MPTP-induced ATP depletion and cell death in neuroblastoma × glioma hybrid NG 108-15 cells: Protection by glucose and sensitization by tetraphenylborate

Abstract

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 × 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 m m) 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.