Extracellular space of brain as determined by diffusion of inulin from the ventricular system

Rall, David P.; Oppelt, W. W.; Patlak, Clifford S.

doi:10.1016/0024-3205(62)90104-2

Cited by 214 publications

(60 citation statements)

References 10 publications

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“…In rabbit brain, the penetration of inulin from the ventricles into the tissue diminishes rapidly with increasing depth (Rall, Oppelt & Patlak, 1962); extrapolation to the region of equilibrium indicates a space of 12 %, that is within 1 % of our value. In bowfin brain few zones are more than 0.5 to 1 mm off a surface exposed to the incubation, and equilibrium is readily attained.…”

Section: Resultssupporting

confidence: 74%

“…Several authors considered the ependyma a barrier capable of active, selective transport of substances (Feldberg & Fleischhauer, 1960;Edstr0m & Steinwall, 1961). However, their conclusions were based on the cessation ofexchanges post mortem, which are, more likely, indicative ofthe obliteration of the extracellular compartment by the post mortem swelling of the cells (Rall et al 1962;Davson, 1967). These conclusions also are inconsistent with the demonstration of the in vivo penetration of peroxidase from ventricles into the tissue along the extracellular clefts (Brightmann, 1965).…”

Section: Resultsmentioning

confidence: 96%

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A new approach for determining the volume of cerebral extracellular fluid and demonstration of its communication with c.s.f

Friede¹,

Hu²

1971

The Journal of Physiology

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SUMMARY1. A new technique is presented for determining the volume of extracellular space in bowfin (Amia calva) brain during in vitro incubation. It consists of solving simultaneous equations which are applied to determine the volume of extracellular space as well as intracellular marker concentration. This technique allows for a better insight into the redistribution of marker between incubation medium and extracellular space as well as between extracellular and intracellular space.2. Na+, K+ and Cl-equilibrated within 10-15 min between incubation medium and extracellular space. There was no evidence of a homoeostatic mechanism controlling the concentration of these ions in the extracellular fluid, which appeared to be in equilibrium with cerebrospinal fluid. The extracellular spaces of these ions were identical: Na+, 23-4; K+,

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Section: Resultssupporting

confidence: 74%

Section: Resultsmentioning

confidence: 96%

A new approach for determining the volume of cerebral extracellular fluid and demonstration of its communication with c.s.f

Friede¹,

Hu²

1971

The Journal of Physiology

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“…A substance such as inulin, which is not actively 403 transported from c.s.f. and diffuses out only very slowly (Pappenheimer & Heisey, 1963;Rall, Oppelt & Patlak, 1962) will be removed essentially only by bulk absorption and by sampling. Thus, the amount removed can be expressed in terms of a constant volume of outflow fluid.…”

Section: Biochemical Methodologymentioning

confidence: 99%

The active transport of 5‐hydroxyindol‐3‐ylacetic acid and 3‐methoxy‐4‐hydroxyphenylacetic acid from a recirculatory perfusion system of the cerebral ventricles of the unanaesthetized dog

Ashcroft¹,

Dow²,

Moir³

1968

The Journal of Physiology

155

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SUMMARY1. An operation on dogs for the implantation ofguide tubes to the lateral ventricle and cisterna magna and a method whereby the ventricular space can be repeatedly perfused in conscious and unrestrained animals are described.2. The characteristics of a recirculatory perfusion system were examined and the bulk formation and absorption of cerebrospinal fluid and the volume of the ventricular space perfused were derived from the concentrations achieved during the infusion of inulin into the system. 3. 5-hydroxyindol-3-ylacetic acid (5-HIAA), the acid metabolite of 5-hydroxytryptamine, and 3-methoxy-4-hydroxyphenylacetic acid (HVA), the main acid metabolite of dopamine, were demonstrated to be mainly removed from cerebrospinal fluid (c.s.f.) by an active transport system localized in the region of the fourth ventricle. 4. It was possible to inhibit the active transport of these acids from cerebrospinal fluid by pre-treating the dogs with probenecid.

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“…A great many studies using a wide variety of tracer substances and multiple different ex vivo/in vivo methods have concluded that the local transport of small and large molecules through the brain ECS of the neuropil is predominantly diffusive in nature; such studies have included ventriculo-cisternal or subarachnoid-cisternal perfusion of radiolabelled tracers [111,135,144], real-time iontophoresis of the small tetramethylammonium ion [126], and integrative optical imaging (IOI) of pressure-injected fluorescently labelled molecules [127,[178][179][180]191]. Electron microscopy studies focused on neuropil ultrastructure have long indicated a brain ECS width of approximately 10-20 nm [21,75,81,136] and, importantly, that these narrow spaces could be accessed with tracers such as HRP (40 kDa) following intracerebroventricular injection [20,21].…”

Section: Diffusion or Flow Of The Isf In The Brain Ecs?mentioning

confidence: 99%

The role of brain barriers in fluid movement in the CNS: is there a ‘glymphatic’ system?

et al. 2018

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Brain fluids are rigidly regulated to provide stable environments for neuronal function, e.g., low K + , Ca 2+ , and protein to optimise signalling and minimise neurotoxicity. At the same time, neuronal and astroglial waste must be promptly removed. The interstitial fluid (ISF) of the brain tissue and the cerebrospinal fluid (CSF) bathing the CNS are integral to this homeostasis and the idea of a glia-lymph or 'glymphatic' system for waste clearance from brain has developed over the last 5 years. This links bulk (convective) flow of CSF into brain along the outside of penetrating arteries, glia-mediated convective transport of fluid and solutes through the brain extracellular space (ECS) involving the aquaporin-4 (AQP4) water channel, and finally delivery of fluid to venules for clearance along peri-venous spaces. However, recent evidence favours important amendments to the 'glymphatic' hypothesis, particularly concerning the role of glia and transfer of solutes within the ECS. This review discusses studies which question the role of AQP4 in ISF flow and the lack of evidence for its ability to transport solutes; summarizes attributes of brain ECS that strongly favour the diffusion of small and large molecules without ISF flow; discusses work on hydraulic conductivity and the nature of the extracellular matrix which may impede fluid movement; and reconsiders the roles of the perivascular space (PVS) in CSF-ISF exchange and drainage. We also consider the extent to which CSF-ISF exchange is possible and desirable, the impact of neuropathology on fluid drainage, and why using CSF as a proxy measure of brain components or drug delivery is problematic. We propose that new work and key historical studies both support the concept of a perivascular fluid system, whereby CSF enters the brain via PVS convective flow or dispersion along larger caliber arteries/arterioles, diffusion predominantly regulates CSF/ISF exchange at the level of the neurovascular unit associated with CNS microvessels, and, finally, a mixture of CSF/ISF/waste products is normally cleared along the PVS of venules/veins as well as other pathways; such a system may or may not constitute a true 'circulation', but, at the least, suggests a comprehensive re-evaluation of the previously proposed 'glymphatic' concepts in favour of a new system better taking into account basic cerebrovascular physiology and fluid transport considerations.

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Extracellular space of brain as determined by diffusion of inulin from the ventricular system

Cited by 214 publications

References 10 publications

A new approach for determining the volume of cerebral extracellular fluid and demonstration of its communication with c.s.f

A new approach for determining the volume of cerebral extracellular fluid and demonstration of its communication with c.s.f

The active transport of 5‐hydroxyindol‐3‐ylacetic acid and 3‐methoxy‐4‐hydroxyphenylacetic acid from a recirculatory perfusion system of the cerebral ventricles of the unanaesthetized dog

The role of brain barriers in fluid movement in the CNS: is there a ‘glymphatic’ system?

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