Toxicity of dieldrin for dopaminergic neurons in mesencephalic cultures.
Dieldrin can be retained for decades in lipid-rich tissue and has been measured in some postmortem PD brains. Dieldrin has been reported to deplete brain monoamines in several species and has been shown to inhibit mitochondrial respiration. To further investigate the possibility that it may be involved in the pathogenesis of parkinsonism, its toxicity for dopaminergic (DA) neurons was assessed in a mesencephalic cell culture model. Primary neuronal cultures of mesencephalic neurons were prepared from fetal rats or fetal mice, grown for 1 week and incubated with Dieldrin (0.01-100 microM) for 24 or 48 h. Toxicity for DA neurons was determined by measuring density of surviving tyrosine hydroxylase immunoreactive (TH-ir) cells. Toxicity for gamma-aminobutyric acid (GABA)-ergic neurons was determined by measuring survival of glutamate decarboxylase (GAD)-ir neurons. General, nonselective cytotoxicity was determined by counting cells visualized by phase contrast microscopy or by DAPI-stained cells with fluorescence microscopy. Dieldrin exposure for 24 h resulted in a dose-dependent decrease in survival of TH-IR cells (DA neurons) with a 50% decrease (EC50) produced by 12 microM in rat mesencephalic cultures. Dieldrin also produced a dose- and time-dependent decrease in mouse DA-ergic and GABA-ergic neurons in mouse mesencephalic cultures. GABA-ergic neurons were less sensitive to the toxin compared to DA-ergic neurons. Cellular uptake of 3H-DA was also affected by lower concentrations of Dieldrin (EC50 = 7.98 microM) than uptake of 3H-GABA (EC50 = 43 microM). Thus, Dieldrin appears to be a relatively selective DA-ergic neurotoxin in mesencephalic cultures. Dieldrin, which may be ubiquitous in the environment, is proposed as an agent which can initiate and promote dopaminergic neurodegeneration in susceptible individuals.
Sanchez-Ramos
J
J
Department of Neurology, University of South Florida, James A. Haley VA Medical Center, Research 151, 13000 Bruce B Downs Boulevard, Tampa, Florida 33612, USA.
Facca
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A
Basit
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A
Song
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D000818:Animals; D001692:Biological Transport; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D004026:Dieldrin / Q000633:toxicity*; D004298:Dopamine / Q000378:metabolism*; D005333:Fetus; D005968:Glutamate Decarboxylase / Q000032:analysis; D007150:Immunohistochemistry; D007700:Kinetics; D008636:Mesencephalon / Q000166:cytology* / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D009474:Neurons / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D051381:Rats; D017207:Rats, Sprague-Dawley; D014446:Tyrosine 3-Monooxygenase / Q000032:analysis*; D005680:gamma-Aminobutyric Acid / Q000378:metabolism
D005680:gamma-Aminobutyric Acid; D014446:Tyrosine 3-Monooxygenase; D005968:Glutamate Decarboxylase; D004026:Dieldrin; D004298:Dopamine