Mesencephalic dopamine neurons become less sensitive to 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine toxicity during development in vitro.
The in vitro development of monoamine oxidase (MAO) activity and [3H]dopamine (DA) uptake capacity of dissociated cell cultures from rat embryo mesencephalon were correlated with the potency of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) and 1-methyl-4-phenylpyridine (MPP+) neurotoxicity. Specific activities of both MAO-A and MAO-B increased during in vitro development of the cultures, with MAO-B activity increasing 20-fold between the first and fourth week. Similarly, [3H]DA accumulation increased 2.6-fold between the first and third week in vitro, when it reached a plateau. Unexpectedly, the toxicities of MPTP and MPP+ were substantially decreased in the older cultures. Exposure to MPTP reduced [3H]DA accumulation per culture by 77% in 1-week-old cultures and by 36% in 4-week-old cultures. Similarly, damage caused by MPPT was reduced from 84% of control in the first week to 34% of control in the fourth week. The attenuation of neurotoxicity was not due to an increase in storage of MPP+ in the synaptic vesicles of DA neurons, nor to a change in the distribution of MPP+ between dopaminergic and other cellular components of the cultures. The damage to DA neurons caused by the mitochondrial toxin, rotenone, also showed a similar reduction in the older cultures. These observations coupled with an increase in lactate formation and glucose consumption during the in vitro development of the cultures suggest a shift toward increased glycolysis and decreased dependence on aerobic metabolism. This would render the cells more resistant to the inhibition of mitochondrial function by MPP+.
Danias
P
P
Department of Neurology, Mount Sinai School of Medicine, New York, New York 10029.
Nicklas
W J
WJ
Ofori
S
S
Shen
J
J
Mytilineou
C
C
D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; D015655:1-Methyl-4-phenylpyridinium; D000818:Animals; D002478:Cells, Cultured; D015198:Designer Drugs / Q000494:pharmacology; D004298:Dopamine / Q000378:metabolism*; D004622:Embryo, Mammalian; D007527:Isoenzymes / Q000378:metabolism; D007700:Kinetics; D008454:Mazindol / Q000494:pharmacology; D008636:Mesencephalon / Q000378:metabolism*; D008995:Monoamine Oxidase / Q000378:metabolism; D009474:Neurons / Q000187:drug effects / Q000378:metabolism*; D009498:Neurotoxins / Q000494:pharmacology*; D011725:Pyridines / Q000494:pharmacology*; D011726:Pyridinium Compounds / Q000494:pharmacology; D051381:Rats; D011919:Rats, Inbred Strains; D012110:Reserpine / Q000494:pharmacology; D012402:Rotenone / Q000494:pharmacology; D013997:Time Factors
D015198:Designer Drugs; D007527:Isoenzymes; D009498:Neurotoxins; D011725:Pyridines; D011726:Pyridinium Compounds; D012402:Rotenone; D012110:Reserpine; D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; D008454:Mazindol; D008995:Monoamine Oxidase; D015655:1-Methyl-4-phenylpyridinium; D004298:Dopamine