Evaluation of the toxicity of the dopaminergic neurotoxins MPTP and MPP+ in PC12 pheochromocytoma cells: binding and biological studies.
This study was designed to investigate the toxicity of both MPTP and MPP+ using some simple cell systems, such as PC12 and C6 cultures, as models. Exposure of PC12 cells to 0.5 mM MPTP for 72 h resulted in a 50% cell loss with respect to the control cells, and clorgyline, a MAO-A inhibitor, antagonized this toxic effect. Higher concentrations of MPTP demonstrated only a weak cytostatic effect on C6 cells. Moreover, MPP+ showed a toxic effect which was 100 times more evident than MPTP toxicity in the PC12. We found a single, saturable class of [3H]MPP+ binding sites with a relatively high affinity both in PC12 and C6 cell lines. Moreover, the most susceptible cell line towards the toxic effects of both MPTP and MPP+, i.e. PC12, has the higher number of MPP+ binding sites. Our results suggest that MPTP can be toxic not only via MAO-B, but also via MAO-A activity and we propose PC12 as a model to study the intracellular mechanisms of MPTP and MPP+ toxicity.
Marongiu
M E
ME
Institute of Microbiology, University of Cagliari, Italy.
Piccardi
M P
MP
Bernardi
F
F
Corsini
G U
GU
Del Zompo
M
M
D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; D015655:1-Methyl-4-phenylpyridinium; D000310:Adrenal Gland Neoplasms / Q000378:metabolism; D000818:Animals; D001665:Binding Sites; D002455:Cell Division / Q000187:drug effects; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D004298:Dopamine / Q000502:physiology*; D004305:Dose-Response Relationship, Drug; D046911:Macromolecular Substances; D008996:Monoamine Oxidase Inhibitors / Q000494:pharmacology; D009498:Neurotoxins / Q000633:toxicity*; D010673:Pheochromocytoma / Q000378:metabolism; D011725:Pyridines / Q000037:antagonists & inhibitors / Q000378:metabolism / Q000633:toxicity*; D011726:Pyridinium Compounds / Q000378:metabolism / Q000633:toxicity*; D051381:Rats; D014407:Tumor Cells, Cultured / Q000166:cytology / Q000187:drug effects / Q000378:metabolism
D046911:Macromolecular Substances; D008996:Monoamine Oxidase Inhibitors; D009498:Neurotoxins; D011725:Pyridines; D011726:Pyridinium Compounds; D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; D015655:1-Methyl-4-phenylpyridinium; D004298:Dopamine