2'-DEOXYADENOSINE SELECTIVELY KILLS NONNEURONAL CELLS WITHOUT AFFECTING SURVIVAL AND GROWTH OF CHICK DORSAL-ROOT GANGLION NEURONS

Recently, we have demonstrated that adenosine and 2'-deoxyadenosine ar e toxic to embryonic sympathetic neurons and proposed that purine and pyrimidine metabolism may play a critical role in the growth and devel opment of sympathetic neurons. To extend this hypothesis further, we e xamined the effects of these nucleosides on two other neuronal populat ions in the chick embryo, sensory dorsal root ganglion neurons and par asympathetic ciliary ganglion neurons. Now, we show that 2'-deoxyadeno sine and adenosine have no visible adverse effect on the viability of either sensory or parasympathetic neurons. Instead, 2'-deoxyadenosine proved to be highly toxic to the nonneuronal cells. The toxic effects of 2'-deoxyadenosine were markedly enhanced by inhibition of adenosine deaminase, In contrast, adenosine was much less toxic to nonneuronal cells than 2'-deoxyadenosine and its effect was not potentiated by inh ibition of adenosine deaminase, Priming of pyrimidine pools by exogeno us uridine and the specific inhibitor of the nucleoside transporter, n itrobenzylthioinosine, did not protect nonneuronal cells from 2'-deoxy adenosine toxicity. Since phosphorylation of internalized nucleosides was a key step in the initiation of toxicity in sympathetic neurons, a denosine kinase activity was compared in sensory and sympathetic neuro nal cultures. The adenosine kinase activity in dorsal root ganglion cu ltures was only 20% of that in sympathetic ganglion cultures. Furtherm ore, inhibition of phosphorylation by blocking 2'-deoxyadenosine kinas e with iodotubercidin and 5'-amino-5'-deoxyadenosine had no protective effect against 2'-deoxyadenosine toxicity. [H-3]-thymidine incorporat ion was inhibited over 90% by 2'-deoxyadenosine as early as 6 h follow ing its addition and for up to 4 days, suggesting inhibition of prolif eration of nonneuronal cells by 2'-deoxyadenosine, The nucleoside was also able to wipe out already well established nonneuronal cells, leav ing behind an enriched population of sensory neurons. The selective vu lnerability of nonneuronal cells to 2'-deoxyadenosine offers a conveni ent and effective tool for removing nonneuronal cells from neuronal cu ltures as well as providing a new model for studying the mechanisms of nucleoside toxicity. (C) 1998 Elsevier Science B.V.