EFFECTS OF ALPHA-DIFLUOROMETHYLORNITHINE, A SPECIFIC IRREVERSIBLE INHIBITOR OF ORNITHINE DECARBOXYLASE, ON NUCLEIC-ACIDS AND PROTEINS IN DEVELOPING RAT-BRAIN - CRITICAL PERINATAL PERIODS FOR REGIONAL SELECTIVITY
EFFECTS OF ALPHA-DIFLUOROMETHYLORNITHINE, A SPECIFIC IRREVERSIBLE INHIBITOR OF ORNITHINE DECARBOXYLASE, ON NUCLEIC-ACIDS AND PROTEINS IN DEVELOPING RAT-BRAIN - CRITICAL PERINATAL PERIODS FOR REGIONAL SELECTIVITY
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DOI：
10.1016/0306-4522(86)90255-1
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发表时间：
1986-02-01
期刊：
影响因子：
3.3
通讯作者：
SLOTKIN, TA
中科院分区：
文献类型：
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作者：
BELL, JM;WHITMORE, WL;SLOTKIN, TA
已知鸟氨酸脱羧酶及其代谢产物多胺可协调发育中的神经组织中的大分子合成：因此，α-二氟甲基鸟氨酸对该酶的抑制会干扰细胞复制和分化。我们检查了出生后（第1-19天）或妊娠期间（第15-17天）施用的α-二氟甲基鸟氨酸的效果的区域选择性，以确定成熟的特定阶段是否对多胺消耗特别敏感。在出生后经历复制和分化的主要阶段的小脑中，出生后施用α-二氟甲基鸟氨酸引起组织重量增加以及DNA、RNA和蛋白质含量的深刻且渐进的缺陷。尽管发育较早的区域（大脑皮层、中脑+脑干）也表现出出生后α-二氟甲基鸟氨酸的不利影响，但其缺陷程度要小得多，并且与药物对全身生长的影响相当。尽管存在这些区域差异，小脑和中脑+脑干中的DNA合成抑制（[3H]胸苷掺入）是相似的，表明α-二氟甲基鸟氨酸诱导的多胺消耗的直接影响在这两个区域中发挥作用：相对于其他两个区域，大脑皮层中的DNA合成不受影响。这些数据表明，α-二氟甲基鸟氨酸对发育的影响部分取决于药物暴露时每个大脑区域的相对成熟程度。为了证实这一假设，在妊娠第15-17天给予产前α-二氟甲基鸟氨酸导致对小脑发育的特异性丧失和对大脑皮层的影响增强，该区域对产后α-二氟甲基鸟氨酸表现出最不敏感。
Ornithine decarboxylase and its metabolic products, the polyamines, are known to coordinate macromolecule synthesis in developing neural tissues: consequently, inhibition of this enzyme by .alpha.-difluoromethylornithine interferes with cellular replication and differentiation. We examined the regional selectivity of the effect of .alpha.-difluoromethylornithine administered either postnatally (days 1-19) or during gestation (days 15-17), in order to determine whether specific phases of maturation are particularly sensitive to polyamine depletion. In the cerebellum, which undergoes major phases of replication and differentiation after birth, postnatal .alpha.-difluoromethylornithine administration caused a profound and progressive deficit in tissue weight gain as well as in DNA, RNA and protein content. Although regions which develop earlier (cerebral cortex, midbrain + brain stem) also showed adverse effects of postnatal .alpha.-difluoromethylornithine, the deficits were of much smaller magnitude and were comparable to the effect of the drug on general body growth. Despite these regional differences, inhibition of DNA synthesis ([3H]thymidine incorporation) was similar in cerebellum and in midbrain + brain stem, indicating that the direct impact of .alpha.-difluoromethylornithine-induced polyamine depletion is exerted in both: DNA synthesis in cerebral cortex was spared relative to the other two regions. These data suggested that the impact of .alpha.-difluoromethylornithine on development depends, in part, upon the relative degree of maturation of each brain region at the time of drug exposure. In confirmation of this hypothesis, prenatal .alpha.-difluoromethylornithine given on gestational days 15-17 resulted in loss of the specificity toward cerebellar development and enhancement of effects on cerebral cortex, the region which had displayed the least sensitivity to postnatal .alpha.-difluoromethylornithine.