Norsalsolinol uptake into secretory vesicles via vesicular monoamine transporter and its secretion by membrane depolarization or purinoceptor stimulation in PC12 cells.
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The intracellular dynamics of norsalsolinol, a neurotoxin candidate causing parkinsonism-like symptoms, in PC12 cells was studied. We found that dopamine and norsalsolinol are co-localized to secretory granule layer by sucrose density gradient in norsalsolinol-treated PC12 cells. The norsalsolinol was actively taken up into isolated secretory vesicle fraction from PC12 cells with a Km value of 41.5+/-6.8 microM. The uptake of 10 microM of norsalsolinol was sensitive to reserpine (1 microM), an inhibitor of vesicular dopamine transporter, and dopamine, an endogenous substrate, but insensitive to GBR-12909, an inhibitor of dopamine transporter on plasma membrane. In norsalsolinol-treated PC12 cells, exposure to high K+ or ATP resulted in simultaneous release of norsalsolinol and dopamine. Time course of a release of dopamine and that of norsalsolinol evoked by 50 mM KCl or 100 microM ATP corresponded to each other. These releases were dependent on the concentrations of secretagogues. These data suggest that norsalsolinol is taken up with dopamine into secretory vesicle via vesicular catecholamine transporter. (+info)
Increased systemic levels of norsalsolinol derivatives are induced by levodopa treatment and do not represent biological markers of Parkinson's disease.
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Endogenously synthesised norsalsolinol derivatives are elevated in Parkinson's disease (PD) and have been considered potentially useful biological markers of the disease. However, little is known about the impact of dopaminergic drugs on the formation of these compounds. We prospectively examined the urine concentrations of norsalsolinol, N-methyl-norsalsolinol and salsolinol in 47 PD patients and 14 control subjects. Patients and control subjects were re-examined after approximately 1 year to assess long term changes. Norsalsolinol derivatives were low in controls and untreated patients with early PD. Increased urine concentrations of norsalsolinol derivatives were significantly associated with levodopa treatment. They were elevated more markedly in the urine of patients treated with high (>600 mg daily) doses of levodopa compared with patients receiving medium (300-600 mg) or low (<300 mg) doses of the drug. There was no correlation with disease parameters such as the severity of motor disability or deficits in the cognitive performance. In the patient group, the concentrations of all three norsalsolinol derivatives declined over the period of investigation, however, they still remained elevated compared with the control group. We conclude that systemic levels of norsalsolinol derivatives in treated patients with PD are likely to derive from the metabolism of levodopa and cannot be regarded as intrinsic markers of the disease. The limited ability of norsalsolinol derivatives to pass the blood-brain barrier prevents an intracerebral accumulation of these possibly harmful compounds, which are biochemically similar to the neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine. (+info)
Quantification of salsolinol enantiomers by stable isotope dilution liquid chromatography with tandem mass spectrometric detection.
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Determination of salsolinol, norsalsolinol, and twenty-one biogenic amines using micellar electrokinetic capillary chromatography-electrochemical detection.
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Dopamine-derived tetrahydroisoquinolines. Novel inhibitors of dihydropteridine reductase.
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Dopamine-derived tetrahydroisoquinolines, such as 3',4'-deoxynorlaudanosolinecarboxylic acid, higenamine-1-carboxylic acid, higenamine, and salsolinol, inhibit human liver dihydropteridine reductase noncompetitively with Ki values ranging from 1.5 to 90 microM. The enzyme is also inhibited noncompetitively by dopamine (Ki = 6 microM) and aminopterin (Ki = 100 microM) but uncompetitively by phenylpyruvic acid (Ki = 6.5 mM). These alkaloids may alter monoamine metabolism in mammals by inhibiting dihydropteridine reductase. (+info)