Toxicity of a Treatment Associating Dopamine and Disulfiram for Catecholaminergic Neuroblastoma SH-SY5Y Cells: Relationships with 3,4-Dihydroxyphenylacetaldehyde Formation
Section snippets
INTRODUCTION
Several reports suggest that an oxidative stress could be responsible for the rather specific loss of dopaminergic neurons which characterizes Parkinson’s disease. Mechanisms underlying this rather selective vulnerability remain unclear, but various experimental evidences suggest that a mitochondrial dysfunction (Orth and Shapira, 2002, Cassarino et al., 1997) could be associated with an altered dopamine (DA) metabolism and a decreased ability to scavenge toxic metabolites (Hornykiewicz and
Chemicals
[3H] DA (6.6 Ci/mmol) was purchased from Amersham. Culture medium, fetal calf serum and antibiotics (streptomycin and penicillin) were purchased from Biowhittaker (Belgium). Disulfiram, DA, DOPAC, NAD, 3-[4,5-dimethylthiazol-2-yl]-2,5 diphenyl tetrazolium bromide (MTT) and rotenone were obtained from Sigma (St. Louis, MO). Proprionaldehyde and pyrazole were purchased from Fluka. Rotenone was dissolved in methanol (0.2% of the final volume). Disulfiram solutions (10 mM) were prepared in a 45%
[3H] Dopamine Uptake by SH-SY5Y Cells
The specific uptake of [3H] DA by SH-SY5Y cells increased linearly with time during the first 20 min of incubation, at a mean rate of 22 fmol/min per 105 cells. Thereafter, this rate slowed down (Fig. 2). Nomifensine blocked the specific uptake in a monophasic manner (not shown); its inhibitory concentration 50% was 4 × 10−8 M for a 5 min incubation period.
Effects of DA or Disulfiram on SH-SY5Y Viability
DA and disulfiram produced time- and concentration-dependent losses in SH-SY5Y viability (Table 1). A 1 h treatment in the presence of various DA
Discussion
The present study shows that a blockade of the ALDH activity can potentiate the DA toxicity on SH-SY5Y cells which display catecholaminergic features. This potentiation was observed in a situation which could occur in parkinsonians submitted to l-DOPA therapy. This treatment, aiming at increasing cerebral concentrations of DA, a substrate of MAO, can be associated with a blockade of the oxidation of DOPAL to DOPAC. This might result from a genetic deficit in ALDH (Goedde and Agarwal, 1987,
Acknowledgements
The authors wish to thank Prof. J.C. Quirion for providing the DOPET chemical synthesis. We would like to acknowledge Prof. C. Lange, Dr. C. Loutelier-Bourhis and Dr. P. Vérité for performing spectral analyses. This work was supported in part by grants from la Direction de la Recherche et de la Technologie (contract 97-187).
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