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At least 145 records · Page 8Linked to original sources
PubMed2003

Equilibrium water exchange between the intra- and extracellular spaces of mammalian brain.

This report describes the measurement of water preexchange lifetimes and intra/extracellular content in intact, functioning mammalian brain. Intra- and extracellular water magnetic resonance (MR) signals from rat brain in vivo were quantitatively resolved in the longitudinal relaxation domain following administration of an MR relaxation agent into the extracellular space. The estimated intracellular water content fraction was 81% +/- 8%, and the intra- to extracellular exchange rate constant was 1.81 +/- 0.89 s(-1) (mean +/- SD, N = 9), corresponding to an intracellular water preexchange lifetime of approximately 550 ms. These results provide a temporal framework for anticipating the water exchange regime (fast, intermediate, or slow) underlying a variety of compartment-sensitive measurements. The method also supplies a means by which to evaluate membrane water permeability and intra/extracellular water content serially in intact tissue. The data are obtained in an imaging mode that permits detection of regional variations in these parameters.

Animals↗
PubMed2005

Changes in extracellular space size and geometry in APP23 transgenic mice: a model of Alzheimer's disease.

Diffusion parameters of the extracellular space (ECS) are changed in many brain pathologies, disturbing synaptic as well as extrasynaptic "volume" transmission, which is based on the diffusion of neuroactive substances in the ECS. Amyloid deposition, neuronal loss, and disturbed synaptic transmission are considered to be the main causes of Alzheimer's disease dementia. We studied diffusion parameters in the cerebral cortex of transgenic APP23 mice, which develop a pathology similar to Alzheimer's disease. The real-time tetramethylammonium (TMA) method and diffusion-weighted MRI were used to measure the ECS volume fraction (alpha = ECS volume/total tissue volume) and the apparent diffusion coefficients (ADCs) of TMA (ADC(TMA)), diffusing exclusively in the ECS and of water (ADC(W)). Measurements were performed in vivo in 6-, 8-, and 17- to 25-month-old hemizygous APP23 male and female mice and age-matched controls. In all 6- to 8-month-old APP23 mice, the mean ECS volume fraction, ADC(TMA), and ADC(W) were not significantly different from age-matched controls (alpha = 0.20 +/- 0.01; ADC(TMA), 580 +/- 16 microm(2).s(-1); ADC(W), 618 +/- 19 microm(2).s(-1)). Aging in 17- to 25-month-old controls was accompanied by a decrease in ECS volume fraction and ADC(W), significantly greater in females than in males, but no changes in ADC(TMA). ECS volume fraction increased (0.22 +/- 0.01) and ADC(TMA) decreased (560 +/- 7 microm(2).s(-1)) in aged APP23 mice. The impaired navigation observed in these animals in the Morris water maze correlated with their plaque load, which was twice as high in females (20%) as in males (10%) and may, together with changed ECS diffusion properties, account for the impaired extrasynaptic transmission and spatial cognition observed in old transgenic females.

Aging↗
PubMed1996

Influence of age on the clearance of K+ from the extracellular space of rat hippocampal slices.

We examined the hypotheses that aging alters the capacity of brain tissue to regulate extracellular K+ activity (K+o), and that age-related decreases in glucose metabolism may underlie these alterations. Hippocampal slices from young adult (6-9 months old), middle-aged (16-19 months old), and aged (26-29 months old) Fischer 344 rats were exposed to physiological solutions containing 5-20 mM glucose maintained at 36-37 degrees C. Schaffer collaterals in each slice were stimulated at 40 Hz for 2 s, and the resulting changes in K+o were recorded with K+o-sensitive microelectrodes placed in stratum pyramidale of hippocampal subfield CA1. We found that K+ clearance from the extracellular space of hippocampal slices was significantly slowed in the middle-aged group compared with the young adult group in physiological solutions containing 5 and 10 mM glucose. Age-related differences in K+o clearance disappeared in 20 mM glucose. Also, the rate of K+o clearance was modified by glucose concentration. These results suggest that K+ transport rates are modified by age, and that age-related alterations in glucose metabolism may be involved.

Aging↗
PubMed2004

Enhanced macromolecular diffusion in brain extracellular space in mouse models of vasogenic edema measured by cortical surface photobleaching.

Diffusion of solutes and macromolecules in brain extracellular space (ECS) is important for normal brain function and efficient drug delivery, and is thought to be impaired in edematous brain. Here we measured the diffusion of an inert macromolecular fluorescent marker (FITC-dextran, 70 kDa) in the ECS by fluorescence recovery after photobleaching after staining the exposed cerebral cortex in vivo. In a brain tumor model of vasogenic (leaky capillary) edema, FITC-dextran diffusion was reduced more than fourfold in hypercellular tumor and surrounding astrogliotic tissue; however, diffusion in brain away from the tumor was approximately 30% faster than in normal contralateral brain. The increased diffusion was abolished by dexamethasone pretreatment. Enhanced ECS diffusion was also found in uninjured brain near a region of leaky brain vessels produced by focal cortical freeze injury. In contrast, ECS diffusion was slowed more than sixfold in cytotoxic brain edema caused by anoxia. Diffusion results were related semiquantitatively to ECS volume fraction and matrix viscosity from in vitro photobleaching studies in a model system consisting of silica particles in a fluorescent water/glycerol matrix. Our data provide in vivo evidence for enhanced ECS diffusion in vasogenic brain edema, yet greatly slowed diffusion in cytotoxic edema and in and around tumors.

Animals↗
PubMed1986

Excitatory amino acids and epilepsy-induced changes in extracellular space size.

Convulsant and stimulus induced seizures are associated with Ca, Na, K and Cl concentration changes in the extracellular space (ES), which are a resultant of transmembrane ionic fluxes and of changes in the ES size. The ES decreases on average by 30% during a single seizure. An analysis of the causes of ES size changes reveal a large contribution from the spatial glia K buffer mechanism which may account for up to 60% of the ES decreases. NaCl and KCl uptake into cells as well as increases in intracellular osmolarity due to anaerobic glycolysis contribute less to the local cytotoxic edema but account for a net gain of osmotic active particle at the site of the focus. Excitatory amino acids such as glutamate, aspartate, N-methyl-D-aspartate (NMDA), kainate and quisqualate also lead to Na, Cl and eventually Ca uptake into cells and to release of K with dose dependent decreases in [Na]o, [Ca]o and [Cl]o, increases in [K]o and transient decreases in ES size by up to 80% which are possibly associated with a net reduction of osmotically active particles. The predominant cause for this cytotoxic edema is NaCl uptake into cells but spatial K buffering through glial cells also contributes to this type of edema. The possible consequences of the various ion movements and the changes in osmolarity as well as ES size for tissue vulnerability are discussed.

Animals↗
PubMed2002

Mechanical control of extracellular space in rabbit atria: an intimate modulator of the translocation of extracellular fluid and released atrial natriuretic peptide.

We have previously shown that extracellular fluid (ECF) is translocated by atrial contraction. Following on from this finding we have proposed a two-step sequential mechanism for the regulation of stretch-activated secretion of atrial natriuretic peptide (ANP): myocytic release of ANP into the surrounding paracellular space followed by the translocation of ECF with the released ANP into the bloodstream. This latter step is induced by atrial contraction, and is therefore controlled by atrial workload. However, the mechanism that regulates the changes in translocation of the ECF has not been defined. To define the relationship between the atrial workload, ECF translocation, size of the extracellular space (ECS) and ANP secretion, experiments have been performed in isolated perfused beating rabbit atria. Atrial workload, transendocardial translocation of the ECF and the secretion of ANP were quantified. Changes in the size of the atrium and the ECS were determined by a newly developed methodology in the beating atria. Atrial workload determined the translocation of the ECF and released ANP with waning of the translocation at higher myocardial workloads. Atrial workload inversely determined the size of the atrium and the ECS. The latter directly determined the translocation of the ECF in terms of atrial workload. From these data we suggest that the size of the ECS is an intimate modulator of the translocation of the ECF and released ANP, and that the phenomenon of waning of the transendocardial translocation that appeared at higher atrial workloads is closely related to the shrinkage of the ECS.

Animals↗
PubMed1978

Blood volume and extracellular space (ECS) of the whole body and some organs of the rat.

Methods are described for estimation of blood volume and extracellular space (ECS) in the whole body and in some organs with 51Cr, 14C-thiocyanate and 3H-inulin. A mean blood volume of 47 ml/kg, a thiocyanate space of 350 ml/kg and a inulin space of 288 ml/kg were determined in the rat. The corresponding values of organs are shown in figures 1--3.

Animals↗
PubMed1985

Effect of CO2 on a brain extracellular space marker and evidence of its neuronal modulation.

Increases in inspired CO2 consistently altered the local concentration of the brain extracellular space marker alpha-naphthalene sulfonate (alpha-NS) as measured with ion-selective micropipettes in the rat thalamus. Stereotaxic injection of lidocaine in the region of the locus coeruleus attenuated this effect of CO2, and amitriptyline, a tricyclic anti-depressant and amine reuptake inhibitor, potentiated the effect. These results suggest that metabolic demand, as mimicked here by the addition of CO2, alters the fluid environment of the brain and central noradrenergic mechanisms may modulate this response.

Amitriptyline↗
PubMed1988

A morphometric analysis of extracellular space in the developing spinal cord of the chick embryo.

The developmental changes in the amount and distribution of the expanded extracellular space (ECS) (i.e. wider than 100 nm) were analyzed in the cervical spinal cord of chick embryos between stage 9 and 29, using electron micrograph montages, which cover one half of the cross-sectional area of the cord. The percentage of the ECS expansion to the whole cross-sectional area of the cord was 11.0% at stage 9, 7.7% at stage 11, 7.8% at stage 15, and 9.7% at stage 17. It decreased markedly to 3.0% at stage 22 and 1.3% at stage 29. The highest percentage at stage 9 may reflect the dynamic structural changes associated with neural groove closure which takes place around this time. The marked decrease after stage 22 is associated with the rapid overall growth of the cord. Until stage 19, the ECS expansions were mostly elongated and arranged radially with respect to the central canal. The ECS became scarce and arranged randomly thereafter. Throughout the stages examined, especially between stages 17 and 19, percentage was higher in the outer half of the cord than in the inner half. The outer glial limiting membrane was not established by stage 29. Between stages 17 and 22, the percentage was higher in the dorsal region than in the ventral region. This appears to be associated with the regional difference in neuronal maturation. The first blood vessels penetrated the ventromedial portion of the cord around stage 22, where the ECS expansions were relatively scarce. The successive rapid decrease in the amount of ECS expansions can be correlated to the development of vascularization.

Animals↗
PubMed1987

Sensitivity of yeast cells to reactive oxygen species generated in the extracellular space.

Even when cytoplasmic scavenging activities are plentiful, yeast cells (S. cerevisiae) remain particularly sensitive towards reactive oxygen species generated in the extracellular space (either by the xanthine/xanthine oxidase reaction or by the redox cycling of menadione). A sharp reduction of the extent of cellular alterations when SOD and/or catalase were supplemented in the incubation buffer, points to a contribution of both O-.2 and H2O2 in the toxic process. Although oxygen metabolites as well as t-butylhydroperoxide (tBH), a highly toxic organic peroxide, may be directly responsible for cellular damage, their toxicity is largely reduced in the presence of Desferal. A role of metal ions in potentiating the toxicity points to the involvement of OH. radicals, actually produced in the medium. With tBH, metal cations would be rather active in promoting peroxidative chain reactions. In the case of an extracellular oxidative attack, it may be foreseen that the plasma membrane will form a preferential target. An increased permeability of the plasma membrane towards ionized molecules and uncharged polycarboxylic acids is indeed observed after an oxidative treatment. The loss of selective permeability is, as a rule, correlated with a drop in viability. Early alterations, disrupting the functional organization of the plasma membrane have been sought. The permease involved in the active transport of purine(s) has appeared to be an appropriate marker for checking its functional integrity. This transport function appears to be very sensitive to damage induced by O-.2 generators, particularly under conditions in which the resulting lethality is still kept low and in which the energization of active transport processes remains unimpaired.

Carboxylic Acids↗
PubMed1980

Transient changes in the size of the extracellular space in the sensorimotor cortex of cats in relation to stimulus-induced changes in potassium concentration.

The time course of local changes of the extracellular space (ES) was investigated by measuring concentration changes of repeatedly injected tetramethylammonium (TMA+) and choline (Ch+) ions for which cell membranes are largely impermeable. After stimulus-induced extracellular [K+] elevations the delta [TMA+] and delta [Ch+] signals recorded with nominally K+-selective liquid ion-exchanger microelectrodes increased by up to 100%, thus indicating a reduction of the ES down to one half of its initial size. The shrinkage was maximal at sites where the K+ release into the ES was also largest. At very superficial and deep layers, however, considerable increases in extracellular K+ concentration were not accompanied by significant reductions in the ES. These findings can be explained as a consequence of K+ movement through spatially extended cell structures. Calculations based on a model combining the spatial buffer mechanism of Kuffler and Nicholls (1966) to osmolarity changes caused by selective K+ transport through primarily K+ permeable membranes support this concept. Following stimulation additional iontophoretically induced [K+]0 rises were reduced in amplitude by up to 35%, even at sites where maximal decreases of the ES were observed. This emphasizes the importance of active uptake for K+ clearance out of the ES.

Animals↗
PubMed2005

Reduced extracellular space in the brain of tenascin-R- and HNK-1-sulphotransferase deficient mice.

Tenascin-R (TN-R), a large extracellular glycoprotein, is an important component of the adult brain's extracellular matrix (ECM); tenascin-C (TN-C) is expressed mainly during early development, while human natural killer 1 (HNK-1) is a sulphated carbohydrate epitope that attaches to these molecules, modifying their adhesive properties. To assess their influence on extracellular space (ECS) volume and geometry, we used the real-time iontophoretic method to measure ECS volume fraction alpha and tortuosity lambda, and diffusion-weighted magnetic resonance imaging (MRI) to measure the apparent diffusion coefficient of water (ADC(W)). Measurements were performed in vivo in the cortex and CA1 hippocampal region of TN-R-, TN-C- and HNK-1 sulphotransferase (ST)-deficient adult mice and their wild-type littermate controls. In both cortex and hippocampus, the lack of TN-R or HNK-1 sulphotransferase resulted in a significant decrease in alpha and lambda. Compared with controls, alpha in TN-R-/- and ST-/- mice decreased by 22-26% and 9-15%, respectively. MRI measurements revealed a decreased ADC(W) in the cortex, hippocampus and thalamus. ADC(W) reflected the changes in alpha; the decrease in lambda indicated fewer diffusion obstacles in the ECS, presumably due to a decreased macromolecular content. No significant changes were found in TN-C-/- animals. We conclude that in TN-R-/- and ST-/- mice, which show morphological, electrophysiological and behavioural abnormalities, the ECS is reduced and its geometry altered. TN-R, as an important component of the ECM, appears to maintain an optimal distance between cells. The altered diffusion of neuroactive substances in the brain will inevitably affect extrasynaptic transmission, neuron-glia interactions and synaptic efficacy.

Animals↗
PubMed1994

Simultaneous measurement of bidirectional capillary permeability, vascular volume, extracellular space, and rCBF in experimental gliomas and surrounding edema.

Measurements of bidirectional capillary permeability in the ASV tumor model revealed a heterogeneous distribution of transport rates for the small water-soluble molecules which are believed to be the driving force in perifocal edema formation. Mean K1 values were 8.1 +/- 5.5 microliters/g/min in whole tumor and 18.89 +/- 12.3 microliters/g/min in highly permeable areas. Tumor blood flow ranged between normal white matter and cortex, whereas the plasma vascular space in the tumors was increased as compared to the normal brain. The size of the extracellular space was depending on the regional capillary permeability, underlining the vasogenic nature of peritumoral edema which was capable of being studied using in vivo methods.

Animals↗
PubMed1999

Monitoring glutamate and ascorbate in the extracellular space of brain tissue with electrochemical microsensors.

This paper describes electrochemical microsensors for the in vivo measurement of glutamate and ascorbate in the extracellular space of brain tissue. To prepare glutamate microsensors, carbon fiber microelectrodes (10 microns in diameter and 300-400 microns long) were modified with a cross-linked redox polymer film containing enzymes. The microsensors were coated with a thin Nafion film before use. The glutamate microsensors were both selective and sensitive toward glutamate, with detection limits in the low micromolar range. Physiologically relevant concentrations of several electroactive compounds found in brain tissue produced no response at the glutamate microsensors and also did not affect their glutamate response, the only exception being glutamine, for which a small response was observed in the absence, but not in the presence, of glutamate. The ascorbate microsensors were used in conjunction with cyclic voltammetry. They were sensitive and selective toward ascorbate, but did exhibit a small sensitivity toward the dopamine metabolite, dihydroxyphenylacetic acid. The in vivo measurements performed establish the ability of the glutamate microsensors to monitor the component of the basal extracellular glutamate level that is derived from the neuronal activity of brain tissue.

Ascorbic Acid↗
PubMed2006

Brain metabolism and extracellular space diffusion parameters during and after transient global hypoxia in the rat cortex.

Hypoxia results in both reversible and irreversible changes in the brain extracellular space (ECS). This study utilized microdialysis to monitor changes in the energy-related metabolites lactate, pyruvate, glucose and glutamate in the rat cortex before, during and after 30-min transient global hypoxia, induced in anesthetized rats by reducing inspired oxygen to 6% O(2) in nitrogen. Changes in metabolite levels were compared with ECS diffusion parameters calculated from diffusion curves of tetramethylammonium applied by iontophoresis. Significant increases in lactate concentration and the lactate/pyruvate ratio, as well as decreased glucose levels, were found in the cortex immediately after the induction of hypoxia. Following recovery to ventilation with air, extracellular lactate and glucose levels and the lactate/pyruvate ratio returned to control levels within 40, 20 and 30 min, respectively. Glutamate levels started to increase 20-30 min after the onset of hypoxia and returned to prehypoxic values within 30-40 min of reoxygenation. The ECS volume fraction alpha decreased by about 5% from 0.18+/-0.01 during the first 20-25 min of hypoxia; after 25 min alpha dropped a further 22% to 0.14+/-0.01. Within 10 min of reoxygenation, alpha returned to control values, then increased to 0.20+/-0.01 and remained at this level until the end of the experiment. The observed 22% decrease in alpha markedly influences dialysate levels measured during hypoxia. In our study, the complete posthypoxic recovery of cortical metabolite levels and ECS diffusion properties suggests that metabolic enzymes and related cellular components (e.g., mitochondria) may tolerate prolonged hypoxic periods and recover to prehypoxic values.

Animals↗
PubMed1997

Detection and characterization of a protein isoaspartyl methyltransferase which becomes trapped in the extracellular space during blood vessel injury.

Injury to rat blood vessels in vivo was found to release intracellular pools of protein D-aspartyl/L-isoaspartyl carboxyl methyltransferase (PIMT) into the extracellular milieu, where it becomes trapped. This trapped cohort of PIMT is able to utilize radiolabeled S-adenosyl-L-methionine (AdoMet) introduced into the circulation to methylate blood vessel proteins containing altered aspartyl residues. As further shown in this study, methylated substrates are detected only at the specific site of injury. In vitro studies more fully characterized this endogenous PIMT activity in thoracic aorta and inferior vena cava. Methylation kinetics, immunoblotting, and the lability of methylated substrates at mild alkaline pH were used to demonstrate that both types of blood vessel contain an endogenous protein D-aspartyl/L-isoaspartyl carboxyl methyltransferase (PIMT). At least 50% of the PIMT activity is resistant to nonionic detergent extraction, suggesting that the enzyme activity becomes trapped within or behind the extracellular matrix (ECM). Quantities of lactate dehydrogenase (LDH), another soluble enzyme of presumed intracellular origin, were found to be similarly trapped in the extracellular space of blood vessels.

Animals↗
PubMed2000

Spatial buffering of potassium ions in brain extracellular space.

It has long been assumed that one important mechanism for the dissipation of local potassium gradients in the brain extracellular space is the so-called spatial buffer, generally associated with glial cells. To date, however, there has been no analytical description of the characteristic patterns of K(+) clearance mediated by such a mechanism. This study reanalyzed a mathematical model of Gardner-Medwin (1983, J. Physiol. (Lond.). 335:393-426) that had previously been solved numerically. Under suitable approximations, the transient solutions for the potassium concentrations and the corresponding membrane potentials of glial cells in a finite, parallel domain were derived. The analytic results were substantiated by numerical simulations of a detailed two-compartment model. This simulation explored the dependence of spatial buffer current and extracellular K(+) on the distribution of inward rectifier K(+) channels in the glial endfoot and nonendfoot membranes, the glial geometric length, and the effect of passive KCl uptake. Regarding the glial cells as an equivalent leaky cable, the analyses indicated that a maximum endfoot current occurs when the glial geometric length is equal to the corresponding electrotonic space constant. Consequently, a long glial process is unsuitable for spatial buffering, unless the axial space constant can match the length of the process. Finally, this study discussed whether the spatial buffer mechanism is able to efficiently transport K(+) over distances of more than several glial space constants.

Animals↗