RESCUE OF MESENCEPHALIC DOPAMINE NEURONS BY ANTICANCER DRUG CYTOSINE-ARABINOSIDE

Nanomolar concentrations of cytosine arabinoside (ara-G), a structural analogue of 2'-deoxycytidine (2'dC) used in the chemotherapy of cance r, proved to be highly effective in preventing the death of postmitoti c dopaminergic neurons that occurs spontaneously by apoptosis in mesen cephalic cultures. The rescued cells were totally functional and highl y differentiated. The trophic/neuroprotective effects of ara-C were (1 ) specific for dopaminergic neurons; (2) long-lived, remaining detecta ble several days after withdrawal of the nucleoside analogue from the culture medium; (3) still observed when the treatment was delayed afte r plating; (4) abolished by an excess of 2'dC or dCTP, or by exposure to the neurotoxin 1-methyl-4-phenylpyridinium; and (5) mimicked by ara -CTP, 5-fluoro-2'-deoxyuridine, and aphidicolin. Autoradiographic stud ies revealed that ara-C was incorporated exclusively into astrocyte nu clei, suggesting that the dopaminotrophic activity was indirect and re sulted from the antiproliferative action of the modified nucleoside on glial cells at concentrations that were not neurotoxic. No evidence w as found for putative deleterious or trophic molecules secreted by pro liferating or ara-C-treated astrocytes, respectively, suggesting that neuroglial contact may play a role. Our results suggest a possible mec hanism underlying neurodegeneration in Parkinson's disease, where sele ctive loss of dopaminergic neurons in the mesencephalon is accompanied by astrogliosis.