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  • 1
    ISSN: 1432-0533
    Keywords: Stroke-prone spontaneously hypertensive rats ; Blood-brain barrier ; Fibrinoid degeneration ; Brain edema
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary The cerebrovascular lesions of severe chronic hypertension were studied by light microscopy in perfusion-fixed, subserially sectioned brains from stroke-prone spontaneously hyptertensive rats (SHRSP). The leakage and spread of plasma proteins were visualized by immunohistochemical detection of extravasated fibrinogen and by using an exogenous marker (Evans blue injected i.v.) for blood-brain barrier (BBB) dysfunction. In most SHRSP the hypertension did not lead to major BBB lesions in spite of a mean arterial pressure around 200 mm Hg at 6–9 months of age. Multifocal BBB damage occurred in a minor group of SHRSP, particularly within the cortex and the deep gray matter. A close spatial correlation was found between the leakage-spread of plasma constituents and the neuropathologic alterations. Fibrinoid degeneration of penetrating arterioles was found within the leakage sites. The surrounding gray matter showed petechial hemorrhages and abundant proteinaceous exudates rich in antifibrinogen-positive material. The current leakage of Evans blue and wide spread of fibrinoid substances suggested long-lasting damage to the BBB. Most neurons within the edematous gray matter had well preserved nuclei surrounded by a rim of cytoplasm with ill-defined outline as if vacuolation or lysis of the peripheral cytoplasm had occurred. The sponginess of the tissue progressed in severe cases to formation of necrotic cysts. Condensed acidophilic neurons were seen in the border zone between the edematous and more compact gray matter. The appearance and distribution of the gray matter lesions deviated in many respects from those commonly seen in regional ischemic infarcts. The fibrin thrombi found close to the cysts might be regarded as secondary events. The extensive spread of antifibrinogen-positive material within the white matter seemed to originate mainly from the chronic leakage sites in the gray matter. Increased number of large astrocytes were seen within the leakage sites and along the spreading pathways for the edema constituents. The white matter showed a rarefied texture with widely dispersed nerve fiber tracts, volume expansion, and occasional cyst formation. The results indicate a crucial pathophysiologic role for the egress, spread, and accumulation of vasogenic edema in the development of the cerebrovascular lesions in SHRSP.
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  • 2
    ISSN: 1432-0533
    Keywords: Stroke-prone spontaneously hypertensive rats ; Blood-brain barrier ; Brain oedema ; Astrocytes ; Glial fibrillary acidic protein
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary The brain lesions in spontaneously hypertensive stroke-prone rats (SHRSP) are characterised by multifocal microvascular damage, breakdown of the blood-brain barrier, massive extravasation of plasma constitutents and severe brain oedema, with consequent spongy and cystic tissue destruction in the cerebral cortex and basal ganglia as well as loosening of the white matter. In this paper we analyse in greater detail the pathogenetic mechanisms by which the spongy and cystic lesions are formed and the response of astrocytic cells. For this purpose, tracer (Evans blue)-stained brain lesions were examined in 8-month-old SHRSP immunohistochemically and electron microscopically. Sponginess of the neuropil in small lesions and at the periphery of larger lesions was due to swollen neuronal and astrocytic cell processes, i.e.at this stage the oedema was mainly intracellular. Cystic lesions were formed in the grey matter both by expansion of the extracellular space (ECS) containing protein-rich ocdema fluid, and by rupture and subsequent loss of massively swollen cellular elements. In the white matter small slit-formed cysts along the fibre tracts were also formed by the expansion of ECS. In apparently recent lesions astrocytes displayed cytoplasmic oedema but otherwise were still fairly normal. In more chronic lesions increased numbers of enlarged astrocytes with prominent staining for glial fibrillary acidic protein were present. Their distribution corresponded well to the spread ofoedema, i.e. they were prominent around the leaky vessels in the grey matter, in the subpial zone and in the white matter. In the reparative phase the grey matter cysts became lined by astrocytic processes, a new glia limitans. Profuse sheets of glial processes in the neuropil around the cysts reestablished the compactness of the brain parenchyma.
    Type of Medium: Electronic Resource
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  • 3
    ISSN: 1432-0533
    Keywords: Stroke-prone spontaneously hypertensive rats ; Blood-brain barrier ; Brain edema ; Plasma proteins ; Brain specific gravity
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary Brain edema associated with severe chronic hypertension was studied in stroke-prone spontaneously neously hypertensive rats (SHRSP), 5 to 9 months of age. Blood-brain barrier (BBB) leakage sites and intracerebral spreading pathways for plasma proteins were delineated by an intravenously (i.v.) injected exogenous dye tracer (Evans blue), known to form a complex with albumin in blood, and by immunohistochemical visualization of extravasated endogenous plasma proteins. The tissue content of edema fluid was estimated by measuring the specific gravity of selected brain regions, stained or unstained by the tracer dye, on a bromobenzene-kerosene gradient column. Multifocal BBB leakage sites were macroscopically detected within the cerebral cortex and the deep gray matter after i. v. circulation of Evans blue-albumin for 30 min. After 24 h of i.v. circulation the dye tracer had spread not only locally in the gray matter but also into the adjacent white matter, where it was widely distributed. Immunohistochemically visualized plasma proteins showed similar distribution. Unilateral superior cervical ganglionectomy performed at 4 weeks of age neither increased the incidence of major BBB opening to Evans blue-albumin nor altered the specific gravity of the ipsilateral cerebral hemisphere in grown-up SHRSP, furthermore, the blood pressure remained unchanged. The lack of significant effect on BBB function may possibly be attributed to the extensive reinnervation of the cerebral arteries, verified in the grown-up SHRSP using the Falck-Hillarp fluorescence method for visualization catecholaminergic nerve fibers. In SHRSP raised on a low-protein and high-salt diet the mean arterial blood pressure was 212 mm Hg compared to 195 mm Hg in controls (P〈0.05) and the incidence of BBB opening was 72% compared to 25% in controls (P〈0.05). After 24 h of i.v. circulation of Evans blue-albumin, brain regions stained by the dye tracer showed significantly reduced specific gravity (P〈0.001), while unstained regions had normal values. Thus the brain edema fluid spread, as revealed by specific gravity measurements, corresponded to the intracerebral distribution of extravasated plasma proteins.
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  • 4
    Electronic Resource
    Electronic Resource
    Springer
    Acta neuropathologica 75 (1988), S. 557-565 
    ISSN: 1432-0533
    Keywords: Hypertension ; Blood-brain barrier ; Immunohistochemistry ; Light microscopy
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary A transient increase in blood pressure was induced in 15 male Sprague Dawley rats by clamping the upper abdominal aorta for 8–10 min. Three rats served as controls. The brains were fixed by perfusion 2 h or 7 days later. Evan's blue-albumin (EBA) was used for macroscopic evaluation of the blood-brain barrier (BBB) integrity. Extravasated plasma albumin, fibrinogen and fibronectin were demonstrated by immunohistochemistry on paraffin sections. Glial fibrillary acidic protein (GFAP) was visualized in the same way. Parallel sections were analyzed for possible parenchymal changes associated with the BBB breakdown. Multiple focal areas of BBB opening were seen in the brains of the three rats killed 2 h after the hypertensive episode. The plasma proteins were present in the vascular wall, extracellular space and within certain neurons. Shrunken acid fuchsin positive neurons were seen in some areas of extravasation. After 7 days, in 5 out of 12 rats a few local lesions with EBA leakage and positive immunostaining for plasma proteins were seen. Structurally these lesions were characterized by shrinkage, fuchsinophilia and disintegration of neurons and proliferation of astrocytes. Thus, a transient opening of the BBB by acute hypertension may lead to permanent tissue damage.
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  • 5
    ISSN: 1432-0533
    Keywords: Blood-brain barrier ; Hyperosmolar solutions ; Electron microscopy
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary Infusion of hypertonic solutions into the carotid artery is one method by which the blood-brain barrier (BBB) can be opened transiently in experimental animals. This technique has also been tried in clinical situations in which an enhanced uptake of intravenously injected chemotherapeutic drugs into the brain is desired. We have previously found that infusion of hypertonic mannitol or urea into the carotid artery of the rat, leading to a BBB opening, is associated with light microscopic signs of cellular damage in the brain parenchyma. An electron microscopic study has now been made to obtain more detailed information about the events taking place in the rat brain 1 to 72 h after an intracarotid infusion of hyperosmolar solution of mannitol. Toluidine blue-stained semithin epon sections were also available for high-resolution light microscopy of brain samples from urea-infused animals. Intravenously injected Evan's blue dye was used to confirm that BBB opening had occurred as a consequence of the carotid infusions. The infused hemispheres had numerous structural changes. The dominating light microscopic alteration was the presence of multifocal lesions in the gray or the white matter with closely packed microvacuoles causing status spongiosus. Ultrastructurally the microvacuoles corresponded to very pronounced watery swelling of astrocytic processes and to a minor degree to expansion of dendrites and axons. There was also a light or moderate perivascular astrocytic swelling. In the “spongy” lesions as well as occasionally in non-vacuolated parts of the cerebral cortex, there were collapsed electron-dense neurons with pronounced mitochondrial alterations such as severe swelling associated with rupture of christae. Rats with a survival period of 24 h or 72 h showed several disintegrating neurons and accumulation of macrophages. This study shows that carotid infusion of hypertonic mannitol in the rat may cause pronounced neuronal changes as well as multifocal astrocytic swelling. The severity of the nerve cell changes and the presence of macrophages indicate that some of the alterations are irreversible and thus, such a procedure may not be as safe as previously suggested.
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  • 6
    ISSN: 1432-0533
    Keywords: Stroke-prone spontaneously hypertensive rats ; Blood-brain barrier ; Brain edema ; Nerve cell injury ; Electron microscopy
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary The brain lesions in stroke-prone spontaneously hypertensive rats (SHRSP) are characterized by multifocal microvascular and spongy-cystic parenchymal alterations particularly in the gray matter. An essential feature of the lesions is the presence of edema with massive extravasation of plasma constituents as evidenced by specific gravity measurements, Evans blue technique and immunohistochemistry. The nerve cell injury occurring in the brain lesions in SHRSP is further characterized by light and electron microscopy in the present study. Two types of neuronal changes were seen within the blood-brain barrier (BBB) leakage sites. A small number of neurons with dark condensed nucleus and cytoplasm were found most often at the periphery of recent lesions. The majority of injured neurons were pale and showed intracellular edema confined to the dendrites and perikarya sparing axons and synapses. Their nuclei were weli preserved with finely dispersed chromatin. The swollen and watery cell processes of neurons and astrocytes gave a spongy appearance to the neuropil. The intracellular edema seemed to result in cytolysis. The results suggest that primary anoxiaischemia is not the major pathogenetic mechanism behind the nerve cell injury in severely hypertensive SHRSP, rather it is the massive BBB leakage and consequent brain edema that causes cytolytic destruction of neurons. Secondary focal ischemia as a consequence of occlusion in microvessels may, however, contribute to the nerve cell destruction.
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  • 7
    ISSN: 1432-0533
    Keywords: Blood-brain barrier ; Vasogenic brain edema ; Plasma proteins ; Immunohistochemistry ; Hyperosmolar solutions
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary An immunohistochemical study was carried out on rat brain to determine if a transient opening of the blood-brain barrier (BBB), leading to extravasation of serum albumin, is also associated with exsudation and cellular uptake of fibronectin and fibrinogen. Both of them might exert important biological effects provided that they pass the BBB and come into contact with cells of the brain parenchyma. Hyperosmolar solutions of urea or mannitol were infused in the carotid artery for 30 s to open the BBB and the animals were killed at various time intervals thereafter. Formaldehyde-fixed, paraffin-embedded material was used for immunohistochemical demonstration of extravasated proteins by an avidin-biotin peroxidase technique. Multifocal, often confluent areas of widely different sizes with signs of albumin extravasation were observed both in the grey and the white matter of the cerebral hemispheres exposed to the hyperosmolar solutions. Much less pronounced changes were observed in rats given an intracarotid saline infusion alone. Immunoreactive material indicating extravasation of fibronectin and fibrinogen was present in the infused cerebral hemispheres but albumin immunoreactivity was much more widespread. Reaction product was observed in vascular walls, presumably in extracellular spaces and in nerve cells. Immunoreactivity in the perikaryon of neurons formed different patterns in various cells. Agranular type most probably represents accumulation of the proteins in lysosomal organelles after pinocytotic uptake into the neuron. The second so-calleddiffuse variety is presumably the result of a severe nerve cell injury with an uncontrolled leakage of proteins into the cytoplasm. Our results indicate that vascular walls, extracellular spaces, glial cells and neurons will be exposed to extravasated fibronectin and fibrinogen as well as to albumin and that antigenic sites in such compounds remain for a long period after the BBB opening. In addition, there are indications that carotid infusions of hyperosmolar solutions may cause nerve cell injuries in regions with BBB opening. These findings have obvious clinical and experimental significance.
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  • 8
    Electronic Resource
    Electronic Resource
    Springer
    Acta neuropathologica 44 (1978), S. 53-56 
    ISSN: 1432-0533
    Keywords: Blood-brain barrier ; Air embolism ; Horseradish peroxidase ; Cerebral cortex ; Electron microscopy ; Carotid artery ; Rat
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary Male albino rats were anaesthetized with diazepam, injected with horseradish peroxidase and Evans blue-labeled albumin and given an embolus of 0.01 ml air in the right common carotid artery after ligation of the external carotid branch. The pial arteries of the right cerebral hemisphere were stained blue, particularly the middle cerebral artery and its main arterial branchlets. Ultrastructurally, some endothelial cells in the right middle cerebral artery, small arteries and arterioles showed a diffuse distribution of horseradish peroxidase in their cytoplasm, although these vessels only occasionally showed peroxidase in their basement membranes. Other endothelial cells in these arterial branchlets showed few if any signs of a diffuse distribution of peroxidase but displayed several pinocytotic vesicles and occasionally trans-endothelial channels filled with peroxidase, sometimes with a slight leakage of peroxidase into adjacent basement membranes and neuropil. Scattered pinocytotic vesicles were observed in capillaries and venules, but there was usually no extravasation of peroxidase around these vessels.
    Type of Medium: Electronic Resource
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  • 9
    Electronic Resource
    Electronic Resource
    Springer
    Experimental brain research 42 (1981), S. 331-336 
    ISSN: 1432-1106
    Keywords: Acute hypertension ; Blood-brain barrier ; Air embolism ; Fat embolism ; Indomethacin
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary The experiments were performed to determine if indomethacin, a prostaglandin synthesis inhibitor, could reduce albumin extravasation and brain edema in some models of blood-brain barrier dysfunction. The blood pressure was increased by i.v. adrenaline or bicuculline in conscious rats with indwelling catheters in the aorta and jugular vein. 125I-labeled serum albumin and Evans blue-albumin were used as tracers of the blood-brain barrier function. Pretreatment with indomethacin significantly reduced albumin extravasation after the administration of adrenaline but not after bicuculline, i.e. when acute hypertension was combined with a metabolically mediated cerebral vasodilatation. It is argued that the protective effect of indomethacin in adrenaline-induced hypertension probably is related to the vasoconstrictory effect of the drug. Five μl of air or Lipiodol were injected into the right internal carotid artery in rats anesthetized with pentobarbitone. The albumin content in the injected hemisphere was seven to nine times higher after fat than after air embolism. No significant reduction of tracer extravasation was obtained in rats treated with indomethacin. Rats subjected to fat embolism had a significant homolateral cerebral edema (i.e. increased water content) which was not reduced by pretreatment with indomethacin. By contrast, the water content was significantly increased also in the non-injected side in rats given indomethacin indicating a larger spread of edema fluid in these animals.
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  • 10
    ISSN: 1432-1041
    Keywords: chlorambucil ; prednimustine ; plasma concentrations ; bioavailability ; pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The pharmacokinetics of chlorambucil has been investigated in a cross over study after oral administration of the free drug (10 mg) and its prednisolone ester (prednimustine, 100 mg). The bioavailability of chlorambucil was about five times lower when given as prednimustine as compared to administration of the free drug. The peak plasma concentration was about twice as high and it was obtained more rapidly when the free drug was given. No intact prednimustine could be detected in plasma.
    Type of Medium: Electronic Resource
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