Role of the Blood–Brain Barrier in the Nutrition of the Central Nervous System

Campos-Bedolla, Patricia; Walter, Fruzsina R.; Veszelka, Szilvia; Deli, Mária A.

doi:10.1016/j.arcmed.2014.11.018

Cited by 153 publications

(141 citation statements)

References 366 publications

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“…Amino acids play numerous integral roles in fetal neurodevelopment. 7,8 We have previously shown that maternal inflammation dysregulates the expression of transporters in both maternal and fetal tissues, as well as in the placenta, at late gestation. During development, the fetus relies primarily on maternally derived amino acids which must be transported across the placenta and developing fetal blood-brain barrier to reach the fetal brain.…”

Section: Introductionmentioning

confidence: 99%

Poly(I:C) alters placental and fetal brain amino acid transport in a rat model of maternal immune activation

McColl

Piquette‐Miller

2019

American J Rep Immunol

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Problem Maternal immune activation (MIA) during pregnancy is associated with increased chances of neurodevelopmental disorders including schizophrenia and autism spectrum disorder (ASD). However, the exact mechanism through which MIA contributes to altered neurodevelopment is unknown. Due to the important role that amino acids play in neurodevelopment, altered amino acid transport could play a role in neurodevelopmental disorders. Indeed, altered plasma concentrations of multiple amino acids have been reported in individuals with ASD or schizophrenia. Therefore, our objective was to determine whether virally mediated MIA induces changes in amino acid transporters in the placenta and fetal brain. Method of study Pregnant rats were administered poly(I:C) on gestational day 14, and placental and fetal tissues were collected 6, 24, and 48 hours later. Amino acid transporter expression was measured in the placenta and fetal brain using qPCR, Western blotting, and Simple Western. Free amino acid concentrations in the fetal brain were quantified using HPLC. Results Poly(I:C) increased mRNA expression of several amino acid transporters in the placenta and fetal brain over these timepoints. Conversely, poly(I:C) imposed significant decreases in the protein expression of ASCT1 and EAAT2 in placenta and expression of SNAT5, EAAT1, and GLYT1 in fetal brain. Functional consequences of altered transporter expression were demonstrated through widespread changes in the concentrations of free amino acids in the fetal brains. Conclusion Together, these results represent novel findings with the poly(I:C) MIA model and contribute to the understanding of how MIA during pregnancy potentially leads to neurodevelopmental disorders.

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Section: Introductionmentioning

confidence: 99%

Poly(I:C) alters placental and fetal brain amino acid transport in a rat model of maternal immune activation

McColl

Piquette‐Miller

2019

American J Rep Immunol

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“…Consisting of a unique, continuous endothelium supported by a composite basement membrane, astrocyte end feet, and pericytes, its preeminent role is to strictly regulate the passage of soluble and cellular elements between the circulation and CNS by imposing severe restrictions on solute transport and cellular migration [1–4]. These restrictions are thought to be due, in significant part, to the presence of junctional complexes between endothelial cells [2, 5–7].…”

Section: Introductionmentioning

confidence: 99%

Appearance of claudin-5+ leukocytes in the central nervous system during neuroinflammation: a novel role for endothelial-derived extracellular vesicles

Paul

Baena

et al. 2016

J Neuroinflammation

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BackgroundThe mechanism of leukocyte transendothelial migration (TEM) across the highly restrictive blood-brain barrier (BBB) remains enigmatic, with paracellular TEM thought to require leukocytes to somehow navigate the obstructive endothelial tight junctions (TJs). Transient interactions between TJ proteins on the respective leukocyte and endothelial surfaces have been proposed as one mechanism for TEM. Given the expanding role of extracellular vesicles (EVs) in intercellular communication, we investigated whether EVs derived from brain microvascular endothelial cells (BMEC) of the BBB may play a role in transferring a major TJ protein, claudin-5 (CLN-5), to leukocytes as a possible basis for such a mechanism during neuroinflammation.MethodsHigh-resolution 3D confocal imaging was used to highlight CLN-5 immunoreactivity in the central nervous system (CNS) and on leukocytes of mice with the neuroinflammatory condition experimental autoimmune encephalomyelitis (EAE). Both Western blotting of circulating leukocytes from wild-type mice and fluorescence imaging of leukocyte-associated eGFP-CLN-5 in the blood and CNS of endothelial-targeted, Tie-2-eGFP-CLN-5 transgenic mice were used to confirm the presence of CLN-5 protein on these cells. EVs were isolated from TNF-α-stimulated BMEC cultures and blood plasma of Tie-2-eGFP-CLN-5 mice with EAE and evaluated for CLN-5 protein by Western blotting and fluorescence-activated cell sorting (FACS), respectively. Confocal imaging and FACS were used to detect binding of endothelial-derived EVs from these two sources to leukocytes in vitro. Serial electron microscopy (serial EM) and 3D contour-based surface reconstruction were employed to view EV-like structures at the leukocyte:BBB interface in situ in inflamed CNS microvessels.ResultsA subpopulation of leukocytes immunoreactive for CLN-5 on their surface was seen to infiltrate the CNS of mice with EAE and reside in close apposition to inflamed vessels. Confocal imaging of immunostained samples and Western blotting established the presence of CLN-5+ leukocytes in blood as well, implying these cells are present prior to TEM. Moreover, imaging of inflamed CNS vessels and the associated perivascular cell infiltrates from Tie-2-eGFP-CLN-5 mice with EAE revealed leukocytes bearing the eGFP label, further supporting the hypothesis CLN-5 is transferred from endothelial cells to circulating leukocytes in vivo. Western blotting of BMEC-derived EVs, corresponding in size to both exosomes and microvesicles, and FACS analysis of plasma-derived EVs from Tie-2-eGFP-CLN-5 mice with EAE validated expression of CLN-5 by EVs of endothelial origin. Confocal imaging and FACS further revealed both PKH-67-labeled EVs from cultured BMECs and eGFP-CLN-5+ EVs from plasma of Tie-2-eGFP-CLN-5 mice with EAE can bind to leukocytes. Lastly, serial EM and 3D contour-based surface reconstruction revealed a close association of EV-like structures between the marginating leukocytes and BMECs in situ during EAE.ConclusionsDuring neuroinflammation, CLN-5+ leukoc...

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“…Six transport systems (PTS1-6) have been identified for peptides at the BBB, which transport enkephalins, arginine vasopressin, or pituitary adenylate cyclase-activating polypeptides, among others (11). The peptide/histidine transporter 2 (PHT2, SLC15a3) was described at the BBB carrying di-and tripeptides, whereas larger peptides or proteins like insulin or transferrin cross the BBB by receptor-mediated transcytosis (15). To reveal if carriers or transporters participate in opiorphin transfer, further experiments are needed.…”

Section: Discussionmentioning

confidence: 99%

“…The transfer of opioid peptides through the BBB was studied previously with isotopically labeled peptides showing a penetration index !0.01% (12e14). Specific features of the BBB, mainly interendothelial tight junctions and efflux transporters (15), as well as peptidase activity in blood, brain microvessels and brain tissue may be responsible for limiting the transfer of these potential biotherapeutics from the blood to brain.…”

Section: Introductionmentioning

confidence: 99%

Transfer of Opiorphin Through a Blood-Brain Barrier Culture Model

Bocsik

Darula

Tóth

et al. 2015

Archives of Medical Research

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Opioid peptides are potent analgesics with therapeutic potential in the treatment of acute and chronic pain. Their efficacy is limited by peptidases (enkephalinases). Opiorphin pentapeptide (QRFSR) is the first characterized human endogenous inhibitor of enkephalinases. The peptide is able to increase the binding and affinity of endogenous opiates to mu opioid receptors; thus, the mechanism of opiorphin may provide a new therapeutic approach in pain management. The analgesic effect of opiorphin was proven in several earlier published in vitro and in vivo studies. Our aim was to test the transfer of opiorphin through a blood-brain barrier model for the first time. The flux of opiorphin was tested on a blood-brain barrier culture model consisting of rat brain endothelial, glial and pericyte cells. Brain endothelial cells in this triple co-culture model form tight monolayers characterized by transendothelial electrical resistance measurement. Relative quantity of the peptide was estimated by mass spectrometry. The transfer of opiorphin through the bloodbrain barrier model was estimated to be |3%, whereas the permeability coefficient was 0.53 AE 1.36 Â 10 À6 cm/s (n 5 4). We also observed rapid conversion of N-terminal glutamine into pyroglutamic acid during the transfer experiments. Our results indicate that opiorphin crosses cultured brain endothelial cells in the absence of serum factors in a significant amount. This is in agreement with previous in vivo data showing potentiation of enkephalin-mediated antinociception. We suggest that opiorphin may have a potential as a centrally acting novel drug to treat pain. Ó 2015 IMSS. Published by Elsevier Inc.

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Role of the Blood–Brain Barrier in the Nutrition of the Central Nervous System

Cited by 153 publications

References 366 publications

Poly(I:C) alters placental and fetal brain amino acid transport in a rat model of maternal immune activation

Poly(I:C) alters placental and fetal brain amino acid transport in a rat model of maternal immune activation

Appearance of claudin-5+ leukocytes in the central nervous system during neuroinflammation: a novel role for endothelial-derived extracellular vesicles

Transfer of Opiorphin Through a Blood-Brain Barrier Culture Model

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