Effects of Age and Endogenous Cortisol Concentrations on Blood-Brain Barrier Development in the Ovine Fetus

Abstract 1337 Poster Session IV, Tuesday, 5/4 (poster 244)

The blood-brain barrier (BBB) is composed of a continuous layer of cerebrovascular endothelial cells connected by intercellular tight junctions. We have previously shown that the BBB exhibits ontogenic decreases in permeability from 60% of gestation up to maturity in adult sheep and is relatively impermeable to a small hydrophilic molecule, α-aminoisobutyric acid (AIB), across this age span. We have also shown decreases in BBB permeability in the fetus at 80% of gestation after corticosteroids had been exogenously given to pregnant ewes. We now examine the ontogeny of BBB permeability to AIB in ovine fetuses at 60% (87 days), 80% (120 days), 90% (137 days) of gestation, and the potential contributions of changes in endogenous fetal plasma cortisol concentrations to barrier maturation. Regional BBB function was quantified with the blood-to-brain transfer constant K_i to AIB in chronically catheterized fetal sheep at 60% (n=7), 80% (n=5, values previously reported, Stonestreet et al., Am. J. Physiol., in press, 1998) and 90% (n=4) of gestation. Plasma cortisol concentrations were measured by RIA. Regional brain K_i was significantly higher across brain regions in fetuses at 60% than 80% of gestation (60% vs 80% ANOVA, interactions: F=14.5, P<0.001), 60% than 90% (60% vs 90%: F=19.7, P<0.001) and 80% than 90% (80% vs 90%: F=6.2, P<0.001). Plasma cortisol concentrations increased with advancing gestation (ANOVA: F=9.0, P<0.01; 60% vs 80%: P=0.13; 60% vs 90%: P<0.004, 1.24±0.06 vs 1.50±0.08; 80% vs 90%: P=0.18, 1.37±0.16 vs 1.50±0.08 log nmol/l, M±SD). Regional brain K_i values demonstrated inverse correlations with both advancing gestation (gest) and increasing plasma cortisol concentrations (cort) in the cerebrum (gest: r= -0.58, P<0.05; cort: r= -0.56, P<0.05); hippocampus (gest: r= -0.68, P<0.05; cort: r= -0.62, P<0.05); thalamus (gest: r= -0.63 P<0.05; cort: r= -0.59 P<0.05) and spinal cord (gest: r= -0.91, P<0.05; cort: r= -0.77, P<0.05). Multilinear partial correlational (pc) analyses were used to evaluate relative contributions of advancing gest and increase in cort to decreases in K_i. Brain K_i, as the dependent variable, was compared to both gest age and plasma cort, as independent variables, in the cerebrum: R=0.61, P<0.05 (gest: pc= -0.31, P=0.27; cort: pc= -0.23, P=0.40); hippocampus: R=0.70 P<0.01 (gest: pc= -0.42, P=0.21; cort: pc= -0.24, P=0.38); thalamus: R=0.66 P<0.02 (gest: pc= -0.36, P=0.18; cort: pc= -0.23, P=0.40); and spinal cord: R=0.92, P<0.001 (gest: pc=-0.80, P=0.0004; cort: pc= -0.35, P=0.20). We conclude that the barrier exhibits ontogenic decreases in regional permeability from early to late in fetal ovine development, and that both advancing gestation and increases in plasma cortisol concentrations contribute to the developmental decreases in permeability. We speculate that changes in endogenous plasma cortisol concentrations and other maturational factors contribute to these developmental changes in the barrier. RO1 HD34618