A Dopaminergic Cell Line Variant Resistant to the Neurotoxin 1‐Methyl‐4‐Phenyl‐1,2,3,6‐Tetrahydropyridine

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Abstract
1‐Methyl‐4‐phenyl‐1,2,3,6‐tetrahydropyridine (MPTP) is known to cause parkinsonism by killing dopaminergic neurons; the toxic substance is a metabolite, 1‐methyl‐4‐phenylpyridinium ion (MPP+). PC12 cells, which are dopaminergic, are killed in culture by MPTP and MPP+ but at concentrations much higher than that required to kill affected neurons in vivo. However, at low concentrations (10–100 μM), MPP+ caused an increased production of lactate by PC12 cells. MPP+‐treated PC12 cells exhibited decreased mitochondrial respiration. Mitochondria from the treated cells respired normally in the presence of added succinate but not β‐hydroxybutyrate, a finding indicating that MPP+ inhibits the oxidation of some substrates selectively. MPP+ was more effective in killing the cells when glycolysis was reduced with 2‐deoxyglucose or by lowering the glucose content of the culture medium. Under these conditions, MPP+ inhibited ATP synthesis and depleted cellular stores of ATP. A PC12 variant that is even more resistant to MPTP and MPP+ than are wild‐type cells has been isolated. The MPTP‐resistant variant is also more resistant to the lethal effects of oligomycin, antimycin A, and rotenone. This variant exhibited altered lactate production and mitochondrial respiration. It is suggested that some brain neurons that accumulate MPP+ without being killed by it may also have an energy metabolism somewhat different from that of more sensitive neurons.