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.
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.
J M
JM
Bell
W L
WL
Whitmore
T A
TA
Slotkin
D000375:Aging; D000818:Animals; D001835:Body Weight; D001921:Brain / Q000187:drug effects / Q000201:enzymology / Q000254:growth & development*; D004247:DNA / Q000378:metabolism*; D000518:Eflornithine; D005260:Female; D007279:Injections, Subcutaneous; D009419:Nerve Tissue Proteins / Q000378:metabolism*; D009929:Organ Size; D009952:Ornithine / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000494:pharmacology; D009955:Ornithine Decarboxylase / Q000502:physiology*; D065108:Ornithine Decarboxylase Inhibitors; D011247:Pregnancy; D011297:Prenatal Exposure Delayed Effects; D012313:RNA / Q000378:metabolism*; D051381:Rats
D009419:Nerve Tissue Proteins; D065108:Ornithine Decarboxylase Inhibitors; D012313:RNA; D004247:DNA; D009952:Ornithine; D009955:Ornithine Decarboxylase; D000518:Eflornithine