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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 ([K.sub.i]) with [alpha]-aminoisobutyric acid in fetuses at 60% and 90% gestation, premature, newborn, and older lambs. [K.sub.i] plotted 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 [K.sub.i] were minimal, but after a break point (threshold) was reached, the increase (P < 0.05) was linear. We examined the responses of [K.sub.i] to 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 Ki plotted 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. [alpha]-aminoisobutyric acid; brain; barrier; development; immature; lambs; mannitol; sheep

A study was conducted to test the hypothesis that antenatal corticosteroids reduce blood-brain barrier permeability in the pre-term ovine fetus. The hypothesis was based on the fact that antenatal corticosteroid therapy decreases the incidence of intraventricular hemorrhage in premature human infants. By administering dexamethasone in ewes, the study found that the blood-brain barrier permeability decreased across brain regions. The results suggest that corticosteroids could accelerate cardiovascular maturation and affect blood-brain function in unborn humans.

The development of the mammalian blood-brain barrier was analyzed in chronically instrumented sheep, during the first month of neonatal and last two months of fetal development. Quantitative analysis of blood-brain barrier function in sheep fetuses indicated the presence of ontogenic reductions in synthetic, inert hydrophilic alpha-amino isobutyric acid [AIB] from gestational to three-year-old sheep. Furthermore, the blood brain barrier and other brain regions were permeable to AIB in all age groups of sheep.

Lipopolsaccharide-(LPS) induced decrease in blood insulin-like growth factor I (IGF-I) concentration is mainly due to a reduction in hepatic production, and is not due to a change in the body's peptide clearance. The decreased production by both parenchymal and Kupffer cells results in this altered state. Hepatic cell isolation reveals that although the LPS decreased the IGF-I content in Kupffer and parenchymal cells, it however, does not affect the endolethial cells.

Cultured astroglial cells obtained from newborn rats are used to determine whether arginine vasopressin and atriopeptin control brain cell volume. The regulators are assumed to be peptide hormones prepared and secreted inside the brain. A clear serum-free medium such as the 3-O-methylglucose (3-MG) space is used as a channel to calculate the cell water content, considered to be the volume. The calculation of the 3-MG space is independent of glucose, though the glucose carrier is required by 3-MG and glucose.

Abstract Background Putatively active drugs are often intraventricularly administered to gain direct access to brain and circumvent the blood-brain barrier. A few studies on the normal central nervous system (CNS) have shown, however, that the distribution of materials after intraventricular injections is much more limited than presumed and their exit from cerebrospinal fluid (CSF) is more rapid than generally believed. In this study, we report the intracranial distribution and the clearance from CSF and adjacent CNS tissue of radiolabeled insulin-like growth factor-1 after injection into one lateral ventricle of the normal rat brain. Methods Under barbiturate anesthesia, 125I-labeled insulin-like growth factor-1 (IGF-1) was injected into one lateral ventricle of normal Sprague-Dawley rats. The subsequent distribution of IGF-1 through the cerebrospinal fluid (CSF) system and into brain, cerebral blood vessels, and systemic blood was measured over time by gamma counting and quantitative autoradiography (QAR). Results Within 5 min of infusion, IGF-1 had spread from the infused lateral ventricle into and through the third and fourth ventricles. At this time, 25% of the infused IGF-1 had disappeared from the CSF-brain-meningeal system; the half time of this loss was 12 min. The plasma concentration of cleared IGF-1 was, however, very low from 2 to 9 min and only began to rise markedly after 20 min. This delay between loss and gain plus the lack of radiotracer in the cortical subarachnoid space suggested that much of the IGF-1 was cleared into blood via the cranial and/or spinal nerve roots and their associated lymphatic systems rather than periventricular tissue and arachnoid villi. Less than 10% of the injected radioactivity remained in the CSF-brain system after 180 min. The CSF and arteries and arterioles within the subarachnoid cisterns were labeled with IGF-1 within 10 min. Between 60 and 180 min, most of the radioactivity within the cranium was retained within and around these blood vessels and by periaqueductal gray matter. Tissue profiles at two sites next to ventricular CSF showed that IGF-1 penetrated less than 1.25 mm into brain tissue and appreciable 125I-activity remained at the tissue-ventricular CSF interface after 180 min. Conclusion Our findings suggest that entry of IGF-1 into normal brain parenchyma after lateral ventricle administration is limited by rapid clearance from CSF and brain and slow movement, apparently by diffusion, into the periventricular tissue. Various growth factors and other neuroactive agents have been reported to be neuroprotective within the injured brain after intraventricular administration. It is postulated that the delivery of such factors to neurons and glia in the injured brain may be facilitated by abnormal CSF flow. These several observations suggest that the flow of CSF and entrained solutes may differ considerably between normal and abnormal brain and even among various neuropathologies.

Effects of postnatal dexamethasone on blood-brain barrier permeability and brain water content in newborn lambs. Am J Physiol Regulatory Integrative Comp Physiol 280: R547-R553, 2001.--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 ([K.sub.i]) to [Alpha]-aminoisobutyric acid, brain plasma volume was measured with polyethylene glycol for the calculation of [K.sub.i], 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. [Alpha]-aminoisobutyric acid; plasma cortisol; postnatal sheep