Functional changes in cocultures of mesencephalon and striatal neurons from embryonic C57/BL6 mice due to low concentrations of 1-methyl-4-phenylpyridinium (MPP+).
1-Methyl-4-phenylpyridinium (MPP+), the active metabolite of 1-Methyl-4-phenyl-1,2,3, 6-tetrahydropyridine (MPTP) is taken up into dopaminergic terminals and selectively destroys dopaminergic neurons, serving as a valuable tool in animal model of Parkinson's disease. Cocultures from ventral mesencephalon and neostriatum of embryonic C57/BL6 mouse brains were used to study the sensitivity of dopaminergic neurons to the toxic agent MPP+. Cultures were grown for 9 days in vitro and exposed to different concentrations of MPP+ for various times. Treatment with (0.1-1.0 microM) MPP+ for 24 hours decreased 3H-dopamine (3H-DA) uptake with an IC50 at 0.2 microM. Exposure of cells to 1 microM MPP+ over time decreased the 3H-DA uptake to 38% of controls within the first two hours of incubation and to 8% after 48 hours. Loss of tyrosine hydroxylase (TH) positive cells became evident at 0.1 microM MPP+ (80% of control) leading to maximal toxicity at 10 microM (20% of control). MPP+ reduced the dopamine content in the cultures in a dose dependent manner (IC50 at 0.1 microM) and failed to show reversibility in recovery studies. These findings provide evidence that exposure of MPP+ even at low concentrations and for short time in our coculture model results in irreversible toxicity for dopaminergic neurons.
Koutsilieri
E
E
Institute of Medical Chemistry, Veterinary University of Vienna, Austria.
Chan
W W
WW
Reinitzer
D
D
Rausch
W D
WD
D000818:Animals; D002478:Cells, Cultured; D004298:Dopamine / Q000378:metabolism / Q000502:physiology; D007150:Immunohistochemistry; D008636:Mesencephalon / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D017072:Neostriatum / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism; D009474:Neurons / Q000187:drug effects* / Q000378:metabolism; D011726:Pyridinium Compounds / Q000633:toxicity*; D014446:Tyrosine 3-Monooxygenase / Q000276:immunology / Q000378:metabolism
D011726:Pyridinium Compounds; C026560:1-(4-methoxyphenyl)pyridinium; D014446:Tyrosine 3-Monooxygenase; D004298:Dopamine