Potential Pathways for CNS Drug Delivery Across the Blood-Cerebrospinal Fluid Barrier

Strazielle, Nathalie; Ghersi-Egea, Jean-François

doi:10.2174/1381612822666160726112115

Cited by 79 publications

(83 citation statements)

References 137 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…Diffusion of molecules through the paracellular transport route is size‐limited, whereas an energy‐requiring receptor can mediate vesicular transcytosis to transport macromolecules. In fact, vesicular transcytosis appears to be the most promising mechanism for improvement of drug delivery through the brain barrier …”

Section: Discussionmentioning

confidence: 99%

Mfsd2a (Major Facilitator Superfamily Domain Containing 2a) Attenuates Intracerebral Hemorrhage–Induced Blood–Brain Barrier Disruption by Inhibiting Vesicular Transcytosis

Yang

Xiong

Liu

et al. 2017

JAHA

View full text Add to dashboard Cite

BackgroundBlood–brain barrier (BBB) disruption aggravates brain injury induced by intracerebral hemorrhage (ICH); however, the mechanisms of BBB damage caused by ICH remain elusive. Mfsd2a (major facilitator superfamily domain containing 2a) has been known to play an essential role in BBB formation and function. In this study, we investigated the role and underlying mechanisms of Mfsd2a in BBB permeability regulation after ICH.Methods and ResultsUsing ICH models, we found that Mfsd2a protein expression in perihematomal brain tissues was significantly decreased after ICH. Knockdown and knockout of Mfsd2a in mice markedly increased BBB permeability, neurological deficit score, and brain water contents after ICH, and these were rescued by overexpressing Mfsd2a in perihematomas. Moreover, we found that Mfsd2a regulation of BBB permeability after ICH correlated with changes in vesicle number. Expression profiling of tight junction proteins showed no differences in Mfsd2a knockdown, Mfsd2a knockout, and Mfsd2a overexpression mice. However, using electron microscopy following ICH, we observed a significant increase in pinocytotic vesicle number in Mfsd2a knockout mice and decreased the number of pinocytotic vesicles in mouse brains with Mfsd2a overexpression. Finally, using multiple reaction monitoring, we screened out 3 vesicle trafficking–related proteins (Srgap2, Stx7, and Sec22b) from 31 vesicle trafficking‐related proteins that were markedly upregulated in Mfsd2a knockout mice compared with controls after ICH.ConclusionsIn summary, our results suggest that Mfsd2a may protect against BBB injury by inhibiting vesicular transcytosis following ICH.

show abstract

Section: Discussionmentioning

confidence: 99%

Mfsd2a (Major Facilitator Superfamily Domain Containing 2a) Attenuates Intracerebral Hemorrhage–Induced Blood–Brain Barrier Disruption by Inhibiting Vesicular Transcytosis

Yang

Xiong

Liu

et al. 2017

JAHA

View full text Add to dashboard Cite

show abstract

“…The CPs are anatomical structures in the third, fourth and lateral ventricles within the brain and are formed of blood vessels lined by the choroidal epithelium [6,7]. The capillary endothelium in the CP is fenestrated and surrounded by these epithelial cells, joined by tight junctions, all of which constitute the blood-CSF-barrier (BCSFB) and control CSF composition [8].…”

Section: Open Accessmentioning

confidence: 99%

“…The total volume of CSF within adult humans is approximately 140 ml and the rate of secretion by each CP is 0.2 ml/min [12]. The pressure required for the circulation of CSF is maintained by a hydrostatic pressure gradient between the CP (where CSF is produced) and the arachnoid villi (where CSF is drained) [8]. The CP epithelial cells are indispensable for directed transport processes from blood into the CSF, for the removal of substances out of the brain, and for CSF production [13].…”

Section: Open Accessmentioning

confidence: 99%

Cerebrospinal fluid dynamics modulation by diet and cytokines in rats

Alimajstorovic

Pascual-Baixauli

Hawkes

et al. 2020

Fluids Barriers CNS

View full text Add to dashboard Cite

Background: Idiopathic intracranial hypertension (IIH) is a neurological disorder characterised by raised cerebrospinal fluid (CSF) pressure in the absence of any intracranial pathology. IIH mainly affects women with obesity between the ages of 15 and 45. Two possible mechanisms that could explain the increased CSF pressure in IIH are excessive CSF production by the choroid plexus (CP) epithelium or impaired CSF drainage from the brain. However, the molecular mechanisms controlling these mechanisms in IIH remain to be determined. Methods:In vivo ventriculo-cisternal perfusion (VCP) and variable rate infusion (VRI) techniques were used to assess changes in rates of CSF secretion and resistance to CSF drainage in female and male Wistar rats fed either a control (C) or high-fat (HF) diet (under anaesthesia with 20 μl/100 g medetomidine, 50 μl/100 g ketamine i.p). In addition, CSF secretion and drainage were assessed in female rats following treatment with inflammatory mediators known to be elevated in the CSF of IIH patients: C-C motif chemokine ligand 2 (CCL2), interleukin (IL)-17 (IL-17), IL-6, IL-1β, tumour necrosis factor-α (TNF-α), as well as glucocorticoid hydrocortisone (HC). Results:Female rats fed the HF diet had greater CSF secretion compared to those on control diet (3.18 ± 0.12 μl/ min HF, 1.49 ± 0.15 μl/min control). Increased CSF secretion was seen in both groups following HC treatment (by 132% in controls and 114% in HF) but only in control rats following TNF-α treatment (137% increase). The resistance to CSF drainage was not different between control and HF fed female rats (6.13 ± 0.44 mmH 2 O min/μl controls, and 7.09 ± 0.26 mmH 2 O min/μl HF). and when treated with CCL2, both groups displayed an increase in resistance to CSF drainage of 141% (controls) and 139% (HF) indicating lower levels of CSF drainage. Conclusions:Weight loss and therapies targeting HC, TNF-α and CCL2, whether separately or in combination, may be beneficial to modulate rates of CSF secretion and/or resistance to CSF drainage pathways, both factors likely contributing to the raised intracranial pressure (ICP) observed in female IIH patients with obesity.

show abstract

“…Much is known and has been written about how substances enter the brain, about how others are prevented from doing this, and about the importance of the blood–brain barrier for delivery of drugs to the brain. Reviews include those dealing with glucose, water, and inorganic ions [ 2 – 4 , 41 ]; those considering amino acids [ 4 , 42 – 44 ]; and those concerned with a wide variety of other substances [ 20 , 30 , 32 , 36 , 38 , 45 – 51 ]. However, much less has been investigated and/or written about how substances are eliminated from the brain.…”

Section: Introductionmentioning

confidence: 99%

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

Hladky

Barrand

2018

Fluids Barriers CNS

167

156

View full text Add to dashboard Cite

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. CLperivascular, 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 CLblood-brain barrier values ranging from < 0.01 for inulin to > 1000 for water and CO2. CLblood-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 CLblood-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 CLblood-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.Electronic supplementary materialThe online version of this article (10.1186/s12987-018-0113-6) contains supplementary material, which is available to authorized users.

show abstract

Potential Pathways for CNS Drug Delivery Across the Blood-Cerebrospinal Fluid Barrier

Cited by 79 publications

References 137 publications

Mfsd2a (Major Facilitator Superfamily Domain Containing 2a) Attenuates Intracerebral Hemorrhage–Induced Blood–Brain Barrier Disruption by Inhibiting Vesicular Transcytosis

Mfsd2a (Major Facilitator Superfamily Domain Containing 2a) Attenuates Intracerebral Hemorrhage–Induced Blood–Brain Barrier Disruption by Inhibiting Vesicular Transcytosis

Cerebrospinal fluid dynamics modulation by diet and cytokines in rats

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

Contact Info

Product

Resources

About