological evidence was obtained that enzyme protein is reduced in the same proportion as enzyme activity. By a reduction of decarboxylase activity in liver without any affect on the enzyme in brain, more L-dopa should be made available to the brain for decarboxylation to dopamine. These findings may explain the clinical observations that the therapeutic efficacy of the drug increases with continued administration.

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Section: Resultssupporting

confidence: 92%

mentioning

confidence: 99%

Decrease in Liver Aromatic L-Amino-Acid Decarboxylase Produced by Chronic Administration of L-Dopa

Dairman

Christenson

Udenfriend

1971

Proc. Natl. Acad. Sci. U.S.A.

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“…Manganese-induced brain lesions tend to occur in regions of intense oxygen consumption (Yamada et al, 1986), and are marked by enhanced auto-oxidation and turnover of dopamine, losses of neurons and demyelination (Cotzias et al, 1971;Donaldson et al, 1984;Gerlach et al, 1994;Erikson et al, 1987). The site-specificity of the pathology and the selective targeting of dopamine have led to the comparison of manganese-induced neurodegeneration to that of other transition metals, iron and copper (Triggs and Willmore, 1984;Rauhala and Chiueh, 2000;Sengstock et al, 1993), i.e.…”

Section: Introductionmentioning

confidence: 99%

Pro- or anti-oxidant manganese: a suggested mechanism for reconciliation

HaMai

Bondy

2004

Neurochemistry International

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“…Table 2 shows the results with some precursors of dopaminergic drugs (see ref. 13) and with some metabolites thereof (see refs. 13 and 14).…”

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confidence: 99%

“…13) and with some metabolites thereof (see refs. 13 and 14). Table 3 The degree of activation found with 10 MM concentrations of activator ( Fig.…”

mentioning

confidence: 99%

Opposing effects of dopaminergic to cholinergic compounds on a cerebral dopamine-activated adenylate cyclase.

Tang¹,

Cotzias²

1977

Proc. Natl. Acad. Sci. U.S.A.

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We have studied these possibilities in the hope of advancing the treatments of Parkinson's disease and of psychosis. To this end we used adenylate cyclase from mouse caudate to screen agents that can affect the symptoms of Parkinson's disease. These included drugs that stimulate the dopaminergic system in man or animals and inactive metabolites and precursors thereof and compounds that activate or inhibit the cholinergic system, which counterbalances the dopaminergic one in the brain (7,8).MATERIALS AND METHODS Animals. These were 5-to 6-week-old male Swiss albino mice, weighing 23-27 g, maintained on Purina Chow and water ad lib., and kept in an air-conditioned room on a 12-hr lightto-darkness cycle. The experiments were started in midday by decapitating the animals in a cold room. The brains were removed within 30 sec and placed on a cold watch glass. The lateral ventricles were entered by removing their roofs. The exposed heads of the caudates were scooped out with forceps.Determination of Dopamine-Stimulated Adenylate Cyclase Activity. The methods are essentially those developed in Greengard's laboratory (9). All fragments of both caudates (about 30 mg) were placed in Krebs-Ringer bicarbonate solution, pH 7.4, which had been gassed for 2 min with 5% CO2/ 95% 02. They were homogenized in 0.5 ml of 50 mM Trismaleate buffer, pH 7.4, containing 12.5 mM theophylline, 0.25 mM ethylene glycol-bis(Q-aminoethyl ether)-NN'-tetraacetic acid, and 2.5 mM MgSO4. Aliquots (0.4 ml) of the homogenates were placed in 5-ml Pyrex tubes that had previously been equilibrated to 30°in an orbital water bath. The control tubes received 50 gl of H20. The experimental tubes received different additives in different series of experiments, the concentrations of which are given below. In one series, 50 ,ul containing either dopamine or a dopaminergic substance was added. In another series, the tubesi received 25 ,ul containing one of the above substances plus 25 jul containing-an inhibitor, a metabolite, or a precursor thereof. In another series, the precursors and metabolites were tested in various concentrations for activation of the cyclase. In still another series, the metabolites were screened for inhibition of the dopamine-dependent activation. Finally, some cholinergic and anticholinergic agents were screened for activation or inhibition of the cyclase.The reaction was started by adding 50 jul of a 0.5 mM solution of ATP with mixing and then incubating in a 30°orbital water bath. After 2.5 min, the reaction was terminated by immersion of the tubes into a boiling water bath for 2 min. The homogenates were centrifuged at 1500 X g for 5 min. The supernatant solutions were quick-frozen until analyzed for adenosine 3': 5'-cyclic monophosphate (cyclic AMP) according to Gilman (10).The results of the cyclic AMP determinations were used as follows. We first computed the mean ±SEM of both nonstimulated and stimulated samples. From these we calculated the net dopamine-stimulated cyclic AMP produced by subtracting the mean nonstimulated acti...

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Metabolic Modification of Parkinson's Disease and of Chronic Manganese Poisoning

Cited by 118 publications

References 0 publications

Decrease in Liver Aromatic L-Amino-Acid Decarboxylase Produced by Chronic Administration of L-Dopa

Decrease in Liver Aromatic L-Amino-Acid Decarboxylase Produced by Chronic Administration of L-Dopa

Pro- or anti-oxidant manganese: a suggested mechanism for reconciliation

Opposing effects of dopaminergic to cholinergic compounds on a cerebral dopamine-activated adenylate cyclase.

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