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At least 199 records · Page 11Linked to original sources
PubMed1997

Blood-brain barrier water permeability and brain osmolyte content during edema development.

OBJECTIVE: To determine mechanisms that limit changes in brain water content during acute edema development. METHODS: A controlled, laboratory investigation of the physiologic and biochemical correlates of osmotic edema was performed in rats. Hypoosmotic hyponatremia was induced by intraperitoneal injection of distilled water. Serum osmolality and electrolytes and regional blood-brain barrier water permeability. Surface area (P.S) product, osmolyte contents, and capillary size were determined during 120 minutes of hypoosmotic brain edema development. Cerebral water content predicted from these data using a mathematical model of brain water movements was compared with measured changes in brain water content. RESULTS: Fifteen minutes after distilled water injection, mean +/- SEM blood serum osmolality and sodium concentration decreased from 291 +/- 3 mOsm and 131 +/- 13 mmol/L to 267 +/- 3 mOsm and 102 +/- 9 mmol/L, respectively. Specific gravity of cerebral gray matter, cerebral white matter, and basal ganglia decreased throughout the hypoosmotic exposure period and, for gray and white matter, correlated with blood serum osmolality and sodium plus potassium content. Glutamate, but not glutamine, glycine, or taurine, decreased 120 minutes after water injection. The regional water P.S product decreased by 40% to 60% within 60 minutes of the water injection, while capillary diameters in gray and white matter were unchanged. Brain water movements calculated from the mathematical model correctly predicted actual brain water content only if the hydraulic conductivity of the blood-brain barrier was allowed to vary in proportion to the measured P.S product and the measured loss of brain osmolytes was incorporated into the formulation. CONCLUSIONS: During the first hours of hypoosmotic hyponatremia, changes in brain volume are limited by increased resistance to osmotic flux of water into the brain and reduction in the brain content of inorganic and, to a smaller degree, organic osmolytes.

Analysis of Variance↗
PubMed1997

Thrombomodulin expression in bovine brain capillaries. Anticoagulant function of the blood-brain barrier, regional differences, and regulatory mechanisms.

Thrombomodulin (TM), a key cofactor of the TM-protein C pathway, is of major biologic significance for the antithrombotic properties of endothelial cells. Yet, there is uncertainty whether TM is expressed in brain and what mechanisms govern brain endothelial anticoagulant activity. In this study, bovine brain capillaries were used as an in vitro model of the blood-brain barrier to determine factors involved in the regulation of TM expression in cerebral vasculature. Quantitative competitive-polymerase chain reaction assay revealed significant regional differences in the amount of brain capillary TM mRNA, i.e., cortical > cerebellar > pontine, consistent with the reverse transcription-polymerase chain reaction findings in which the abundance of TM mRNA was analyzed relative to beta-actin mRNA. Regional differences in TM mRNA brain capillary level correlated well with differences in protein C activation. The TM mRNA and activity were not detectable in brain parenchyma. Pathogenic mediators of ischemic stroke, interleukin 1 beta (10 U/mL), and tumor necrosis factor alpha (10 U/mL), produced a time-dependent decrease in brain capillary TM mRNA (t1/2 of 2.1 and 3.9 hours, respectively) and reduced endothelial TM activity. Incubation of brain capillaries with retinoic acid (10 mumol/L) and dibutyryl cAMP (3 mmol/L) resulted in a 4-fold increase in TM mRNA at 4 and 8 hours, respectively, followed by an increase in protein C activation. We conclude that TM at the blood-brain barrier is likely to be an important physiologic anticoagulant in brain microcirculation. Its downregulation by cytokines may contribute to ischemic brain damage and potentially could be counteracted by retinoic acid and cAMP.

Animals↗
PubMed1986

Development of brain insulin receptors: structural and functional studies of insulin receptors from whole brain and primary cell cultures.

We studied the structural and functional characteristics of insulin receptors from rat brain and liver from late gestation through adulthood as well as from cultured neuronal and glial cells from neonatal rats. Specific insulin binding was present on membrane preparations from brain and liver at all stages of development studied, with maximal binding in neonates greater than 19-day-old fetuses greater than adults for both brain and liver. Maximal specific binding to cultured neuronal and glial cell membranes was similar (6.2% vs. 7.1%, respectively). [125I]Iodoinsulin cross-linking to the insulin receptor demonstrated that the mol wt (Mr) of the brain alpha-subunit was less than that of the liver alpha-subunit at all stages. [125I]Iodoinsulin cross-linking also demonstrated that the glial cell alpha-subunit (Mr, 130,000) migrated on sodium dodecyl sulfate-polyacrylamide gel electrophoresis to a position intermediate between the liver (Mr, 135,000) and brain (Mr, 119,000), whereas the neuronal cell alpha-subunit (Mr, 118,000) comigrated with the brain alpha-subunit. In solubilized lectin-purified preparations from brain and liver during development as well as from neuronal and glial cells, insulin stimulated phosphorylation of the beta-subunit. The Mr of the brain beta-subunit, as determined by migration on sodium dodecyl sulfate-polyacrylamide gel electrophoresis, was less than that of the liver beta-subunit. The neuronal cell beta-subunit comigrated with the brain beta-subunit while the glial cell beta-subunit migrated to a position intermediate between the brain and liver beta-subunit. Solubilized lectin-purified preparations from all tissues demonstrated insulin-stimulable phosphorylation of exogenous substrates. From these studies we conclude that 1) functional insulin receptors are present in the brain during development in the rat; and 2) the structural differences demonstrated between neuronal and glial cell and between brain and nonneuronal insulin receptors taken together with previously demonstrated functional differences of the insulin receptor on these tissues suggest a unique function for insulin receptors on neuronal tissues.

Age Factors↗
PubMed2005

Brain tissue oxygenation in brain death.

INTRODUCTION: The value of brain tissue oxygenation (PbtO2) measurements in determining brain death is unknown. METHODS: Eleven of 72 patients who had brain tissue oxygen monitors placed experienced brain death. Admission diagnoses included six severe traumatic brain injuries, one multiple trauma with cardiac arrest, one brain tumor, one subarachnoid hemorrhage, one intracerebral hemorrhage, and one cerebral stroke. Eleven males and zero females were studied, with an average age of 26 years (range: 20-70 years). Nine patients had Glasgow Coma Scores (GCS) of 3 on admission, one patient had a GCS of 5, and one patient had a GCS of 15. RESULTS: Time from admission to declaration of brain death varied from 5 hours to 7 days; the most common interval was 1 or 2 days. Cerebral perfusion pressure (CPP) fell to 0 in eight patients, which indicated primary failure of cerebral perfusion. CPP stayed above 60 mmHg in three patients, indicating primary tissue failure, possibly of the cerebral microvasculature. PbtO2 fell to 0 in all patients who experienced brain death, and all patients with PbtO2 of 0 experienced brain death. None of the 61 patients who did not experience brain death had confirmed PbtO2 readings of 0. CONCLUSION: PbtO2 can be successfully and accurately used as a bedside adjunctive test for brain death. The use of PbtO2 as a sole confirmatory test for brain death in the setting of an appropriate clinical examination will require the evaluation of a larger number of patients to assess its sensitivity and specificity.

Adult↗
PubMed2005

Fetal microchimerism in the maternal mouse brain: a novel population of fetal progenitor or stem cells able to cross the blood-brain barrier?

We investigated whether fetal cells can enter the maternal brain during pregnancy. Female wild-type C57BL/6 mice were crossed with transgenic Green Mice ubiquitously expressing enhanced green fluorescent protein (EGFP). Green Mouse fetal cells were found in the maternal brain. Quantitative real-time polymerase chain reaction (PCR) of genomic DNA for the EGFP gene showed that more fetal cells were present in the maternal brain 4 weeks postpartum than on the day of parturition. After an excitotoxic lesion to the brain, more fetal cells were detected in the injured region. The presence of fetal cells in the maternal brain was also confirmed by quantitative real-time PCR for the sex-determining region of the Y chromosome. Four weeks postpartum, EGFP-positive Green Mouse fetal cells in the maternal brain were found to adopt locations, morphologies, and expression of immunocytochemical markers indicative of perivascular macrophage-, neuron-, astrocyte-, and oligodendrocyte-like cell types. Expression of morphological and immunocytochemical characteristics of neuron- and astrocyte-like cell types was confirmed on identification of fetal cells in maternal brain by Y chromosome fluorescence in situ hybridization. Although further studies are required to determine whether such engraftment of the maternal brain has any physiological or pathophysiological functional significance, fetomaternal microchimerism provides a novel model for the experimental investigation of the properties of fetal progenitor or stem cells in the brain without prior in vitro manipulation. Characterization of the properties of these cells that allow them to cross both the placental and blood-brain barriers and to target injured brain may improve selection procedures for isolation of progenitor or stem cells for brain repair by intravenous infusion.

Animals↗
PubMed2004

[An experimental study on distribution of musk into the brain through blood brain barrier].

OBJECTIVE: To study the possible pathway of the effect of musk on brain disorder, distributing into the brain through blood brain barrier. METHODS: We used the musk ketone (muscone), a main composition of musk, to inject through the tail vein of the rats into the blood and took the brain and other organs at different times to make samples. Then gas chromatography was used to measure the distribution of muscone in the brain and other organs. RESULTS: Muscone could pass through the normal rat's blood brain barrier into the brain and soon reached the highest peak and remained in higher concentration, and more slowly metabolized as compared with other organs. CONCLUSION: Musk distributing into the brain through blood brain barrier provides the basis for its effect in treating brain disorders. Chromatography is an effective method to study the active composition of Chinese herbal medicine distributing through the blood brain barrier into the brain.

Animals↗
PubMed1999

[The brain hypothermia therapy for prevention of vegetation after severe brain injury].

We have presented a new concept of brain hypoxia oriented brain hypothermia treatments. All severe brain injury patients (148 cases) were GCS < 6. The masking brain hypoxia by brain thermo pooling, catecholamine surge induced cardiac dysfunction and intestinal vasodilatation, reduction of Hb-2.3 diphosphoglyserate were major target of initial treatment. These specific brain hypoxia was only controlled by brain hypothermia (34-32 degrees C), oxygen delivery > 800 ml/min. and AT-III > 100%. 2. The brain hypothermia were very successful to prevent masking brain hypoxia, selective radical attack to A10 dopamine nervous system, and brain edema. However, metabolic shift to lipid metabolism and lower growth hormone related immune crisis were recorded as a negative factors. Clinical results were so advanced. The mortality were 44 in 148 cases (30%), good recovery were 59 in 148 cases (40%), mild disability were 20 in 148 cases (13%) and vegetate state were only 15 in 148 cases (10%). The combination of brain hypothermia and replacement of cerebral dopamine were very successful to prevent the vegetation in severe brain injury.

Adult↗
PubMed2003

Adenosine 5'-triphosphate-sensitive potassium channel-mediated blood-brain tumor barrier permeability increase in a rat brain tumor model.

Brain tumor microvessels/capillaries limit drug delivery to tumors by forming a blood-brain tumor barrier (BTB). The BTB overexpresses ATP-sensitive potassium (K(ATP)) channels that are barely detectable in normal brain capillaries, and which were targeted for BTB permeability modulation. In a rat brain tumor model, we infused minoxidil sulfate (MS), a selective K(ATP) channel activator, to obtain sustained, enhanced, and selective drug delivery, including various sized molecules, across the BTB to brain tumors. Glibenclamide, a selective K(ATP) channel inhibitor, significantly attenuated the MS-induced BTB permeability increase. Immunocytochemistry and glibenclamide binding studies showed increased K(ATP) channel density distribution on tumor cells and tumor capillary endothelium, which was confirmed by K(ATP) channel potentiometric assay in tumor cells and brain endothelial cells cocultured with brain tumor cells. MS infusion in rats with brain tumors significantly increased transport vesicle density in tumor capillary endothelial and tumor cells. MS facilitated increased delivery of macromolecules, including Her-2 antibody, adenoviral-green fluorescent protein, and carboplatin, to brain tumors, with carboplatin significantly increasing survival in brain tumor-bearing rats. K(ATP) channel-mediated BTB permeability increase was also demonstrated in a human, brain tumor xenograft model. We conclude that K(ATP) channels are a potential target for biochemical modulation of BTB permeability to increase antineoplastic drug delivery selectively to brain tumors.

Adenosine Triphosphate↗
PubMed1992

Blood-brain barrier and new approaches to brain drug delivery.

Morbidity caused by brain dysfunction affects more than 50 million persons in the United States. Although new neuropharmaceuticals have the potential for treating specific brain diseases, they may not effectively enter brain from blood. Safe strategies are needed for drug delivery through the brain capillary wall, which makes up the blood-brain barrier in vivo. Two of these strategies are reviewed, as are related new developments in the molecular and cell biology of the brain capillary endothelium. The production of chimeric peptides represents a physiologic-based strategy for drug delivery. It entails the covalent coupling of the neuropharmaceutical to a brain transport vector, allowing transportation through the blood-brain barrier. Another strategy is biochemical opening of the blood-brain barrier: intracarotid leukotriene infusion is a method for selectively increasing blood-brain barrier permeability in brain tumors without affecting barrier permeability in normal brain tissue.

Animals↗
PubMed1997

Quantitative evaluation of brain distribution and blood-brain barrier efflux transport of probenecid in rats by microdialysis: possible involvement of the monocarboxylic acid transport system.

This study was performed to evaluate quantitatively the brain distribution and the efflux transport across the blood-brain barrier of probenecid, using in vivo microdialysis and in situ brain perfusion techniques. The brain interstitial fluid (ISF)-to-plasma cerebrospinal fluid (CSF)-to-plasma and brain tissue-to-plasma unbound concentration ratios of probenecid at steady state were less than unity, which suggests restricted distribution in the brain. An uphill concentration gradient from ISF to plasma and a downhill concentration gradient from CSF to ISF were observed. Kinetic analysis revealed that the efflux clearance from brain ISF to plasma (0.0373 ml/min/g brain) was significantly greater than the influx clearance from plasma to brain (0.00733 ml/min/g brain). The ratio of the ISF concentration (Cisf) to the plasma unbound concentration (Cp,f) of probenecid was increased 2- to 3-fold by salicylate (3.7 mM) and benzoate (3.6 mM), which are accepted as substrates of the monocarboxylic acid transport system, compared with the same ratio for the control. In addition, the ratio Cisf/Cp,f was increased by treatment with N-ethylmaleimide, a sulfhydryl-modifying agent, whereas p-aminohippuric acid and choline did not produce increasing effects on Cisf/Cp,f. These data suggest that the restricted distribution of probenecid in the brain may be ascribed to efficient efflux from the brain ISF, which may be regulated by the monocarboxylic acid transport system at a relatively high ISF concentration.

Animals↗
PubMed1989

Blood-brain barrier sodium transport limits development of brain edema during partial ischemia in gerbils.

Sodium derived from the blood is known to accumulate in brain tissue during the early stages of incomplete ischemia. Our present studies were undertaken to determine the relation between blood-brain barrier sodium transport and the development of ischemic brain edema. Incomplete cerebral ischemia was produced in gerbils by ligation of the left common carotid artery under ether anesthesia. Following recovery from the anesthetic, the gerbis were evaluated for the presence of neurologic symptoms and were divided into symptomatic (n = 77) and asymptomatic (n = 94) groups. Tissue water, sodium, and potassium contents, tissue plasma volume, and brain uptake of 22Na were measured in both groups 1.5, 3, 6, 12, and 24 hours after carotid ligation. There was a progressive accumulation of sodium and water in the ipsilateral cerebral cortex of the symptomatic group compared with either the corresponding contralateral cortex of the same gerbils or with the asymptomatic group. Net changes in brain sodium and potassium concentrations appeared to be the main determinants of fluid accumulation. Brain edema was not due to opening of the blood-brain barrier because the unidirectional transport of 22Na remained low and was even reduced by 35-55% in the ischemic cortex. Nevertheless, this sodium transport activity appeared to be rate-limiting in the development of brain edema during the first 3 hours of ischemia because the rate of sodium accumulation in the tissue was the same as the rate of 22Na transport from the blood to the brain. We conclude that blood-brain barrier sodium transport is an important factor in the formation of ischemic brain edema.

Animals↗