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Journal of Neuroscience, Vol 10, 184-193, Copyright © 1990 by Society for Neuroscience
Cytosine arabinoside kills postmitotic neurons in a fashion resembling trophic factor deprivation: evidence that a deoxycytidine-dependent process may be required for nerve growth factor signal transduction
DP Martin, TL Wallace and EM Johnson Jr
Department of Pharmacology, Washington University School of Medicine, St. Louis, Missouri 63110.
Cytosine arabinoside (AraC) is a pyrimidine antimetabolite that kills
proliferating cells by inhibiting DNA synthesis. In this paper we report
that AraC kills postmitotic rat sympathetic neurons in a fashion similar to
the neuronal death that follows nerve growth factor (NGF) deprivation.
Postmitotic rat sympathetic neurons were cultured for 1 week in the
presence of NGF and then treated with AraC, still in the presence of NGF.
AraC killed neurons after 4 d with an EC50 of 50 microns. The morphological
and temporal characteristics of neuronal death that began around 3 d after
addition of AraC were indistinguishable from those observed beginning 24 hr
after NGF deprivation. Death caused by AraC was prevented by the same
agents that prevent the death of NGF-deprived neurons, which included
inhibitors of RNA and protein synthesis, a cAMP analog, and depolarizing
concentrations of KCl. In contrast, neuronal death caused by ultraviolet
irradiation, ricin toxin, and a variety of other toxic insults did not
share these morphological, biochemical, or temporal characteristics. Other
antimitotic drugs, including adenine arabinoside, thymine arabinoside,
fluorodeoxyuridine, hydroxyurea, and aphidicolin, did not kill neurons.
AraC caused neurons to behave as if deprived of NGF by interfering with
deoxycytidine (dC) metabolism distinct from DNA biosynthesis. dC entirely
prevented the neurotoxicity of AraC, even when present at a concentration
1000-fold less than that of AraC. Other deoxynucleosides, and cytidine, did
not prevent AraC neurotoxicity. dC could not, however, substitute for NGF
and thus is unlikely to be a direct mediator of NGF action. It is
hypothesized that dC may participate in a pathway, distinct from DNA
synthesis, that is necessary for neurons to respond to exogenous trophic
factors.
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