Arya Vikram, Demarco Vincent G, Issar Manish, Hochhaus Günther
Department of Pharmaceutics, College of Pharmacy, JHMHC, University of Florida, Gainesville, FL 32610, USA.
Drug Metab Dispos. 2006 Jun;34(6):939-42. doi: 10.1124/dmd.105.007419. Epub 2006 Feb 28.
Neurotoxic adverse effects after systemic corticosteroid administration are elevated in preterm infants. To test whether this might be related to an immature blood-brain barrier (BBB) that permits corticosteroids to enter the brain and induce neurotoxic effects, this study assessed the differences in brain permeability of triamcinolone acetonide after intratracheal administration to neonatal (10- to 11-day-old) and adult rats. Triamcinolone acetonide (or the phosphate prodrug in the case of neonatal rats) was administered intratracheally to neonatal rats at doses of 2.5, 25, or 50 microg/kg and to adult rats at 100 microg/kg. An ex vivo receptor binding assay was used to monitor the cumulative brain and liver glucocorticoid receptor occupancies over 6 h. Brain and liver receptor occupancies in neonates were similar for the 25 and 50 microg/kg triamcinolone acetonide phosphate (brain/liver receptor occupancy ratio, 1.10 +/- 0.14 and 0.87 +/- 0.13, respectively), whereas some reduction in the brain permeability was seen at the lower dose. After intratracheal administration of 100 microg/kg triamcinolone acetonide to adult rats, receptor occupancies in the brain were significantly lower (brain/liver ratio, 0.21 +/- 0.14; p < 0.001). The study demonstrated that glucocorticoids enter the brain of neonatal rats because of an immature BBB. The results of this study support the hypothesis that neurotoxic adverse effects in preterm infants after systemic corticosteroid administration might be related to an immature BBB.
全身使用皮质类固醇后，早产儿出现神经毒性不良反应的几率会升高。为了验证这是否可能与血脑屏障（BBB）不成熟有关，即允许皮质类固醇进入大脑并诱发神经毒性作用，本研究评估了气管内给予新生（10至11日龄）和成年大鼠曲安奈德后，其脑通透性的差异。将曲安奈德（新生大鼠使用磷酸盐前药）以2.5、25或50微克/千克的剂量气管内给予新生大鼠，以100微克/千克的剂量给予成年大鼠。采用体外受体结合试验监测6小时内大脑和肝脏糖皮质激素受体的累积占有率。对于25微克/千克和50微克/千克的曲安奈德磷酸盐，新生大鼠大脑和肝脏的受体占有率相似（大脑/肝脏受体占有率分别为1.10±0.14和0.87±0.13），而在较低剂量时大脑通透性有所降低。成年大鼠气管内给予100微克/千克曲安奈德后，大脑中的受体占有率显著降低（大脑/肝脏比率为0.21±0.14；p<0.001）。该研究表明，由于血脑屏障不成熟，糖皮质激素可进入新生大鼠的大脑。本研究结果支持以下假设：全身使用皮质类固醇后，早产儿出现神经毒性不良反应可能与血脑屏障不成熟有关。
