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Open Access 01-12-2018 | Review

Elimination of substances from the brain parenchyma: efflux via perivascular pathways and via the blood–brain barrier

Authors: Stephen B. Hladky, Margery A. Barrand

Published in: Fluids and Barriers of the CNS | Issue 1/2018

Abstract

This review considers efflux of substances from brain parenchyma quantified as values of clearances (CL, stated in µL g⁻¹ min⁻¹). Total clearance of a substance is the sum of clearance values for all available routes including perivascular pathways and the blood–brain barrier. Perivascular efflux contributes to the clearance of all water-soluble substances. Substances leaving via the perivascular routes may enter cerebrospinal fluid (CSF) or lymph. These routes are also involved in entry to the parenchyma from CSF. However, evidence demonstrating net fluid flow inwards along arteries and then outwards along veins (the glymphatic hypothesis) is still lacking. CL_perivascular, that via perivascular routes, has been measured by following the fate of exogenously applied labelled tracer amounts of sucrose, inulin or serum albumin, which are not metabolized or eliminated across the blood–brain barrier. With these substances values of total CL ≅ 1 have been measured. Substances that are eliminated at least partly by other routes, i.e. across the blood–brain barrier, have higher total CL values. Substances crossing the blood–brain barrier may do so by passive, non-specific means with CL_{blood-brain barrier} values ranging from < 0.01 for inulin to > 1000 for water and CO₂. CL_{blood-brain barrier} values for many small solutes are predictable from their oil/water partition and molecular weight. Transporters specific for glucose, lactate and many polar substrates facilitate efflux across the blood–brain barrier producing CL_{blood-brain barrier} values > 50. The principal route for movement of Na⁺ and Cl⁻ ions across the blood–brain barrier is probably paracellular through tight junctions between the brain endothelial cells producing CL_{blood-brain barrier} values ~ 1. There are large fluxes of amino acids into and out of the brain across the blood–brain barrier but only small net fluxes have been observed suggesting substantial reuse of essential amino acids and α-ketoacids within the brain. Amyloid-β efflux, which is measurably faster than efflux of inulin, is primarily across the blood–brain barrier. Amyloid-β also leaves the brain parenchyma via perivascular efflux and this may be important as the route by which amyloid-β reaches arterial walls resulting in cerebral amyloid angiopathy.

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The limitation of movements from cisterna magna towards the IIIrd ventricle occurs presumably because the volume displaced in the to and fro fluid movements through the cerebral aqueduct [7, 602] is too small for efficient transfer of solutes. More movement occurs in the opposite direction as a consequence of net flow. However, Vartan Kurtcuoglu (personal communication) has pointed out that simulation of the convective mixing in the IIIrd ventricle and aqueduct indicates that the transient jet of fluid entering the IIIrd ventricle from the aqueduct in each cardiac cycle (see the sub-figures for 0.2 T and 0.3 T in Figure 8 of [8]) is as long as the aqueduct itself implying that some transfer from the IVth to the IIIrd ventricle should occur. The data reported by Ringstad et al. [15] indicate that gadobutrol added to lumbar CSF does reach the IIIrd ventricle in control patients, but at a low concentration, while the concentration seen in patients with idiopathic normal pressure hydrocephalus is substantially higher. This is consistent with the view that the net flow through the aqueduct is normally from IIIrd to IVth ventricle but in communicating hydrocephalus it is reversed in direction (for references, review and discussion see sections 4.2.2–4.2.5 in [41]).

The effects of diffusion across the ependyma lining the ventricles are usually restricted to regions close to the ventricles [21, 25, 603‐605]. However, in the presence of oedema or in the immediate aftermath of infusion of even quite small amounts of fluid into the parenchyma [129] flow across the ependymal layer lining the ventricles can be substantial (see e.g. [129, 606, 607]). Rosenberg et al. [65] investigated the penetration of sucrose from the ventricles into the parenchyma during ventriculo-cisternal perfusions. In grey matter they found concentration profiles in the parenchyma consistent with simple diffusion. However, in white matter the profile was altered as if there were a 10 µm min⁻¹ flow of ISF towards the ventricles that countered diffusion into the tissue. Flow at this velocity could move solutes as far as a millimetre in 100 min.

The relative lack of consideration of the choroid plexuses is not meant to suggest that the only important function of the choroid plexuses is to secrete CSF. The choroid plexuses are the "obvious" best route for transfer to or from the blood for anything that is intended to act on regions of the brain close to the surfaces of the ventricles or that is produced in those regions for actions elsewhere in the body. They must also be considered for transfer into the brain of anything that is needed neither quickly nor in large quantity such as Ca2⁺, Mg²⁺, micronutrients and some hormones. Finally they should be considered as a potential pathway for drug delivery to the brain via CSF [36].

While the tight junctions have a very low permeability to Na⁺ and Cl⁻, the passive influx or efflux of these across the blood–brain barrier may still be primarily paracellular as proposed by Crone [151]. However the passive influxes are almost equal to the passive effluxes and the net fluxes for Na⁺ and Cl⁻ across the endothelial layer may be determined primarily by the mechanisms for transfer through the cells (see Section 5.6 and Sections. 4.3.4 and 4.3.5 of [4] for further discussion).

It is clear that extramural, fluid-filled perivascular spaces can exist, because large particles can be introduced into them (see e.g. [70, 95] and fluorescent tracers injected into the cisterna magna are seen in regions extending well outside the vessel walls (see e.g. Figures 2 and 3 in [25] and Figure 2 in [96]). Furthermore, after subarachnoid haemorrhage blood can accumulate between the walls of arteries and the glial endfeet [92]. The question is whether normally the spaces are inflated with fluid or collapsed virtual spaces [53]. A need for "inflation" would provide a ready explanation for why altering CSF pressures, e.g. by puncture of the cisterna magna [608], can greatly reduce perivascular influx. In fixed, sectioned tissue of gray matter inflated spaces are rarely if ever seen [98, 99]. However, spaces particularly, one imagines, labile spaces, are difficult to fix, or as Coles et al. [1] put it "in fixed tissue, extracellular spaces tend to be occluded, and marker molecules are bound to host tissue". It is not clear that this type of evidence obtained with fixed material is a valid description of perivascular spaces in vivo.

A study by Bradbury et al. [82] comparing the distribution of radio-iodinated serum albumin (RISA) in rabbits after intraparenchymal injection with that after intraventricular injection remains one of the most informative undertaken on the routes of elimination of large solutes. Their finding of RISA in the walls of arteries in the circle of Willis after intraparenchymal injection provides strong evidence that some of the albumin leaves the parenchyma along or within arterial walls and continues along them beyond the subarachnoid spaces. This evidence does not, however, indicate how large a fraction of the RISA takes this route. Bradbury et al. also observed that after intraparenchymal injection a smaller fraction of the amount injected passed through the cisterna magna and a larger fraction reached lymph than was evident after intraventricular injection. The RISA distribution following intraventricular injection can be interpreted as tracing the routes followed by CSF emerging from the ventricles. After mixing and passing through the cisterna magna, the CSF flows out of the brain by more than one route, some via the arachnoid villi leading to venous sinuses and some via the cribriform plate leading to the nasal mucosa. From the nasal mucosa large solutes including RISA pass into lymph. After intraventricular injection, the fraction of RISA reaching lymph is somewhat greater than half and represents that fraction of CSF from the ventricles that flows out via the cribriform plate [82]. After intraparenchymal injection, the fraction of RISA reaching lymph is substantially larger than that seen after intraventricular injection. This observation was interpreted by Bradbury et al. [82] as indicating that most of the RISA contained in ISF flowed out of the parenchyma into a portion of CSF that subsequently left the brain via the cribriform plate to the nasal mucosa rather than via the arachnoid villi. Weller, Carare and associates [95, 98, 107], who have used mice for their functional experiments, have since favoured the view that outflow of ISF from the parenchyma occurs via a route that does not entail mixing with any portion of the CSF. In their view ISF drains from the parenchyma along intramural periarterial pathways and exchange of large solutes is not possible between these pathways and CSF as the vessels pass through the subarachnoid spaces or basal cisternae.

In terms of resisting putative water flow from periarterial to perivenular spaces, the endfeet are in parallel with the gaps between them and in series with the parenchymal tissue. Jin et al. conclude that the overall calculated resistance to flow is similar with or without a water permeability of the endfeet—i.e. the permeability of the slits is sufficient for the overall resistance to be determined largely by that of the parenchymal tissue.

The macromolecular components of ISF may greatly influence the resistance to bulk flow as emphasized for peripheral extracellular fluid by Guyton and associates [609]. Quantitatively macromolecules in peripheral extracellular fluid can increase resistance to flow by orders of magnitude [138, 610, 611] while having much less effect on diffusion of small molecules [76, 81, 612]. A well-known illustration of a closely related effect is the reduced flow with maintained diffusion when agar is added to solutions.

Charles Nicholson and Anthony Gardner-Medwin (personal communications reported in [41]) have observed that the adequacy of diffusion to explain movements of solutes in the interstitium and the observed symmetrical spread does not preclude the existence of net flows of the order of those proposed by Cserr and coworkers [83, 130] or Rosenberg et al. [65]. It is not clear whether the flows envisaged in the glymphatic hypothesis are sufficiently larger that they should produce observable asymmetry in the spread of markers. Comparison of the flow required if glymphatic circulation accounts for the movement of markers like inulin through the perivascular spaces (0.6 µL g⁻¹ min⁻¹ or more as discussed above) and the largest flow that could have been missed by Smith et al. [79] would be very welcome.

Compared to the change in rate of efflux of inulin, Xie et al. [128] observed a much larger change in the rate of delivery of Texas Red dextran from the cisterna magna to the parenchyma: 20-fold less influx when the mice were awake compared to when they were anaesthetized. Benveniste et al. [613] have also observed increases in delivery of a gadolinium chelate with anaesthesia. However, Gakuba et al. [147] using another gadolinium chelate, Evan's blue and indocyanine green have observed that anaesthesia greatly reduces the spread of the markers into the parenchyma from the cisterna magna. It is not yet clear how to reconcile these results (see also [426]). It is also unclear whether the effects of sleep/wakefulness/anaesthesia on influx of markers are mediated primarily in the subarachnoid spaces, in the perivascular spaces or within the parenchyma (see Section 2.4 in [146]).

The polar headgroups of lipid membranes produce a large dipole potential (membrane core positive) which favours permeation of anions over cations (see e.g. [529, 614‐619]. None of the descriptors that are suitable for describing neutral molecules can be expected to allow the LFER approach to be able to cope with this difference. It is thus not at all surprising that when Abraham came to consider charged molecules explicitly, he found it necessary to introduce descriptors that allow for the charge on the molecule [168].

One difficulty encountered when attempting to correlate permeability and lipophilicity for ions is that it is only possible to measure K_{n-octanol/water} for neutral combinations of ions. This is an example of the consequences of the Principle of electroneutrality (see Section 6.1.2 in [4] for another example and further discussion). This difficulty could be avoided by measuring partition into unilamellar liposomes, lipid bilayers or biological membranes rather than into a hydrophobic solvent, because with these systems the counterions can remain in the aqueous phases. However, while partition into membranes has been measured, there has not been any attempt to correlate these measurements with blood–brain barrier permeability (see e.g. [161]).

Both the Oat and Oatp transporters appear to be exchangers. Using Xenopus oocytes transfected with Oat3, influx of labelled p-aminohippuric acid (PAH) or estrone sulphate was found to be coupled in some way to movement of glutarate, and probably other dicarboxylates, in the opposite direction, i.e. there was trans-stimulation of transport [620]. Interestingly however, influx of labelled estrone sulphate, was not stimulated by increased internal concentration of estrone sulphate, or PAH, i.e. there was no "self" trans-stimulation [236]. For Oatp transporters the exchange has different properties. For instance for Oatp1a4 (Oatp2) expressed in Xenopus oocytes suspended in low bicarbonate solution, increased concentrations of a variety of solutes present inside the cells, including taurocholate, glutathione, and glutathione conjugates, stimulate influx of labelled taurocholate [621]. However, when Oatp1a4 is expressed in a HeLa cell line suspended in bicarbonate buffered solution, the influx of taurocholate seems to be coupled to efflux of bicarbonate [622]. This coupling with bicarbonate has been confirmed using a number of different Oatp transporters expressed in CHO cells [623].

Exchangers are able to perform secondary active transport by coupling the downhill transport of one solute to the uphill movement of the other. Thus the demonstration of uphill transport from brain to blood might correspond to abluminal secondary active transport into the endothelial cells driven by an outward gradient of something like glutarate or glutathione or to luminal primary active transport out of the endothelial cells via an ABC transporter or to both. For instance PAH may be taken up into the cells by secondary active transport via Oat3 and subsequently expelled from them by primary active transport via an ABC transporter, possibly MRP4 [560]. Further work is required to establish the interplay of the effects of the various transporters.

TfR has been shown to be accessible to antibodies on both surfaces of the endothelial cells [280, 624]. This suggests that transferrin could bind to or dissociate from TfR on either side. Furthermore there is effective transfer across the blood–brain barrier of low-affinity antibodies to TfR [625], which strongly suggests that there can be transcytosis of substances bound to the TfR.

In terms of one current conceptual model (see Figure 1 in [280]) there are two possible fates of transferrin and iron after endocytosis. In the first fate, holo-transferrin is exocytosed across the abluminal membrane as in the original hypothesis. However the current consensus is that relatively little holo-transferrin is in fact exocytosed on the brain side [262, 279‐282, 626‐628]. In the second fate, dissociation of the holo-transferrin occurs within endosomes in the endothelial cells with the iron being transported across the abluminal membrane by ferroportin. In this option, one that is preferred by Simpson et al. [280], the iron-free apo-transferrin is exocytosed, part across the abluminal membrane accounting for the observed transfer of transferrin from blood to brain but primarily across the luminal membrane back to blood. This model allows the possibility that transcytosis of apo-transferrin can occur from brain to blood. The site of dissociation of the iron from the holo-transferrin inside the endothelial cell layer and the intervening steps are still under active investigation [281, 282]).

Simpson et al. [315] have calculated the distribution of glucose using estimates of the rates of metabolism and the rates of transport across the various barriers in the brain including diffusion through basal laminae and interstitial spaces and transport across the various cell membranes. Their calculated concentrations in ISF 1.4 mM, in neurons 1.2 mM and in astrocytes 0.9 mM are consistent with the relatively uniform distribution of glucose over brain water found by NMR.

There has been a claim that "The glymphatic [perivascular] pathway is important for the brain-wide delivery of nutrients, specifically glucose" [109]. This was based on results presented by Lundgaard et al. [629] for movements of a near-infrared 2-deoxyglucose probe (2DG-IR). However, Lundgaard et al. showed that 2DG-IR could not be delivered across the blood–brain barrier and thus it is at best a poor substrate for GLUT1. Since GLUT1 is essential for the normal entry and distribution of glucose, the results for 2DG-IR cannot be used to infer the relative importance of the blood–brain barrier and perivascular routes for the distribution of glucose. Petit and Magistretti [344] have also criticized the use of 2DG-IR as a probe for glucose movements into astrocytes and neurons.

Lundgaard et al. [630] have shown that four different manoeuvres that decrease perivascular efflux of markers increase lactate levels in the brain and decrease them in the submandibular and parotid lymph nodes. In their view some lactate leaves the brain in CSF notably via the cribriform plate to the nasal mucosa from which it is removed in lymph. There may be removal of lactate from the brain via lymph, but Bradbury and Westrop [125] noted that while high molecular weight markers like albumin delivered to the nasal mucosa are removed from the mucosa by lymph, low molecular weight substances like lactate may be removed from the mucosa by the peripheral blood flow. Lundgaard et al's results provide no means to verify that the lactate found in the lymph nodes originated in the brain and even if the lactate in the glands originates by perivascular efflux from the brain, they do not quantify the rate of efflux. The effects of sleep and wakefulness on lactate clearance from the brain were considered further in [146]. Lundgaard et al's results indicate that the manoeuvres that affect perivascular efflux do not alter lactate concentrations in the brain of usually awake mice (dark phase of 24 h cycle), which is evidence that perivascular efflux is not important under just the circumstances when there is likely to be a need for lactate removal.

The concentrations in plasma and CSF have been measured in samples of the fluids, but those in ISF have been measured using microdialysis. In the microdialysis procedure a probe is inserted and fluid perfused through the probe. To avoid grossly disturbing the ISF around the probe, the composition of the perfusion fluid must be close to that of ISF. The perfusate comes into contact with ISF only through a dialysis membrane. The diffusable solutes to be measured enter the perfusate during the relatively brief time that it is within the probe, and thus the slower the perfusion rate, the closer the concentration emerging from the probe is to the concentration in ISF in the region surrounding it. The ISF data in Table 3 were obtained by measuring concentrations at several different flow rates and extrapolating back to zero flow. However, even with these precautions, without measurements for substances whose concentrations are already known it is difficult to be certain that the ISF concentration measured is the same as that in ISF that isn't close to the probe. Because in all the studies in Table 3 the probe removes the substance being measured, there is an obvious risk of bias towards values that are too low. Evidence that these concerns are not just theoretical is provided by measurements for glucose. The early microdialysis measurements yielded values, e.g. 0.47 mM [631] or 0.35 mM [632], that are substantially smaller than the lower limit of ISF concentration obtained from NMR data, ca 1.2 mM for 6 mM in plasma (see Sect. 5.3). More recent microdialysis measurements have yielded larger concentrations [314], e.g 1 mM [633]; 1.66, [634]; 1.26 [635] and 1.4 [636].

The results were later extended to allow calculation of Michaelis–Menten constants for each of the amino acids [372]. For the large neutral amino acids the V_max and K_m values varied from 30 nmol g⁻¹ min⁻¹ and 0.12 mM for phenylalanine to 49 nmol g⁻¹ min⁻¹ and 0.63 mM for valine. Competition reduces the fluxes seen for each amino acid but for any one transporter may have a V_max for the combination of amino acids present somewhere in the range observed for the individual amino acids. Thus from these results from the rat studies the maximum collective influx of the large neutral amino acids is expected to be less than 50 nmol g⁻¹ min⁻¹. Smith and Stoll [43] provide a useful table of influxes from nearly normal composition of plasma with a total influx of 72 nmol g⁻¹ min⁻¹. It should be noted that (a) this total is for the influx not the net flux and (b) virtually all of the data for tracer influxes have been obtained with rats.

It should be noted that the total net flux of N as part of amino acids is not zero in any of the studies measuring net fluxes. The estimates for studies that included glutamine and at least 10 other amino acids are + 26 nmol g⁻¹ min⁻¹ [588]; − 17.3 nmol g⁻¹ min⁻¹ [589] and − 30 nmol g⁻¹ min⁻¹ [590]. Eriksson et al. [588] noted that their data could not be reconciled with N balance. The net effluxes found by Grill et al. [589] and Strauss et al. [590] were dominated by net release of glutamine, which conceivably could be balanced by small net influxes for many amino acids, each below the limit of detection, or a net influx of NH₄⁺ though there is no evidence for this [359]. How N balance is achieved remains to be clarified.

This may explain the only modest success of attempts to understand the effects of raised concentration of one amino acid in plasma on the fluxes and ISF concentrations of other amino acids. Those attempts have considered only the concentrations in plasma while it is now clear that concentrations on both sides are important. (See [42] for discussion of the early work and [637] for a more recent example).

The results of Kress et al. [514] differ from the earlier studies described above. Kress et al. have reported the fractions of Aβ and inulin remaining in the brain 1 h after parenchymal injection in young, middle aged, or old mice. In each group they found that the fraction remaining of Aβ was smaller than that of inulin but the difference between Aβ and inulin was much less marked than in the earlier studies primarily because more Aβ remained in the brain. It is difficult to suggest any reason for this discrepancy.

In a number of studies (see e.g. [341]) the net flux during low nervous activity has been compared to an estimate of the transport maximum, T_max. T_max is typically two to threefold larger. However, T_max gives a false impression of the transport reserve as these large fluxes can only be reached by increasing c_plasma to levels that are never achieved.

("Systems" have functional definitions and may be mediated by one or more transporters. Transporters are gene products).

Chikhale et al. [638] looked at the permeability of a series of peptides and found that the permeabilities did not correlate with the n-octanol/water partition coefficient but did correlate with the number of hydrogen bonds they could form. If the hydrogen bonds were formed only in the water and not in either n-octanol or the membrane core, then n-octanol would be expected to be a reasonable model for the core and the discrepancy they observed should not have been seen. See also [169].

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Title: Elimination of substances from the brain parenchyma: efflux via perivascular pathways and via the blood–brain barrier
Authors: Stephen B. Hladky
Margery A. Barrand
Publication date: 01-12-2018
Publisher: BioMed Central
Published in: Fluids and Barriers of the CNS / Issue 1/2018
Electronic ISSN: 2045-8118
DOI: https://doi.org/10.1186/s12987-018-0113-6

Keynote webinar | Spotlight on sleep in brain health

Springer Medicine

Elimination of substances from the brain parenchyma: efflux via perivascular pathways and via the blood–brain barrier

Abstract

Keynote webinar | Spotlight on sleep in brain health

Springer Medicine

Abstract

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