Toxicological sciences : an official journal of the Society of Toxicology
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The present study determined effects of thalidomide on three successive generations of New Zealand White rabbits after oral dosing to F0 maternal rabbits during the later third of gestation (post major organogenesis) and lactation. One hundred and twenty four time-mated F0 rabbits (31/dose) were gavaged with 0, 30, 150, or 500 mg/kg thalidomide from gestation day 18 (DG 18) to lactation day 28 (DP or day postpartum 28) for approximately 42 days. At 6 months, 12 F1 males and 12 F1 females were randomly paired within each dose group and mated. ⋯ No F2 fetal gross external alterations were observed. In summary, pregnant rabbits orally dosed with up to 500 mg/kg thalidomide from gestation day 18 to lactation day 28 had increased abortion, changes in some natural delivery and litter parameters, and limb splay in some F1 pups. No gross external changes were observed in F1 and F2 pups.
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Ketamine is a widely used pediatric anesthetic recently reported (C. Ikonomidou et al., 1999, Science 283, 70-74) to enhance neuronal death in neonatal rats. To confirm and extend these results, we treated four groups of PND 7 rats with seven sc doses, one every 90 min, of either saline, 10 mg/kg ketamine, 20 mg/kg ketamine, or a single dose of 20 mg/kg ketamine. ⋯ Levels of ketamine in blood following exposure to the multiple 10 mg/kg doses of ketamine or to a single 20 mg/kg dose ranged around 2-5 micrograms/ml; although these blood levels are close to an anesthetic level in humans, they failed to produce neurodegeneration. To investigate the mode of ketamine-induced neuronal death, coronal sections were stained with both Fluoro-Jade B (a green fluorescent stain selective for neurodegeneration) and DAPI (a blue DNA stain), as well as for caspase-3 (using an antisera labeled red with rhodamine). These histochemical results confirmed the developmental neurotoxicity of ketamine, demonstrated that Fluoro-Jade B (FJ-B), like silver methods, successfully stained degenerating neurons in neonatal rats, and indicated that ketamine acts by increasing the rate of neuronal apoptosis.