MPTP-induced ATP depletion and cell death in neuroblastoma X glioma hybrid NG 108-15 cells: protection by glucose and sensitization by tetraphenylborate.
The toxic effect of the Parkinsonism-producing neurotoxin MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine) was investigated using a neuronal cell culture system, namely, neuroblastoma X glioma hybrid NG 108-15. The cells were able to metabolize MPTP into its active metabolite MPP+ (1-methyl-4-phenylpyridinium ion) and to convert its derivative, 2'-methyl MPTP, to the corresponding pyridinium ion. Degenerative changes were observed in NG 108-15 cells when they were examined with a phase-contrast microscope following exposure to MPTP, MPP+, or 2'-methyl MPTP. These compounds also caused an increased leakage of LDH from the treated cells. An enhanced release of [14C]adenine nucleotides was observed from treated cells which were prelabeled with [14C]adenine. The cell death as indicated by the leakage of LDH and the release of adenine nucleotides was markedly reduced in the presence of a high concentration (25 mM) of glucose in the medium. MPTP and MPP+ induced a drastic depletion in cell ATP content prior to cell death. The ATP depletion was also reduced by the presence of a high concentration of glucose. In contrast, tetraphenylborate, a lipophilic anion, highly potentiated the ATP depletion and the subsequent cell death induced by MPTP. Thus, ATP depletion could be a major factor in MPTP-induced neuronal cell death.
Kutty
R K
RK
Section on Drug-Tissue Interaction, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, Maryland 20892.
Santostasi
G
G
Horng
J
J
Krishna
G
G
D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine / Q000031:analogs & derivatives; D015655:1-Methyl-4-phenylpyridinium / Q000633:toxicity; D000227:Adenine Nucleotides / Q000378:metabolism; D000255:Adenosine Triphosphate / Q000172:deficiency / Q000378:metabolism*; D002470:Cell Survival / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D005910:Glioma / Q000188:drug therapy / Q000473:pathology*; D005947:Glucose / Q000494:pharmacology*; D006801:Humans; D007770:L-Lactate Dehydrogenase / Q000378:metabolism; D020267:MPTP Poisoning; D009447:Neuroblastoma / Q000188:drug therapy / Q000473:pathology*; D009474:Neurons / Q000166:cytology / Q000187:drug effects; D013775:Tetraphenylborate / Q000494:pharmacology*; D014407:Tumor Cells, Cultured
D000227:Adenine Nucleotides; C048977:1-methyl-4-(2'-methylphenyl)-1,2,3,6-tetrahydropyridine; D013775:Tetraphenylborate; D000255:Adenosine Triphosphate; D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; D007770:L-Lactate Dehydrogenase; D005947:Glucose; D015655:1-Methyl-4-phenylpyridinium