Ischemia-Induced Changes in the Extracellular Space Diffusion Parameters, K<sup>+</sup>, and pH in the Developing Rat Cortex and Corpus Callosum

Voříšek, Ivan; Syková, Eva

doi:10.1097/00004647-199702000-00009

Cited by 128 publications

(73 citation statements)

References 48 publications

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“…Two curves are shown for EGF, one in which it migrates through tissue with the experimentally determined low (1.79) and the other in which its diffusion is more hindered, with a typical of the proteins and dextrans Ͼ10,000 M r in Table 2 (average ϭ 2.26). Only EGF exhibiting a low reaches a level substantially above the receptor affinity constant (K D ϭ 0.67 nM; Waters et al 1990) at this distance from the release site (r ϭ 600 m). EGF exhibiting high manages only a slightly higher peak concentration than NGF.…”

Section: Low Will Allow Egf To Elicit Effects Further From Sources Inmentioning

confidence: 93%

“…For example, the RTI method has been used in vivo to show that increases significantly for the small TMA ϩ ion (74 M r ) during progressive ischemia (Syková et al 1994), terminal anoxia (Syková et al 1994;Voříšek and Syková 1997), and astrogliosis (Roitbak and Syková 1999;Voříšek et al 2002). Increases in have also been described for 3,000 M r dextran in a thick slice model of ischemia (Hrabětová et al 2003) and in slices exposed to osmotic stress by hypotonic media (Tao 1999).…”

Section: Low Will Allow Egf To Elicit Effects Further From Sources Inmentioning

confidence: 99%

“…1 in METHODS). Concentration at radius ϭ 600 m following diffusion from a point source (UC p ϭ 10 Ϫ14 mol) with linear elimination constant, k e , set equal to the endocytic rate constant for EGF (0.19 min Ϫ1 ; K D ϳ 0.7 nM; Waters et al 1990). B: continuous release from an interface (e.g., from the ventricles or subarachnoid space during continuous infusion; see Eq.…”

Section: Low Will Allow Egf To Elicit Effects Further From Sources Inmentioning

confidence: 99%

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Diffusion of Epidermal Growth Factor in Rat Brain Extracellular Space Measured by Integrative Optical Imaging

Thorne

Hrabětová

Nicholson

2004

Journal of Neurophysiology

152

132

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Diffusion of epidermal growth factor in rat brain extracellular space measured by integrative optical imaging. J Neurophysiol 92: 3471-3481, 2004. First published July 21, 2004 doi:10.1152/jn. 00352.2004. Epidermal growth factor (EGF) stimulates proliferation, process outgrowth, and survival in the CNS. Understanding the actions of EGF necessitates characterizing its distribution in brain tissue following drug delivery or release from cellular sources. We used the integrative optical imaging (IOI) method to measure diffusion of fluorescently labeled EGF (6,600 M r ; 4 g/ml) in the presence of excess unlabeled EGF (90 g/ml) to compete off specific receptor binding and reveal the "true" EGF diffusion coefficient following injection in rat brain slices (400 m). The effective diffusion coefficient was 5.18 Ϯ 0.16 ϫ 10 Ϫ7 (SE) cm 2 /s (n ϭ 22) in rat somatosensory cortex and the free diffusion coefficient, determined in dilute agarose gel, was 16.6 Ϯ 0.12 ϫ 10 Ϫ7 cm 2 /s (n ϭ 27). Tortuosity ( ), a parameter representing the hindrance imposed on EGF by the convoluted brain extracellular space (ECS), was 1.8, the lowest yet measured by IOI for a protein in brain. Control experiments with fluorescent dextran of similar molecular weight and tetramethylammonium confirmed EGF did not affect local ECS structure. We conclude that transport of smaller growth factors such as EGF through brain ECS is less hindered than that of larger proteins (Ͼ10,000 M r , e.g., nerve growth factor) where typically Ͼ 2.1. Modeling was used to predict that low will allow EGF sources in the brain to be further from target cells and still elicit a biological response. High values for larger growth factors imply more constrained local biological effects than with smaller proteins such as EGF.

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Section: Low Will Allow Egf To Elicit Effects Further From Sources Inmentioning

confidence: 93%

Section: Low Will Allow Egf To Elicit Effects Further From Sources Inmentioning

confidence: 99%

Section: Low Will Allow Egf To Elicit Effects Further From Sources Inmentioning

confidence: 99%

See 1 more Smart Citation

Diffusion of Epidermal Growth Factor in Rat Brain Extracellular Space Measured by Integrative Optical Imaging

Thorne

Hrabětová

Nicholson

2004

Journal of Neurophysiology

152

132

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“…All of the above phenomena also are linked intimately with pathological processes: changes in extracellular diffusivity have been described in the very early stages of cerebral ischemia, both with diffusion-weighted magnetic resonance imaging (11,12) and with electrochemical measurements of inorganic ions injected into the extracellular space (13,14,15). These changes, which are likely to play a major role in neurotoxicity and seizure initiation, again underline the need for a comprehensive description of extracellular diffusion.…”

mentioning

confidence: 98%

“…The values of ␣ and have hitherto been estimated in various brain areas by comparing the concentration profiles of dyes or inorganic ions injected into the brain with the corresponding solutions of diffusion equations (16,18,19,20). Simultaneous measurements of ␣ and also have been reported in the same tissue in the face of alterations in osmolarity, either by direct manipulation of the perfusion medium in vitro (21) or secondary to ischemia in vivo (13,15). These experiments show that changes in ␣ and are anticorrelated, although a quantitative explanation of this relationship is lacking.…”

mentioning

confidence: 99%

Geometric and viscous components of the tortuosity of the extracellular space in the brain

Rusakov¹,

Kullmann²

1998

Proc. Natl. Acad. Sci. U.S.A.

167

142

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To understand the function of neuro-active molecules, it is necessary to know how far they can diffuse in the brain. Experimental measurements show that substances confined to the extracellular space diffuse more slowly than in free solution. The diffusion coefficients in the two situations are commonly related by a tortuosity factor, which represents the increase in path length in a porous medium approximating the brain tissue. Thus far, it has not been clear what component of tortuosity is due to cellular obstacles and what component represents interactions with the extracellular medium (''geometric'' and ''viscous'' tortuosity, respectively). We show that the geometric tortuosity of any random assembly of space-filling obstacles has a unique value (Ϸ1.40 for radial f lux and Ϸ1.57 for linear f lux) irrespective of their size and shape, as long as their surfaces have no preferred orientation. We also argue that the Stokes-Einstein law is likely to be violated in the extracellular medium. For molecules whose size is comparable with the extracellular cleft, the predominant effect is the viscous drag of the cell walls. For small diffusing particles, in contrast, macromolecular obstacles in the extracellular space retard diffusion. The main parameters relating the diffusion coefficient within the extracellular medium to that in free solution are the intercellular gap width and the volume fraction occupied by macromolecules. The upper limit of tortuosity for small molecules predicted by this theory is Ϸ2.2 (implying a diffusion coefficient approximately five times lower than that in a free medium). The results provide a quantitative framework to estimate the diffusion of molecules ranging in size from Ca 2؉ ions to neurotrophins.

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Changes in glial K+ currents with decreased extracellular volume in developing rat white matter

et al. 1997

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Whole cell patch-clamp recordings of K+ currents from oligodendrocyte precursors in 10-day-old rats (P10) and, following myelination, in mature oligodendrocytes from 20-day-old rats (P20) were correlated with extracellular space (ECS) diffusion parameters measured by the local diffusion of iontophoretically injected tetramethylammonium ions (TMA+). The aim of this study was to find an explanation for the changes in glial currents that occur with myelination. Oligodendrocyte precursors (P10) in slices from corpus callosum were characterized by the presence of A-type K+ currents, delayed and inward rectifier currents, and lack of tail currents after the offset of a voltage jump. Mature oligodendrocytes in corpus callosum slices from P20 rats were characterized by passive, decaying currents and large tail currents after the offset of a voltage jump. Measurements of the reversal potential for the tail currents indicate that they result from increases in [K+]e by an average of 32 mM during a 20 msec 100 mV voltage step. Concomitant with the change in oligodendrocyte electrophysiological behavior after myelination there is a decrease in the ECS of the corpus callosum. ECS volume decreases from 36% (P9-10) to 25% (P20-21) of total tissue volume. ECS tortuosity lambda = (D/ADC)0.5, where D is the free diffusion coefficient and ADC is the apparent diffusion coefficient of TMA+ in the brain, increases as measured perpendicular to the axons from 1.53 +/- 0.02 (n = 6, mean +/- SEM) to 1.70 +/- 0.02 (n = 6). TMA+ non-specific uptake (k') was significantly larger at P20 (5.2 +/- 0.6 x 10(-3) s(-1), n = 6) than at P10 (3.5 +/- 0.4 x 10(-3) s(-1), n = 6). It can be concluded that membrane potential changes in mature oligodendrocytes are accompanied by rapid changes in the K+ gradient resulting from K+ fluxes across the glial membrane. As a result of the reduced extracellular volume and increased tortuosity, the membrane fluxes produce larger changes in [K+]e in the more mature myelinated corpus callosum than before myelination. These conclusions also account for differences between membrane currents in cells in slices compared to those in tissue culture where the ECS is essentially infinite. The size and geometry of the ECS influence the membrane current patterns of glial cells and may have consequences for the role of glial cells in spatial buffering.

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Ischemia-Induced Changes in the Extracellular Space Diffusion Parameters, K⁺, and pH in the Developing Rat Cortex and Corpus Callosum

Cited by 128 publications

References 48 publications

Diffusion of Epidermal Growth Factor in Rat Brain Extracellular Space Measured by Integrative Optical Imaging

Diffusion of Epidermal Growth Factor in Rat Brain Extracellular Space Measured by Integrative Optical Imaging

Geometric and viscous components of the tortuosity of the extracellular space in the brain

Changes in glial K+ currents with decreased extracellular volume in developing rat white matter

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Ischemia-Induced Changes in the Extracellular Space Diffusion Parameters, K+, and pH in the Developing Rat Cortex and Corpus Callosum

Cited by 128 publications

References 48 publications

Diffusion of Epidermal Growth Factor in Rat Brain Extracellular Space Measured by Integrative Optical Imaging

Diffusion of Epidermal Growth Factor in Rat Brain Extracellular Space Measured by Integrative Optical Imaging

Geometric and viscous components of the tortuosity of the extracellular space in the brain

Changes in glial K+ currents with decreased extracellular volume in developing rat white matter

Contact Info

Product

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About

Ischemia-Induced Changes in the Extracellular Space Diffusion Parameters, K⁺, and pH in the Developing Rat Cortex and Corpus Callosum