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PubMed1993

The "subdural" space: a new look at an outdated concept.

This review considers the structure of the meninges, as seen at the electron microscopic level, with particular emphasis on the dura-arachnoid junction and whether a naturally occurring space is found at this interface. The classic view has been that a so-called subdural space is located between the arachnoid and dura and that subdural hematomas or hygromas are the result of blood or cerebrospinal fluid accumulating in this (preexisting) space. The dura is composed of elongated, flattened fibroblasts and copious amounts of extracellular collagen. A specialized layer of fibroblasts, the dural border cell layer, is found at the dura-arachnoid junction and is characterized by flattened fibroblasts, no extracellular collagen, extracellular spaces, and few cell junctions. These features combine to create a layer of the inner dura that is structurally weak when compared with external portions of the dura and the internally located arachnoid. The arachnoid layer is composed of larger cells with numerous cell junctions, no extracellular space, and no extracellular collagen. The occurrence of many tight junctions in this layer also serves as a barrier to the movement of fluids and ions. Fibroblasts specialized to form the arachnoid trabeculae attach to the inner surface of the arachnoid layer, bridge the subarachnoid space, and surround vessels in the subarachnoid space as well as attach to pia on the surface of the brain. Under normal conditions, there is no evidence of a naturally occurring space being extant at the dura-arachnoid junction. A space may appear at this point subsequent to pathological/traumatic processes that result in tissue damage with a cleaving opening of the structurally weakest plane in the meninges--through the dural border cell layer. Furthermore, when a space does appear, it is not "subdural" in location but rather within a morphologically distinct cell layer.

Animals↗
PubMed1986

Dynamic variations of the brain cell microenvironment in relation to neuronal hyperactivity.

Neuronal hyperactivity has been shown to cause transient changes in ionic concentrations as well as in the volume of the extracellular space (ECS). During enhanced neuronal activity in the sensorimotor cortex of the cat, increases in the extracellular K+ concentration to a ceiling value of 10 mM have been observed concomitant with decreases in the Na+ concentration of similar magnitude. Simultaneously, the Cl- concentration rose steadily during the enhanced neuronal activity, and the extracellular space decreased by about 30%. A mathematical model allowed the interpretation of these concentration and volume changes as results of K+ release by active neurons in exchange for Na+, removal of K+ from the ECS by spatial glial buffering and movements of KCl into glial cells, as well as cell swelling due to metabolically induced transient increases in cellular osmolarity. Similar mechanisms have also been found to operate in gliotic scar tissue, where glial cells appeared to function the same way as in normal cortex, in rat hippocampal slices, and in preparations studied by other investigators.

Animals↗
PubMed2003

Brain edema -- a new classification.

Brain edema is a reaction to any brain injury and can be the first stage in the beginning of intracranial hypertension. This paper puts forth a modern classification of brain edema types, based on a etiopathogenic interpretation. The hydroelectrolitic and/or proteinic buildup can occur within cells and/or in the extracellular space and differentiates three types of brain edema: cellular brain edema; extracellular brain edema and combined brain edema. Cellular brain edema (cytotoxic brain edema) occurs through intracellular hyperosmolarity or extracellular hypotonicity. Extracellular brain edema (interstitial) appears as a result of the buildup of edema fluid in the extracellular space of the brain parenchyma and can be: hydrostatic extracellular brain edema (through ultrafiltration), oncotical extracellular brain edema (vasogen brain edema) and hydrocephalic extracellular brain edema. Combined brain edema includes in variable ratios both types of brain edema, cellular and extracellular; they can be present together from the beginning or can appear successively.

Animals↗
PubMed2002

Quantitative dual-probe microdialysis: mathematical model and analysis.

Steady-state microdialysis is a widely used technique to monitor the concentration changes and distributions of substances in tissues. To obtain more information about brain tissue properties from microdialysis, a dual-probe approach was applied to infuse and sample the radiotracer, [3H]mannitol, simultaneously both in agar gel and in the rat striatum. Because the molecules released by one probe and collected by the other must diffuse through the interstitial space, the concentration profile exhibits dynamic behavior that permits the assessment of the diffusion characteristics in the brain extracellular space and the clearance characteristics. In this paper a mathematical model for dual-probe microdialysis was developed to study brain interstitial diffusion and clearance processes. Theoretical expressions for the spatial distribution of the infused tracer in the brain extracellular space and the temporal concentration at the probe outlet were derived. A fitting program was developed using the simplex algorithm, which finds local minima of the standard deviations between experiments and theory by adjusting the relevant parameters. The theoretical curves accurately fitted the experimental data and generated realistic diffusion parameters, implying that the mathematical model is capable of predicting the interstitial diffusion behavior of [3H]mannitol and that it will be a valuable quantitative tool in dual-probe microdialysis.

Agar↗
PubMed1985

Electron dense mitochondrial inclusions in a pituitary oncocytoma.

A 65-year-old man had a pituitary adenoma with a large expansion of the sella turcica; computerized tomography demonstrated suprasellar extension. The tumor, removed surgically, was diagnosed as nonsecretory partly chromophobic, partly acidophilic adenoma by light microscopy and immunocytology. Electron microscopic investigation revealed a pituitary oncocytoma with an unusual mitochondrial abnormality. Some mitochondria harbored single or multiple electron dense bodies which were also found in the cytoplasm as well as in the extracellular space. It appears that these bodies were originally formed in the mitochondria, then extruded into the cytoplasm and subsequently to the extracellular space.

Adenoma↗
PubMed1989

Estimation of physiological volumes in the isolated perfused porcine skin flap.

A requirement for pharmacokinetic modeling of isolated perfused organ systems used for in vitro to in vivo extrapolations is a measure of the organ's physiological spaces. Two methods were employed to estimate intravascular and extracellular spaces in four isolated perfused porcine skin flaps (IPPSF) from 2 pigs. One of these methods used regression techniques based on a one-compartment model, and was found to be a good estimator of intravascular volume only. The other method was a non-parametric numerical integration technique, and was found to give reasonable estimates for both intravascular and extracellular volumes. The latter method's estimate for extracellular space was 0.20 +/- 0.03 mL/g, and the estimated vascular space by both methods was 0.08 +/- 0.01 mL/g.

Animals↗
PubMed1992

pH transients evoked by excitatory synaptic transmission are increased by inhibition of extracellular carbonic anhydrase.

Excitatory synaptic transmission has been associated with a rapid alkalinization of the brain extracellular space. These pH shifts are markedly increased by acetazolamide, an inhibitor of carbonic anhydrase. Although this effect can be readily explained by inhibition of extracellular carbonic anhydrase, this enzyme has been considered strictly intracellular in the central nervous system. To determine whether these alkaline shifts are regulated by extracellular carbonic anhydrase, we studied the effects of a membrane impermeant, dextran-bound inhibitor of this enzyme. Extracellular alkaline transients, measured with pH-sensitive microelectrodes, were generated in the CA1 region of rat hippocampal slices by repetitive electrical stimulation of Schaeffer collateral fibers or by local ejection of glutamate. More direct alkalinizations were elicited by focal ejection of NaOH in the vicinity of a pH microelectrode. These pH transients were reversibly enhanced by addition of the dextran-bound inhibitor. We conclude that there is significant carbonic anhydrase activity in the extracellular space of the brain. We postulate that this enzyme functions in the regulation and modulation of extracellular pH transients associated with neuronal activity.

Acetazolamide↗
PubMed1983

Analysis of potassium dynamics in mammalian brain tissue.

Equations are derived for potassium (K+) dynamics in simplified models of brain tissue. These describe K+ movement in extracellular space, transfer of K+ associated with current flow through cells (the so-called spatial buffer mechanism) and equilibration between extracellular space and cytoplasm. Numerical calculations show that the principal data on K+ dynamics from various laboratories can be accounted for with simple assumptions about spatial buffer action and uptake. Much of the data is inconsistent with extracellular diffusion being the main mechanism for K+ flux through brain tissue, including some that has earlier been cited in support of this hypothesis. The buffering actions of spatial buffer transfer of K+ and of cytoplasmic equilibration, in which these mechanisms reduce rises of [K+]o that would otherwise occur, are analysed quantitatively for specific K+ source distributions and for spatial and temporal frequency components of general disturbances. Spatial buffer action has most effect in reducing [K+]o rises with net release over extensive zones of tissue (greater than ca. 200 micron in diameter) for periods of the order of minutes. Reductions greater than 75% may be achieved. With localized but prolonged release, the maximum [K+]o rise is little affected but the volume of tissue affected by more moderate rises is substantially reduced. Cytoplasmic K+ uptake also has most effect with widespread release, but its effect diminishes with prolonged periods of release. The effects of the buffering mechanisms and of K+ re-uptake into active neurones in determining the decline of [K+]o after a period of stimulation are considered. Re-uptake is unlikely to be the major factor responsible for [K+]o decline when this has a time course of only a few seconds. The properties necessary for the cells mediating the spatial buffer mechanisms, possibly glial cells, are assessed.

Animals↗
PubMed1983

Ultrastructure of blood-retinal barrier permeability in rat phototoxic retinopathy.

It has been shown previously that the blood-retinal barrier (BRB) of rats with phototoxic retinopathy is permeable to sodium fluorescein and to fluoresceinated dextrans as large as 32A ESR (Einstein-Stokes radius). The leakage presumably occurs from retinal capillaries that have invaded the retinal pigment epithelium (RPE) and become fenestrated. In this report, the ultrastructural tracers horseradish peroxidase and catalase were used to further localize the leakage site, and to evaluate the size limit of molecules penetrating the phototoxic BRB. Horseradish peroxidase (HRP: 30A ESR) freely penetrates the BRB of phototoxic rats, since it is present in the retinal extracellular space 10 min after intravenous injection. HRP penetrates the fenestrae of capillaries which invade the RPE from the retina. It then diffuses along the pericapillary space of the intraepithelial capillaries, which is confluent with that of their parent retinal capillaries, and into the retinal extracellular space. HRP thus circumvents the tight junctions between RPE cells and between capillary endothelial cells, which appear intact in thin sections. Catalase (52A ESR) does not freely penetrate the BRB of phototoxic rats. As long as 40 min after intravenous injection, catalase is still confined to the lumen of fenestrated capillaries in the RPE, retinal capillaries, and the choriocapillaris. Although present in intraendothelial vesicles, no evidence of deposition in the pericapillary space is observed. It is concluded fenestrated capillaries in the RPE are a major site where blood-borne tracers penetrate the BRB in phototoxic retinopathy.

Animals↗
PubMed2000

Activation of DNA synthesis and AP-1 by profilin, an actin-binding protein, via binding to a cell surface receptor in cultured rat mesangial cells.

Profilin is known to bind to actin monomers (to regulate actin polymerization) and to phosphatidylinositol-4,5-bisphosphate (to inhibit hydrolysis by unphosphorylated phospholipase C-gammal). It was recently reported that profilin is overexpressed in glomerular mesangial cells (MC) of rats with anti-Thy-1.1-induced glomerulonephritis and is accumulated in the extracellular space around MC. In this study, the biologic activities of extracellular profilin were examined. Scatchard analysis indicated the existence of a single class of cell surface binding sites, with similar equilibrium dissociation constants for purified splenic profilin and recombinant profilin, in cultured rat MC. Profilin increased [(3)H]thymidine incorporation in a dose-dependent manner and produced additive effects on platelet-derived growth factor-induced [(3)H]thymidine incorporation. Profilin increased AP-1 DNA-binding activity in a concentration-dependent (ED(50) = 30 nM) and time-dependent manner after transient c-jun gene expression, as measured using gel-shift assays and competitive reverse transcription-PCR. Pretreatment of profilin with an anti-profilin inhibitory antibody suppressed profilin-induced AP-1 activation and [(3)H]thymidine incorporation. Furthermore, profilin induced rapid transient activation of protein kinase C, and staurosporine and H-7 reduced the profilin-induced activation of AP-1, suggesting protein kinase C-dependent activation of AP-1. These findings indicate that profilin in the extracellular space can bind to cell surface receptors of MC and act as an inducer of signal transduction. These results suggest that extracellular profilin may be involved in the progression of glomerular diseases, by affecting cell growth.

Animals↗
PubMed2004

The role of ECM molecules in activity-dependent synaptic development and plasticity.

Growth and guidance of neurites (axons and dendrites) during development is the prerequisite for the establishment of functional neural networks in the adult organism. In the adult, mechanisms similar to those used during development may regulate plastic changes that underlie important nervous system functions, such as memory and learning. There is now ever-increasing evidence that extracellular matrix (ECM)-associated factors are critically involved in the formation of neuronal connections during development, and their plastic changes in the adult. Here, we review the current literature on the role of ECM components in activity-dependent synaptic development and plasticity, with the major focus on the thrombospondin type I repeat (TSR) domain-containing proteins. We propose that ECM components may modulate neuronal development and plasticity by: 1) regulating cellular motility and morphology, thus contributing to structural alterations that are associated with the expression of synaptic plasticity, 2) coordinating transsynaptic signaling during plasticity via their cell surface receptors, and 3) defining the physical parameters of the extracellular space, thereby regulating diffusion of soluble signaling molecules in the extracellular space (ECS).

Animals↗
PubMed1983

A study of the mechanisms by which potassium moves through brain tissue in the rat.

The flux of K+ produced by electric current across the pia-arachnoid surface of the neocortex of anaesthetized rats has been studied with K+-selective electrodes in a cup at the surface and with flame photometry. The potential differences developed across three regions of the rat brain (neocortex, cerebellum, hippocampus) have been measured as [K+] was altered in fluid at the surface. The experimental results have been related to those that would be expected (i) if K+ moved principally by diffusion in extracellular space and (ii) if current flow through cells makes a significant contribution to K+ transfer. K movement produced by current across the neocortical surface accounted for 0.06 of the transfer of electric charge with small currents in either direction (ca. 5 microA mm-2) and with larger currents out of the tissue. Large currents (ca. 20 microA mm-2) into the tissue produced less K+ movement, but still more than the fraction 0.012 expected for purely extracellular flux. Alternating current pulses (5 Hz) with zero net transfer of charge produced no flux of K+ across the surface, while alternation with unequal durations produced the same effects as the equivalent steady charge transfer. The K+ flux lagged behind the onset and cessation of current with a time constant ca. 45 sec, approximately as expected from calculations with a model of the tissue. A surface-negative potential shift averaging 2 mV was observed when [K+ ]at the brain surface was increased from 3 to 12 mM. The time for development of half of the full potential change was 20 sec, with the solution changes complete in less than 4 sec. These results are inconsistent with the hypothesis that K+ movement through brain tissue occurs principally through intercellular clefts, except where these movements involve very localized gradients. They are consistent with the conclusion that ca. 5 times as much K+ flux passes through cells (probably largely glial cells) as through extracellular space, with fluxes driven by either extracellular voltage or concentration gradients.

Animals↗
PubMed1985

Validation of [57Co]cyanocobalamin as an extracellular fluid marker and measurement of albumin exclusion from the interstitium in the rabbit.

The use of [57Co]cyanocobalamin as an extracellular marker has been validated. Its simultaneous use with 51Cr-labeled erythrocytes and 125I-human serum albumin allows quantitative measurement of tissue water and the fractional exclusion of albumin from the interstitial compartment. The extravascular extracellular spaces of rabbit tissue are lung, 32 +/- 4%; heart, 25 +/- 2%; gut, 24 +/- 4%; and muscle, 13 +/- 1%. The fractional excluded albumin spaces are lung, 0.78 +/- 0.05; heart, 0.37 +/- 0.03; gut, 0.69 +/- 0.05; and muscle 0.58 +/- 0.03. The oversimplification that the extravascular extracellular space is a homogeneous region defined by a small tracer molecule and has the composition of lymph must be reconsidered. Albumin has a vastly different distribution in the interstitial spaces of different organs. Use of the three tracers reported here allows efficient measurement of blood volume, interstitial space, and interstitial albumin exclusion in whole tissues and organs, and thus can lead to further understanding of the in vivo changes occurring in various physiologic and disease states.

Animals↗
PubMed2002

Effect of the glial envelope on extracellular K(+) diffusion in olfactory glomeruli.

In many species, including vertebrates and invertebrates, first-order olfactory neuropils are organized into spherical glomeruli, partially enveloped by glial borders. The effect of this characteristic organization on olfactory information processing is poorly understood. The extracellular concentration of potassium ions ([K(+)]) must rise around olfactory receptor axons in specific glomeruli following odor-induced activation. To explore the time course and magnitude of K(+) accumulation and possible effects of such accumulation on neural activity within and among glomeruli, we developed a theoretical model to simulate the diffusion of K(+) in extracellular spaces of the glomeruli of the moth Manduca sexta. K(+) released by activated axons was assumed to diffuse through the extracellular spaces in glomeruli and the glial borders that surround them. The time-dependent diffusion equations were solved in spherical coordinates using a finite-difference method. The results indicate that the glial envelope forms a significant barrier to the spread of K(+) between neighboring glomeruli, thus reducing the likelihood of cross-talk between glomeruli, and may cause elevation of extracellular [K(+)] to levels that influence neural activity within the activated glomerulus for many seconds. Such effects could enhance olfactory discrimination and sensitivity, respectively.

Animals↗
PubMed1976

The connective tissue coverings of leech peripheral nerves: anatomical evidence for the absence of cerebrospinal fluid in the leech.

The central nervous system of Hirudo medicinalis is contained within a blood vessel, the ventral longitudinal sinus, but the nervous system is separated from the blood by the visceral endothelium. The visceral endothelium possesses many pinocytotic vesicles and basal infoldings and thus appears active whereas the parietal endothelium appears inactive. The junction between the visceral and parietal endothelia is abrupt. Peripheral nerves in this animal, as in vertebrates, are covered by endoneurium, perineurium, and epineurium. The endoneurium is continous with the fibrous tissue of the segmental ganglia. The perineurium, consisting of a single layer of flattened cells that surrounds the peripheral nerve like a sleeve, is not continuous with the endothelium of the ventral sinus, but is separated from it by 5-10 microns. Therefore, at the point where the peripheral nerve joins the segmental ganglion, the extracellular spaces of the central nervous system, the peripheral nervous system, and the body wall are all confluent. Thus, there are only two compartments of the extracellular space in the leech: the blood, which is enclosed by the endothelia of the coelomic sinuses, and the extracellular fluid of the body, which includes the extracellular fluid of the nervous system. There seems to be no equivalent of cerebrospinal fluid in the gnathobdellid leech.

Animals↗
PubMed1994

Immunocytochemical localization of extracellular superoxide dismutase in human lung.

BACKGROUND: Extracellular superoxide dismutase (EC-SOD) is a principal enzymatic scavenger of the superoxide anion in extracellular spaces. It is thought to be important as a defense against superoxide-mediated damage to both cell surfaces and extracellular matrix proteins. EC-SOD may also be important in regulating intercellular signalling by extracellular superoxide. EC-SOD is believed to be mainly located in the extracellular matrix of tissues. However, the specific localization of EC-SOD is unknown. Knowledge of the distribution of EC-SOD is an essential step in defining its functions. EXPERIMENTAL DESIGN: Using light microscopic immunohistochemistry, electron microscopic immunocytochemistry and an EC-SOD affinity-purified polyclonal rabbit antibody to human recombinant EC-SOD, we evaluated the distribution of EC-SOD in human lungs. RESULTS: These studies revealed that in the lung EC-SOD is primarily located in the extracellular matrix. Specifically, EC-SOD is found in areas containing high amounts of type I collagen and other unidentified matrix elements, but was not seen in areas rich in elastin or cartilage. In the lung, EC-SOD is predominantly located around larger vessels and airways, and, to a lesser degree, in the extracellular matrix around alveolar and capillary regions. Some EC-SOD was found in bronchiolar epithelial cell junctions and around the surface of vascular and airway smooth muscle cells. No labeling was seen on endothelial cell surfaces of capillaries, small muscular, or large elastic vessels in the lung. Labeling for EC-SOD was limited to the extracellular spaces, consistent with it being a secreted protein, with the exception of a small amount of intracellular labeling seen in bronchial epithelial cells and type II cells. CONCLUSIONS: The labeling distribution of EC-SOD in human lungs was defined using immunohistochemistry and immunocytochemical techniques. The findings suggest that EC-SOD is not diffusely located throughout the lung, but has a specific distribution in the extracellular matrix. These findings on the distribution of EC-SOD suggest that specific roles for EC-SOD may include the protection of matrix elements such as collagen from oxidative stress and that it may also function in the regulation of intercellular signals that are modulated by reactive oxygen species.

Adult↗
PubMed1994

Correlative light and electron microscopy studies of PrP localisation in 87V scrapie.

The transmissible neurodegenerative diseases, of which scrapie is the archetype, are caused by unconventional infectious agents. Prion protein (PrP), a widespread host coded, cell surface sialoglycoprotein, is thought to be an essential or, controversially, sole component of these agents. During infection, disease specific accumulations of PrP may be observed in immunostained brain sections of mice infected with the 87V scrapie strain as amyloid plaques or as diffuse or granular foci within the neuropil. Using serial light and electron microscopical preparations we determined immunocytochemically that infection specific PrP is present in amyloid fibrils, and accumulates on the plasmalemma of neurites at the periphery of plaques and in the neuropil, irrespective of the morphological form of PrP accumulation when viewed by light microscopy. In some brain areas with dense granular PrP expression complete disruption of neuropil with loss of neurites was associated with fibrils lying free in expanded extracellular space. These results suggest that normal PrP may be converted to its pathological form at the neuronal plasmalemma or in the extracellular space and, furthermore, that amyloid fibrils are formed following the accumulation and aggregation of subunit proteins at these sites.

Animals↗
PubMed1991

Extracellular levels of adenosine and its metabolites in the striatum of awake rats: inhibition of uptake and metabolism.

The level of purines in the striatum of awake, freely moving rats was studied using microdialysis. The calculated extracellular concentration of adenosine and its metabolites inosine and hypoxanthine was very high immediately after implantation of the dialysis probe but decreased within 24 h to a level which remained stable for two days. Using in vitro calibration to determine the relative recovery of the dialysis probes we estimated resting levels in the striatal extracellular space to be 40, 110 and 580 nM, respectively. Inhibition of adenosine deaminase by deoxycoformycin produced a significant 1.4-fold increase in extracellular adenosine levels and a fall in inosine and hypoxanthine. A combination of three uptake blockers (dipyridamole, lidoflazine and nitrobenzylthioinosine), caused a 4.5-fold increase in extracellular adenosine levels without any change in inosine or hypoxanthine levels. After uptake inhibition deoxycoformycin did not have any significant effect. The present results show that the microdialysis technique can be used to determine levels of purines in the extracellular fluid of defined brain regions in awake animals. The high levels recorded during the first several hours after implantation may be artefactually high and reflect trauma. The results also show that adenosine levels can be altered in vivo by inhibitors of adenosine transport and adenosine deaminase. The present results indicate that the physiological adenosine level in striatal extracellular space is in the range 40-460 nM.

Adenosine↗