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Age‐Dependent Sensitivity of Cultured Peripheral Sympathetic Neurons to 1‐Methyl‐4‐Phenylpyridinium: Role of Glutathione
Author(s) -
Bhave Sanjiv V.,
Johannessen Jan N.,
Lash Lawrence H.,
Wakade Taruna D.,
Wakade Arun R.
Publication year - 1996
Publication title -
journal of neurochemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.75
H-Index - 229
eISSN - 1471-4159
pISSN - 0022-3042
DOI - 10.1046/j.1471-4159.1996.67020557.x
Subject(s) - glutathione , medicine , buthionine sulfoximine , endocrinology , nerve growth factor , programmed cell death , neurotoxin , chemistry , superior cervical ganglion , toxicity , neuron , desipramine , biology , biochemistry , apoptosis , neuroscience , antidepressant , receptor , hippocampus , enzyme
We demonstrate that 1‐methyl‐4‐phenylpyridinium (MPP + ) is toxic to chick peripheral sympathetic neurons maintained in culture in the presence of nerve growth factor (NGF). When MPP + was added to the culture medium at the time the neurons were plated, cell loss after 3 days in culture was evident at concentrations as low as 3 n M , and near maximal at 1 µ M . Toxicity was blocked by brief preincubation with the norepinephrine (NE)‐reuptake blocker desipramine (DMI; 10 µ M for 30 min). MPP + blocked the uptake of [ 3 H]NE by sympathetic neurons in a dose‐dependent manner with a potency roughly equal to DMI. At concentrations up to 10 µ M , MPP + had no neurotoxic effect on the survival of sensory neurons maintained in the presence of NGF. The sensitivity of sympathetic neurons to the toxic effects of MPP + diminished gradually with increasing lengths of time in culture. When MPP + was added to the culture medium 48 h after plating, concentrations up to 100 µ M did not cause neuronal death. This increasing resistance of sympathetic neurons to MPP + ‐induced cell death could not be explained by an increasing capacity for sequestration of MPP + within synaptic vesicles. The loss of sensitivity with time in culture was, however, accompanied by a threefold increase in the levels of glutathione (GSH). Furthermore, addition of MPP + (1 µ M ) to cultures previously maintained for 2 days in the presence of the GSH‐synthesis inhibitor l ‐buthionine‐[ S,R ]‐sulfoximine (1 µ M ) caused the same degree of cell death as when added to freshly plated neurons. These results suggest that the observed toxicity of MPP + in freshly plated chick sympathetic neurons may involve the formation of free radicals and that GSH plays a role in protecting sympathetic neurons in vivo from the toxicity of MPP + .