Elsevier

Neurochemistry International

Volume 45, Issue 4, September 2004, Pages 545-552
Neurochemistry International

Evidence for bulk flow of brain interstitial fluid: significance for physiology and pathology

https://doi.org/10.1016/j.neuint.2003.11.006Get rights and content

Abstract

This review surveys evidence for the flow of brain interstitial fluid (ISF) via preferential pathways through the brain, and its relation to cerebrospinal fluid (CSF). Studies over >100 years have raised several controversial points, not all of them resolved. Recent studies have usefully combined a histological and a mathematical approach. Taken together the evidence indicates an ISF bulk flow rate of 0.1–0.3 μl min−1 g−1 in rat brain along preferential pathways especially perivascular spaces and axon tracts. The main source of this fluid is likely to be the brain capillary endothelium, which has the necessary ion transporters, channels and water permeability to generate fluid at a low rate, c1/100th of the rate per square centimeter of CSF secretion across choroid plexus epithelium. There is also evidence that a proportion of CSF may recycle from the subarachnoid space into arterial perivascular spaces on the ventral surface of the brain, and join the circulating ISF, draining back via venous perivascular spaces and axon tracts into CSF compartments, and out both through arachnoid granulations and along cranial nerves to the lymphatics of the neck. The bulk flow of ISF has implications for non-synaptic cell:cell communication (volume transmission); for drug delivery, distribution, and clearance; for brain ionic homeostasis and its disturbance in brain edema; for the immune function of the brain; for the clearance of β-amyloid deposits; and for the migration of cells (malignant cells, stem cells).

Introduction

Neurons are bathed by the extracellular (or interstitial) fluid of the brain (ECF=ISF) which forms the microenvironment of the central nervous system (CNS). The nature of this fluid, its origin, its relation to cerebrospinal fluid (CSF) and its dynamics have been the subject of speculation and experiment for more than 100 years (Cserr and Patlak, 1992). The topic is important not only for understanding the ways in which cell:cell communication within the CNS may depend on and be influenced by ISF, but also in interpreting changes that can occur in pathology, and their implications for therapy and repair. This review surveys key developments in understanding, and recent new findings.

Section snippets

CNS fluid compartments and barriers

The ventricles and subarachnoid space (SAS) contain cerebrospinal fluid (CSF), secreted by choroid plexuses in the lateral, third and fourth ventricles (Davson and Segal, 1995). Three barrier layers limit and regulate molecular exchange at the interfaces between the blood and the neural tissue or its fluid spaces: the blood–brain barrier (BBB) formed by the cerebrovascular endothelial cells between blood and ISF, the choroid plexus epithelium between blood and ventricular CSF, and the arachnoid

Relation of CSF and brain ISF

The relations between the blood–brain and blood–CSF barriers are shown in Fig. 1, Fig. 2. The choroid plexuses are frond-like expansions of the ependymal epithelium lining the ventricles, with a surface area further expanded by apical microvilli (Keep and Jones, 1990). The choroid plexus is highly vascularised from vessels in the pia mater. The plexus capillaries are leaky (Fig. 1, Fig. 2), to permit large volume flow, the blood–CSF barrier being formed by tight junctions between the epithelial

Evidence for ISF flow

His (1865) injected colloidal material into the brain and showed that tracer spread away from the injection site predominantly along perivascular spaces. He regarded these as analogous to the lymphatics of other tissues. Weed (1914) perfused ferrocyanide into the Virchow–Robin (VR) perivascular spaces, and observed some penetration into the tissue, but raised CSF pressure was needed to fill the perivascular spaces. Woollam and Millen (1992) on the basis of light microscopic examination claimed

Controversy over ‘paravascular’ ISF circulation: extent, nature and driving force

The majority of studies have shown that tracers introduced by VC perfusion penetrate only short distances into the brain; however, Rennels et al. (1985) found that VC perfusion of HRP was followed within 10 min by widespread appearance of tracer around blood vessels. Partial ligation of the cerebral circulation reduced the spread. They proposed a rapid ‘paravascular’ circulation of ISF, from CSF into brain along arteries, and back out along the venous perivascular spaces, driven by the arterial

Recent studies combining histological and mathematical analysis of ISF flow

Most of the studies reported so far have concentrated either on mathematical or anatomical mapping of tracer spread to give insights into ISF dynamics, but few studies have attempted to combine the two techniques. We extended the study of Geer and Grossman (1997) using a similar injection protocol, but adding mathematical analysis to the histological study. In anaesthetised rats tracers were infused into the frontal lobe at the grey-white matter boundary over 1 h in a volume of 20 μl aCSF, then

Source of ISF

The studies summarised above show clear evidence for the presence of bulk flow of brain ISF, at a rate of ∼0.1–0.3 μl g−1 min−1 in rat brain. There are several possible sources for this fluid. Since ventricular CSF is apparently able to flow out into the SAS, and some is thence able to flow back into the brain along perivascular channels from the ventral surface, it may be able to percolate through the parenchyma before flowing out again predominantly along venular perivascular spaces. On this

Role of ISF in cell:cell communication

The research summarised above, especially recent work showing widespread tracer distribution within brain following ventricular or parenchymal injection, demonstrates that chemical signals produced within the brain are able to use the flowing ISF as a communication route. The evidence points to there being preferential routes for such communication. In the conscious/awake individual, where rapid bulk flow can occur within the CSF system, and preferential fluid movement occurs along particular

Implications for pathology

The information about brain ISF flow provided above has implications for a number of clinical conditions and pathologies:

  • Drug therapy: If new fluid is being secreted by brain capillaries it will influence the local concentration of drugs entering across the BBB—with the most significant effect being on polar (poorly penetrating) compounds, and the least effect being on more lipophilic agents. Attempts to model drug pharmacokinetics in the brain interstitium (e.g. Endres et al., 1997) need to

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