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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 (K(i)) in immature fetuses, premature, and newborn lambs. K(i) increased as a function of increases in osmolality. A segmented regression model described the relationship between K(i) and osmolality. At lower osmolalities, changes in K(i) were minimal but after a threshold, increases were linear. We examined responses of K(i) 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.

The hypothesis that the arterial input function (AIF) of gadolinium-diethylenetriaminepentaacetic acid injected by intravenous bolus and measured by the change in the T(1)-relaxation rate (Delta R(1); R(1) = 1/T(1)) of superior sagittal sinus blood (AIF-I) approximates the AIF of (14)C-labeled gadolinium-diethylenetriaminepentaacetic acid measured in arterial blood (reference AIF) was tested in a rat stroke model (n = 13). Contrary to the hypothesis, the initial part of the Delta R(1)-time curve was underestimated, and the area under the normalized curve for AIF-I was about 15% lower than that for the reference AIF. Hypothetical AIFs for gadolinium-diethylenetriaminepentaacetic acid were derived from the reference AIF values and averaged to obtain a cohort-averaged AIF. Influx rate constants (K(i)) and proton distribution volumes at zero time (V(p) + V(o)) were estimated with Patlak plots of AIF-I, hypothetical AIFs, and cohort-averaged AIFs and tissue Delta R(1) data. For the regions of interest, the K(i)s estimated with AIF-I were slightly but not significantly higher than those obtained with hypothetical AIFs and cohort-averaged AIF. In contrast, V(p) + V(o) was significantly higher when calculated with AIF-I. Similar estimates of K(i) and V(p) + V(o) were obtained with hypothetical AIFs and cohort-averaged AIF. In summary, AIF-I underestimated the reference AIF; this shortcoming had little effect on the K(i) calculated by Patlak plot but produced a significant overestimation of V(p) + V(o)., ((c) 2010 Wiley-Liss, Inc.)

An intravenous step-down infusion procedure that maintained a constant gadolinium-diethylenetriaminepentaacetic acid (Gd-DTPA) blood concentration and magnetic resonance imaging (MRI) were used to localize and quantify the blood-brain barrier (BBB) opening in a rat model of transient cerebral ischemia (n=7). Blood-to-brain influx rate constant (K(i)) values of Gd-DTPA from such regions were estimated using MRI-Patlak plots and compared with the K(i) values of Gd-[(14)C]DTPA, determined minutes later in the same rats with an identical step-down infusion, quantitative autoradiography (QAR), and single-time equation. The normalized plasma concentration-time integrals were identical for Gd-DTPA and Gd-[(14)C]DTPA, indicating that the MRI protocol yielded reliable estimates of plasma Gd-DTPA levels. In six rats with a BBB opening, 14 spatially similar regions of extravascular Gd-DTPA enhancement and Gd-[(14)C]DTPA leakage, including one very small area, were observed. The terminal tissue-plasma ratios of Gd-[(14)C]DTPA tended to be slightly higher than those of Gd-DTPA in these regions, but the differences were not significant. The MRI-derived K(i) values for Gd-DTPA closely agreed and correlated well with those obtained for Gd-[(14)C]DTPA. In summary, MRI estimates of Gd-DTPA concentration in the plasma and brain and the influx rate are quantitatively and spatially accurate with step-down infusions.

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 alpha-aminoisobutyric acid in fetuses at 60% and 90% gestation, premature, newborn, and older lambs. Ki 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 Ki were minimal, but after a break point (threshold) was reached, the increase (P < 0.05) was linear. We examined the responses of Ki 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.

Objective: 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., Methods: 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 (K(i)) for alpha-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., Results: Both single (analysis of variance [ANOVA]; main effects for dexamethasone treatment, F = 5.92, P <.04) and multiple (ANOVA; main effects for dexamethasone treatment, F = 4.74, P <.04) courses of antenatal corticosteroids were associated with decreases in blood-brain barrier permeability in the brain regions of the ovine fetus. However, the multiple courses did not accentuate (ANOVA; main effects for single versus multiple courses, F = 1.06, P = .32) the decreases in permeability observed after a single course., Conclusion: Contrary to our hypothesis, antenatal treatment with a 5-week course of corticosteroids did not accentuate the reductions in blood-brain barrier permeability that we observed after a single course of corticosteroids in the fetus.

An intravenous step-down infusion procedure that maintained a constant gadolinium-diethylenetriaminepentaacetic acid (Gd-DTPA) blood concentration and magnetic resonance imaging (MRI) were used to localize and quantify the blood–brain barrier (BBB) opening in a rat model of transient cerebral ischemia (n=7). Blood-to-brain influx rate constant (Ki) values of Gd-DTPA from such regions were estimated using MRI–Patlak plots and compared with the Ki values of Gd-[14C]DTPA, determined minutes later in the same rats with an identical step-down infusion, quantitative autoradiography (QAR), and single-time equation. The normalized plasma concentration–time integrals were identical for Gd-DTPA and Gd-[14C]DTPA, indicating that the MRI protocol yielded reliable estimates of plasma Gd-DTPA levels. In six rats with a BBB opening, 14 spatially similar regions of extravascular Gd-DTPA enhancement and Gd-[14C]DTPA leakage, including one very small area, were observed. The terminal tissue–plasma ratios of Gd-[14C]DTPA tended to be slightly higher than those of Gd-DTPA in these regions, but the differences were not significant. The MRI-derived Ki values for Gd-DTPA closely agreed and correlated well with those obtained for Gd-[14C]DTPA. In summary, MRI estimates of Gd-DTPA concentration in the plasma and brain and the influx rate are quantitatively and spatially accurate with step-down infusions.Journal of Cerebral Blood Flow & Metabolism (2009) 29, 1048–1058; doi:10.1038/jcbfm.2009.20; published online 25 March 2009 [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Presents a quantitative measurement of blood-brain barrier function in ovine fetuses, lambs and adult sheep. Plasma radioactivity profile of aminoisobutyric acid and polyethylene glycol; Physiological variables in fetuses, lambs and adult sheep; Brain plasma volume measured with polyethylene glycol.

Comments on the study by G.D. Sysyn, K.H. Peterson and C.S. Patlak regarding the effects of postnatal dexamethasone on blood-brain barrier permeability and brain water content in newborn lambs.