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Hypoxic ischemic insults predispose to perinatal brain injury. Pro-inflammatory cytokines are important in the evolution of this injury. Interleukin-1β (IL-1β) is a key mediator of inflammatory responses and elevated IL-1β levels in brain correlate with adverse neurodevelopmental outcomes after brain injury. Impaired blood-brain barrier (BBB) function represents an important component of hypoxic-ischemic brain injury in the fetus. In addition, ischemia-reperfusion increases cytokine transport across the BBB of the ovine fetus. Reducing pro-inflammatory cytokine entry into brain could represent a novel approach to attenuate ischemia-related brain injury. We hypothesized that infusions of neutralizing IL-1β monoclonal antibody (mAb) reduce IL-1β transport across the BBB after ischemia in the fetus. Fetal sheep were studied 24-h after 30-min of carotid artery occlusion. Fetuses were treated with placebo- or anti-IL-1β mAb intravenously 15-min and 4-h after ischemia. Ovine IL-1β protein expressed from IL-1β pGEX-2T vectors in E. Coli BL-21 cells was produced, purified, and radiolabeled with 125I. BBB permeability was quantified using the blood-to-brain transfer constant (Ki) with 125I-radiolabeled-IL-1β. Increases in anti-IL-1β mAb were observed in the brain of the mAb-treated group (P

Impaired blood-brain barrier function represents an important component of hypoxic-ischemic brain injury in the perinatal period. Proinflammatory cytokines could contribute to ischemia-related blood-brain barrier dysfunction. IL-6 increases vascular endothelial cell monolayer permeability in vitro. However, contributions of IL-6 to blood-brain barrier abnormalities have not been examined in the immature brain in vivo. We generated pharmacologic quantities of ovine-specific neutralizing anti-IL-6 mAbs and systemically infused mAbs into fetal sheep at 126 days of gestation after exposure to brain ischemia. Anti–IL-6 mAbs were measured by ELISA in fetal plasma, cerebral cortex, and cerebrospinal fluid, blood-brain barrier permeability was quantified using the blood-to-brain transfer constant in brain regions, and IL-6, tight junction proteins, and plasmalemma vesicle protein (PLVAP) were detected by Western immunoblot. Anti–IL-6 mAb infusions resulted in increases in mAb (P < 0.05) in plasma, brain parenchyma, and cerebrospinal fluid and decreases in brain IL-6 protein. Twenty-four hours after ischemia, anti–IL-6 mAb infusions attenuated ischemia-related increases in blood-brain barrier permeability and modulated tight junction and PLVAP protein expression in fetal brain. We conclude that inhibiting the effects of IL-6 protein with systemic infusions of neutralizing antibodies attenuates ischemia-related increases in blood-brain barrier permeability by inhibiting IL-6 and modulates tight junction proteins after ischemia.—Zhang, J., Sadowska, G. B., Chen, X., Park, S. Y., Kim, J.-E., Bodge, C. A., Cummings, E., Lim, Y.-P., Makeyev, O., Besio, W. G., Gaitanis, J., Banks, W. A., Stonestreet, B. S. Anti–IL-6 neutralizing antibody modulates blood-brain barrier function in the ovine fetus.

Objectives: The blood-brain barrier is a selective diffusion barrier between brain parenchyma and the intravascular compartment. Tight junctions are integral components of the blood-brain barrier. Pro-inflammatory cytokines are important in the pathogenesis of brain injury and could modify the protein constituents of tight junctions. We hypothesized that interleukin-6 (IL-6) downregulates key protein constituents of endothelial tight junctions (e.g. occludin and claudin-5). Methods: We examined the effects of IL-6 on tight junction protein expression using an in vitro blood-brain barrier model. We isolated microvessels from yearling and adult ovine cerebral cortex and placed them into culture with IL-6 concentrations of 0 (control, phosphate-buffered saline), 1, 10, and 100 ng/ml for 24 h. Cerebral microvessels were harvested, Western immunoblot performed for occludin and claudin-5, densitometry performed, and results expressed as a ratio to control values. Results: Western immunoblot analysis showed that treatment with 100 ng/ml of IL-6, but not the lower concentrations, reduced (p < 0.05) occludin expression in microvessels from yearling and adult sheep and claudin-5 in microvessels from adult sheep. However, treatment with 10 ng/ml of IL-6 increased claudin-5 in microvessels from yearling sheep. The percent of lactate dehydrogenase released from the microvessels into the surrounding media was not increased by IL-6 treatment, suggesting that the reductions in tight junction proteins did not result from cell death. Treatment of adult cerebral cortical microvessels with IL-6 preincubated with anti-IL-6 monoclonal antibodies partially attenuated the reduction in claudin-5. Conclusion: We conclude that IL-6 modulates tight junction protein expression in cerebral cortical microvessels from yearling and adult sheep.

Objectives: The cytokines interleukin (IL)-1β and IL-6 are modulators of the neuroimmune axis and have been implicated in neuronal cell death cascades after ischemia or infection. Previous work has shown that some cross-species conservation exists between human and rodent blood-brain barrier (BBB) transport systems. To further assess cross-species conservation of cytokine transport across the BBB, the current studies investigated permeability and inhibition of ovine IL-1β and IL-6 in the mouse. Methods: IL-1β or IL-6 was radioactively labeled with 131I and injected into the jugular vein at time zero. A subset of mice received 1 or 3 µg/mouse of an unlabeled ovine or murine cytokine (IL-1β or IL-6) to assess self- and/or cross-inhibition of transport. Permeability was assessed using multiple-regression analysis. Results: There was a significant linear relationship for both ovine 131I-IL-1β and 131I-IL-6 between brain/serum ratios and exposure time, indicating BBB permeability. Inclusion of 3 µg/mouse unlabeled ovine IL-1β or IL-6 significantly reduced the transport of ovine 131I-IL-1β or 131I-IL-6, respectively, across the BBB. Transport of both ovine 131I-IL-1β and 131I-IL-6 was significantly inhibited by 1 µg/mouse of murine IL-1β or IL-6, respectively. In contrast, 1 µg/mouse of unlabeled ovine IL-1β or IL-6 did not inhibit the transport of murine 131I-IL-1β or 131I-IL-6. Conclusions: Ovine IL-1β and IL-6 cross the mouse BBB by saturable transport. Inhibition of transport by murine homologs indicates that both species use the same transport mechanisms. Conversely, an inability of ovine cytokines to significantly inhibit the transport of murine cytokines indicates that mouse BBB has a lower affinity for ovine than murine cytokines. Knowledge of species-conserved BBB transport mechanisms may facilitate the development of novel animal models of central nervous system pathogenesis.

Tight junctions of the blood-brain barrier are composed of transmembrane and associated cytoplasmic proteins. The transmembrane claudin proteins form the primary seal between endothelial cells and junctional adhesion molecules (JAMs) regulate tight junction formation. We have previously shown that claudin-1, claudin-5, zonula occludens (ZO)-1, and ZO-2 exhibit differential developmental regulation from 60% of gestation up to maturity in adult sheep. The purpose of the current study was to examine developmental changes in claudin-3, -12, and JAM-A protein expression in cerebral cortices of fetuses at 60%, 80%, and 90% gestation, and in newborn and adult sheep. We also examined correlations between changes in endogenous cortisol levels and tight junction protein expression in cerebral cortices of the fetuses. Claudin-3, -12 and JAM-A expressions were determined by Western immunoblot. Claudin-3 and -12 were lower (P

Pro-inflammatory cytokines contribute to hypoxic–ischemic brain injury. Blood–brain barrier (BBB) dysfunction represents an important component of hypoxic–ischemic brain injury in the fetus. Hypoxic–ischemic injury could accentuate systemic cytokine transfer across the fetal BBB. There has been considerable conjecture suggesting that systemic cytokines could cross the BBB during the perinatal period. Nonetheless, evidence to support this contention is sparse. We hypothesized that ischemia–reperfusion increases the transfer of systemic interleukin-1β (IL-1β) across the BBB in the fetus. Ovine fetuses at 127 days of gestation were studied 4 hours after 30 minutes of bilateral carotid artery occlusion and compared with a nonischemic group. Recombinant ovine IL-1β protein was expressed from an IL-1β pGEX-2 T vector in E. coli BL-21 cells and purified. The BBB function was quantified in 12 brain regions using a blood-to-brain transfer constant with intravenous 125I-radiolabeled IL-1β (125I-IL-1β). Interleukin-1β crossed the intact BBB in nonischemic fetuses. Blood-to-brain transport of 125I-IL-1β was higher ( P < 0.05) across brain regions in fetuses exposed to ischemia–reperfusion than nonischemic fetuses. We conclude that systemic IL-1β crosses the intact fetal BBB, and that ischemia–reperfusion increases transfer of this cytokine across the fetal BBB. Therefore, altered BBB function after hypoxia–ischemia facilitates entry of systemic cytokines into the brain of the fetus.

We examined the effects of hyperosmolality on blood-brain barrier (BBB) permeability during development to test the vulnerability of the immature barrier to stress. The BBB response to hyperosmolality was quantified using the blood-to-brain transfer constant ( Ki) with α-aminoisobutyric acid in fetuses at 60% and 90% gestation, premature, newborn, and older lambs. Kiplotted against osmolality increased as a function of increases in osmolality in all groups and brain regions. The relationship was described ( P < 0.05) by a segmented regression model. At lower osmolalities, changes in Kiwere minimal, but after a break point (threshold) was reached, the increase ( P < 0.05) was linear. We examined the responses of Kito hyperosmolality within each brain region by comparing the thresholds and slopes of the second regression segment. Lower thresholds and higher slopes imply greater vulnerability to hyperosmolality in the younger groups. Thresholds increased ( P < 0.05) with development in the thalamus, superior colliculus, pons, and spinal cord, and slopes of the second regression segment decreased ( P < 0.05) in the cerebellum, hippocampus, inferior colliculus, medulla, and spinal cord. BBB resistance to hyperosmolality increased ( P < 0.05) with development in most brain regions. The pattern of the Kiplotted against osmolality was ( P < 0.05) heterogenous among brain regions in fetuses and premature and newborn lambs, but not in older lambs. We conclude that 1) BBB permeability increased as a function of changes in osmolality, 2) the barrier becomes more resistant to hyperosmolality during development, and 3) the permeability response to hyperosmolality is heterogenous among brain regions in fetuses and premature and newborn lambs.

In adult rats, when plasma osmolality increases, water flows across the blood-brain barrier down its concentration gradient from brain to plasma, and brain volume deceases. The brain responds to this stress by gaining osmotically active solutes, which limit water loss. This phenomenon is termed brain volume (water) regulation. We tested the hypothesis that brain volume regulation is more effective in young lambs and adult sheep than in fetuses, premature lambs, and newborn lambs. Brain water responses to acute hyperosmolality were measured in the cerebral cortex, cerebellum, and medulla of fetuses at 60 and 90% of gestation, premature ventilated lambs at 90% of gestation, newborn lambs, young lambs at 20–30 days of age, and adult sheep. After exposure of the sheep to increases in systemic osmolality with mannitol plus NaCl, brain water content and electrolytes were quantified. The ideal osmometer is a system in which impermeable solutes do not enter or leave in response to an osmotic stress. There were significant differences from an ideal osmometer in the cerebral cortex of fetuses at 90% of gestation, cerebral cortex, and cerebellum of newborn lambs, and cerebral cortex, cerebellum, and medulla of young lambs and adult sheep; however, there were no differences in the brain regions of fetuses at 60% of gestation and premature lambs, cerebellum and medulla of fetuses at 90% of gestation, and medulla of newborn lambs. We conclude that 1) brain water loss is maximal and brain volume regulation impaired in most brain regions of fetuses at 60 and 90% of gestation and premature lambs; 2) brain volume regulation develops first in the cerebral cortex of the fetuses at 90% of gestation and in the cerebral cortex and cerebellum of newborn lambs, and then it develops in the medulla of the lambs at 20–30 days of age; 3) brain water loss is limited and volume regulation present in the brain regions of young lambs and adult sheep; and 4) the ability of the brain to exhibit volume regulation develops in a region- and age-related fashion.

article i nfo We have previously shown that increases in blood-brain barrier permeability represent an important compo- nent of ischemia-reperfusion related brain injury in the fetus. Pro-inflammatory cytokines could contribute to these abnormalities in blood-brain barrier function. We have generated pharmacological quantities of mouse anti-ovine interleukin-1β monoclonal antibody and shown that this antibody has very high sensitivity and specificity for interleukin-1β protein. This antibody also neutralizes the effects of interleukin-1β protein in vitro. In the current study, we hypothesized that the neutralizing anti-interleukin-1β monoclonal antibody at- tenuates ischemia-reperfusion related fetal blood-brain barrier dysfunction. Instrumented ovine fetuses at 127 days of gestation were studied after 30 min of carotid occlusion and 24 h of reperfusion. Groups were sham operated placebo-control- (n = 5), ischemia-placebo- (n = 6), ischemia-anti-IL-1β antibody- (n = 7), and sham-control antibody- (n = 2) treated animals. Systemic infusions of placebo (0.154 M NaCl) or anti- interleukin-1β monoclonal antibody (5.1 ± 0.6 mg/kg) were given intravenously to the same sham or ischemic group of fetuses at 15 min and 4 h after ischemia. Concentrations of interleukin-1β protein and anti-interleukin- 1β monoclonal antibody were measured by ELISA in fetal plasma, cerebrospinal fluid, and parietal cerebral cortex. Blood-brain barrier permeability was quantified using the blood-to-brain transfer constant (Ki) with α-aminoisobutyric acid in multiple brain regions. Interleukin-1β protein was also measured in parietal ce- rebral cortices and tight junction proteins in multiple brain regions by Western immunoblot. Cerebral cortical interleukin-1β protein increased (P b 0.001) after ischemia-reperfusion. After anti-interleukin-1β monoclonal antibody infusions, plasma anti-interleukin-1β monoclonal antibody was elevated (P b 0.001), brain anti- interleukin-1β monoclonal antibody levels were higher (P b 0.03), and interleukin-1β protein concentrations (P b 0.03) and protein expressions (P b 0.001) were lower in the monoclonal antibody-treated group than in placebo-treated-ischemia-reperfusion group. Monoclonal antibody infusions attenuated ischemia-reperfusion- related increases in Ki across the brain regions (P b 0.04), and Ki showed an inverse linear correlation (r = �0.65, P b 0.02) with anti-interleukin-1β monoclonal antibody concentrations in the parietal cortex, but had little effect on tight junction protein expression. We conclude that systemic anti-interleukin-1β mono- clonalantibody infusionsafter ischemiaresult inbrainanti-interleukin-1βantibodyuptake, andattenuate ische- mia-reperfusion-related interleukin-1β protein up-regulation and increases in blood-brain barrierpermeability across brain regions in the fetus. The pro-inflammatory cytokine, interleukin-1β, contributes to impaired blood- brain barrier function after ischemia in the fetus.

We have been studying the ontogeny of the blood-brain barrier function in ovine fetuses and lambs. During these studies, we have found that the duration of ventilation also influences blood-brain barrier permeability in premature lambs. Chronically instrumented hysterotomy-delivered surfactant-treated premature lambs were studied at 90% or 137 days of gestation ( n = 9). Blood-brain barrier function was quantified with the blood-to-brain transfer constant Kito α-aminoisobutyric acid. Linear regression analysis was used to compare the Kivalues in the brain regions, as the dependent variable, to the duration of ventilation, as the independent variable. There were direct correlations ( P < 0.05) between the Kivalues and the duration of ventilation [306 min (mean), 162–474 min (range)] in the cerebral cortex, cerebellum, medulla, caudate nucleus, hippocampus, superior colliculus, inferior colliculus, thalamus, pons, cervical spinal cord, and choroid plexus, but not in the pituitary gland. Ventilatory pressures and rates were established before the onset of the permeability studies. Calculated mean airway pressures [14 cmH2O (mean), 7–20 cmH2O (range)] from similarly studied premature lambs did not correlate with the duration of positive-pressure ventilation. We conclude that increases in the duration of positive-pressure ventilation predispose premature lambs to increases in regional blood-brain barrier permeability. These alterations in barrier function occur over relatively short time intervals (minutes to hours). In our study, these changes in permeability are most likely not attributable to changes in mean airway pressure.

The blood-brain barrier is a restrictive interface between the brain parenchyma and the intravascular compartment. Tight junctions contribute to the integrity of the blood-brain barrier. Hypoxic-ischemic damage to the blood-brain barrier could be an important component of fetal brain injury. We hypothesized that increases in blood-brain barrier permeability after ischemia depend upon the duration of reperfusion and that decreases in tight junction proteins are associated with the ischemia-related impairment in blood-brain barrier function in the fetus. Blood-brain barrier function was quantified with the blood-to-brain transfer constant (K(i)) and tight junction proteins by Western immunoblot in fetal sheep at 127 days of gestation without ischemia, and 4, 24, or 48 h after ischemia. The largest increase in K(i) (P

We examined the effects of hyperglycemic hyperosmolality on blood-brain barrier (BBB) permeability during development. We hypothesized that the barrier becomes more resistant to hyperglycemic hyperosmolality during development, and the immature BBB is more resistant to glucose than to mannitol hyperosmolality. We quantified the BBB response to hyperosmolality with the blood-to-brain transfer constant ( Ki) in immature fetuses, premature, and newborn lambs. Ki increased as a function of increases in osmolality. A segmented regression model described the relationship between Ki and osmolality. At lower osmolalities, changes in Ki were minimal but after a threshold, increases were linear. We examined responses of Ki to hyperglycemic hyperosmolality by comparing the thresholds and slopes of the second regression segments. Lower thresholds and steeper slopes indicate greater vulnerability to hyperosmolality. Thresholds increased ( P < 0.05) during development in pons and superior colliculus. Thresholds were higher ( P < 0.05) during glucose than mannitol hyperosmolality in thalamus, superior colliculus, inferior colliculus and medulla of premature lambs, and in cerebrum and cerebellum of newborns. We conclude that BBB permeability increased as a function of changes in glucose osmolality, the barrier becomes more resistant to glucose hyperosmolality in two brain regions during development, and the barrier is more resistant to glucose than to mannitol hyperosmolality in some brain regions of premature and newborn lambs.

We examined the expression of tight junction (TJ) proteins in the cerebral cortex, cerebellum, and spinal cord of fetuses after maternal treatment with single and multiple courses of dexamethasone. Ewes received either single courses of four 6-mg dexamethasone or placebo injections every 12 h for 48 h between 104 and 107 days or the same treatment once a week between 76–78 and 104–107 days of gestation. TJ protein expression was determined by Western immunoblot analysis on tissue harvested at 105–108 days of gestation. Blood-brain barrier permeability has been previously quantified with the blood-to-brain transfer constant ( Ki) with α-aminoisobutyric acid ( 39 ). After a single course of dexamethasone, claudin-5 increased ( P < 0.05) in the cerebral cortex, occludin and claudin-1 increased in the cerebellum, and occludin increased in the spinal cord. After multiple dexamethasone courses, occludin and zonula occludens (ZO)-1 increased in the cerebral cortex, and occludin and claudin-1 increased in the cerebellum. Junctional adhesion molecule-A and ZO-2 expressions did not change. Linear regression comparing Kito TJ proteins showed inverse correlations with claudin-1 and claudin-5 in the cerebral cortex after a single course and ZO-2 in the spinal cord after multiple courses and direct correlations with ZO-1 in the cerebellum and spinal cord after multiple courses. We conclude that maternal glucocorticoid treatment increases the expression of specific TJ proteins in vivo, patterns of TJ protein expression vary after exposure to single and multiple glucocorticoid courses, and decreases in blood-brain barrier permeability are associated with increases in claudin-1, claudin-5, and ZO-2 expression and decreases in ZO-1 expression. In utero glucocorticoid exposure alters the molecular composition of the barrier and affects fetal blood-brain barrier function.

Maternal glucocorticoid treatment reduces blood-brain permeability early, but not late in fetal development, and pretreatment with glucocorticoids does not affect barrier permeability in newborn lambs. In addition, endogenous increases in plasma cortisol levels are associated with decreases in blood-brain barrier permeability during normal fetal development. Therefore, we tested the hypotheses that development as well as endogenous and exogenous glucocorticoids alters the expression of tight junction proteins in the cerebral cortex of sheep. Cerebral cortices from fetuses at 60%, 70%, and 90% of gestation, newborn and adult sheep were snap frozen after four 6-mg dexamethasone or placebo injections were given over 48-h to the ewes and adult sheep. Lambs were treated similarly with 0.25 mg/kg-dexamethasone or placebo. Tight junction protein expression was measured by Western immunoblot. Claudin-1 was higher (P

To test the hypothesis that multiple courses of antenatal corticosteroids accentuate the decreases in blood-brain barrier permeability observed after a single course of corticosteroids in preterm ovine fetuses. Chronically instrumented 106-day gestation ovine fetuses were studied after single and multiple courses of dexamethasone or placebo were given to ewes beginning at 104 to 106 or 76 to 78 days of gestation, respectively. In the single-course groups, the ewes received dexamethasone (6 mg, n = 6) or placebo (n = 6) as four intramuscular injections every 12 hours over 48 hours. In the multiple course groups, the ewes received the same treatment (dexamethasone, n = 9, or placebo, n = 8), once per week for 5 weeks starting at 76 to 78 days of gestation. Blood-brain barrier permeability was quantified with the blood-to-brain transfer constant (Ki) for α-aminoisobutyric acid (AIB) in the brain regions of the fetuses 12 hours after the last injection of dexamethasone was given to the ewes at 106 to 107 days of gestation. Both single (analysis of variance [ANOVA]; main effects for dexamethasone treatment, F = 5.92, P

We showed that antenatal corticosteroids reduced blood-brain barrier permeability in fetuses at 60 and 80%, but not 90% of gestation, and decreased brain water content in fetuses. Our objective was to examine the effects of postnatal corticosteroids on regional blood-brain barrier permeability and brain water content in newborn lambs. Three dexamethasone treatment groups were studied in 3- to 5-day-old lambs. A 0.01 mg/kg dose was selected to estimate the amount of dexamethasone that might have reached fetuses via antenatal treatment of ewes in our previous studies. The other doses (0.25 and 0.5 mg/kg) were chosen to approximate those used clinically to treat infants with bronchopulmonary dysplasia. Lambs were randomly assigned to receive four intramuscular injections of dexamethasone or placebo given 12 h apart on days 3 and 4 of age. Blood-brain barrier function was measured with the blood-to-brain transfer constant ( Ki) to α-aminoisobutyric acid, brain plasma volume was measured with polyethylene glycol for the calculation of Ki,and brain water was measured by wet-to-dry tissue weights. Postnatal treatment with corticosteroids did not reduce barrier permeability in newborn lambs. Brain blood volume was higher in the 0.25 and 0.5 mg/kg dose dexamethasone groups than in the placebo group. Brain water content did not differ among the groups. We conclude that postnatal treatment with corticosteroids did not reduce regional blood-brain barrier permeability or brain water content but increased the brain plasma volume in newborn lambs. These findings are consistent with our previous work indicating that barrier permeability is responsive to corticosteroids at 60 and 80% of gestation and brain water regulation at 60% of gestation, but not in near-term fetuses or newborn lambs.

We previously reported decreases in blood-brain barrier permeability in the ovine fetus at 80% of gestation after antenatal corticosteroids and shown that permeability is not reduced in newborn lambs after postnatal corticosteroids. We now test the hypotheses that exogenous antenatal corticosteroids decrease blood-brain barrier permeability at 60% but not 90% of gestation in ovine fetuses and that endogenous increases in plasma cortisol concentrations are associated with ontogenic decreases in barrier permeability during gestation. Chronically instrumented ovine fetuses were studied 12 h after the last of four 6-mg dexamethasone or placebo injections were given 12 h apart over 48 h to ewes. Fetuses at 80% of gestation from placebo-treated ewes studied under the same protocol were also included. Blood-brain barrier function was quantified with the blood-to-brain transfer constant ( K i) to α-aminoisobutyric acid. K i values were lower in cerebral cortex, caudate nucleus, hippocampus, superior colliculus, thalamus, medulla, and cervical spinal cord in fetuses of dexamethasone- than placebo-treated ewes at 60% but not 90% of gestation. Regional brain K i values demonstrated inverse correlations with increases in gestation and plasma cortisol concentrations in most brain regions. We conclude that maternal treatment with exogenous corticosteroids was associated with decreases in blood-brain barrier permeability at 60% but not 90% of gestation and that increases in gestation and endogenous cortisol concentrations were associated with ontogenic decreases in barrier permeability during fetal development.

Antenatal corticosteroid therapy reduces the incidence of intraventricular hemorrhage in premature infants. Enhanced microvascular integrity might provide protection against intraventricular hemorrhage. In the adult, there is evidence to suggest that the blood-brain barrier may be under hormonal control. We hypothesized that antenatal corticosteroids decrease blood-brain barrier permeability in the preterm ovine fetus. Chronically instrumented 120-day-gestation fetuses were studied 12 h after the last of four 6-mg dexamethasone ( n = 5) or placebo ( n = 6) injections had been given over 48 h to the ewes. Blood-brain barrier function was quantified with the blood-to-brain transfer constant ( K i) for α-aminoisobutyric acid (AIB). K i was significantly lower across brain regions in the fetuses of ewes that received antenatal dexamethasone compared with placebo (ANOVA; interaction, F = 2.54, P < 0.004). In fetuses of dexamethasone- and placebo-treated ewes, K i(μl ⋅ g brain wt−1 ⋅ min−1, mean ± SD) was, respectively, 2.43 ± 0.27 vs. 3.41 ± 0.74 in the cortex, 4.46 ± 0.49 vs. 5.29 ± 0.85 in the cerebellum, and 3.70 ± 0.49 vs. 5.11 ± 0.70 in the medulla. We conclude that antenatal treatment with corticosteroids reduces blood-brain permeability in the ovine fetus.

The Effect of Duration of Positive-Pressure Ventilation on Blood-Brain Barrier Function in Premature Lambs

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

The Duration of Positive-Pressure Ventilation Influences Blood-Brain Barrier Function in Preterm Lambs 233