Martin D P, Wallace T L, Johnson E M
Department of Pharmacology, Washington University School of Medicine, St. Louis, Missouri 63110.
J Neurosci. 1990 Jan;10(1):184-93. doi: 10.1523/JNEUROSCI.10-01-00184.1990.
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.
阿糖胞苷（AraC）是一种嘧啶抗代谢物，通过抑制DNA合成来杀死增殖细胞。在本文中，我们报告阿糖胞苷以类似于神经生长因子（NGF）剥夺后发生的神经元死亡的方式杀死有丝分裂后的大鼠交感神经元。有丝分裂后的大鼠交感神经元在NGF存在的情况下培养1周，然后仍在NGF存在的情况下用阿糖胞苷处理。阿糖胞苷在4天后杀死神经元，半数有效浓度（EC50）为50微米。添加阿糖胞苷后约3天开始的神经元死亡的形态和时间特征与NGF剥夺后24小时开始观察到的特征无法区分。阿糖胞苷引起的死亡可被与防止NGF剥夺神经元死亡相同的药物阻止，这些药物包括RNA和蛋白质合成抑制剂、一种环磷酸腺苷（cAMP）类似物以及去极化浓度的氯化钾。相比之下，紫外线照射、蓖麻毒素和其他多种毒性损伤引起的神经元死亡不具有这些形态、生化或时间特征。其他抗有丝分裂药物，包括阿糖腺苷、胸苷阿拉伯糖苷、氟脱氧尿苷、羟基脲和阿非科林，不会杀死神经元。阿糖胞苷通过干扰不同于DNA生物合成的脱氧胞苷（dC）代谢，使神经元表现得好像被剥夺了NGF。dC完全阻止了阿糖胞苷的神经毒性，即使其浓度比阿糖胞苷低1000倍。其他脱氧核苷和胞苷不能阻止阿糖胞苷的神经毒性。然而，dC不能替代NGF，因此不太可能是NGF作用的直接介质。据推测，dC可能参与了一条不同于DNA合成的途径，该途径对于神经元对外源营养因子的反应是必需的。
