Contrary to adult, neonatal rats show pronounced brain uptake of corticosteroids.
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.
Arya
Vikram
V
Department of Pharmaceutics, College of Pharmacy, JHMHC, University of Florida, Gainesville, FL 32610, USA.
Demarco
Vincent G
VG
Issar
Manish
M
Hochhaus
Günther
G
D000305:Adrenal Cortex Hormones / Q000008:administration & dosage / Q000493:pharmacokinetics*; D000818:Animals; D000831:Animals, Newborn; D001812:Blood-Brain Barrier / Q000254:growth & development / Q000378:metabolism*; D001921:Brain / Q000254:growth & development / Q000378:metabolism*; D007442:Intubation, Intratracheal; D008099:Liver / Q000378:metabolism; D051381:Rats; D011916:Rats, Inbred F344; D011965:Receptors, Glucocorticoid / Q000032:analysis / Q000378:metabolism*; D013997:Time Factors; D014222:Triamcinolone Acetonide / Q000008:administration & dosage / Q000493:pharmacokinetics
D000305:Adrenal Cortex Hormones; D011965:Receptors, Glucocorticoid; D014222:Triamcinolone Acetonide