Glutamate Transporters in the Blood-Brain Barrier

Helms, Hans Christian Cederberg; Nielsen, Carsten Uhd; Waagepetersen, Helle S.; Brodin, Birger

doi:10.1007/978-3-319-55769-4_15

Cited by 16 publications

(14 citation statements)

References 107 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Scant consideration has been given within the literature to GDH activity within the vasculature. The study of Helms et al, (2012) was one of the first to consider the potential for glutamate metabolism within endothelial cells, corroborated by our study.…”

Section: Discussionsupporting

confidence: 82%

Distribution of the branched-chain α-ketoacid dehydrogenase complex E1α subunit and glutamate dehydrogenase in the human brain and their role in neuro-metabolism

Hull

Moraes

Brookes

et al. 2018

Neurochemistry International

View full text Add to dashboard Cite

Glutamate is the major excitatory neurotransmitter of the central nervous system, with the branched-chain amino acids (BCAAs) acting as key nitrogen donors for de novo glutamate synthesis. Despite the importance of these major metabolites, their metabolic pathway in the human brain is still not well characterised. The metabolic pathways that influence the metabolism of BCAAs have been well characterised in rat models. However, the expression of key proteins such as the branched-chain α-ketoacid dehydrogenase (BCKD) complex and glutamate dehydrogenase isozymes (GDH) in the human brain is still not well characterised. We have used specific antibodies to these proteins to analyse their distribution within the human brain and report, for the first time, that the E1α subunit of the BCKD is located in both neurons and vascular endothelial cells. We also demonstrate that GDH is localised to astrocytes, although vascular immunolabelling does occur. The labelling of GDH was most intense in astrocytes adjacent to the hippocampus, in keeping with glutamatergic neurotransmission in this region. GDH was also present in astrocyte processes abutting vascular endothelial cells. Previously, we demonstrated that the branched-chain aminotransferase (hBCAT) proteins were most abundant in vascular cells (hBCATm) and neurons (hBCATc). Present findings are further evidence that BCAAs are metabolised within both the vasculature and neurons in the human brain. We suggest that GDH, hBCAT and the BCKD proteins operate in conjunction with astrocytic glutamate transporters and glutamine synthetase to regulate the availability of glutamate. This has important implications given that the dysregulation of glutamate metabolism, leading to glutamate excitotoxicity, is an important contributor to the pathogenesis of several neurodegenerative conditions such as Alzheimer's disease.

show abstract

Section: Discussionsupporting

confidence: 82%

Distribution of the branched-chain α-ketoacid dehydrogenase complex E1α subunit and glutamate dehydrogenase in the human brain and their role in neuro-metabolism

Hull

Moraes

Brookes

et al. 2018

Neurochemistry International

View full text Add to dashboard Cite

show abstract

“…EAAT transporters participate in the efflux transport of glutamate across the BBB and are responsible for the low level of glutamate in the brain interstitial fluid (Helms et al, 2017 ). L-glutamate is taken up via EAAT1 at the abluminal membrane of brain endothelial cells and exits at the luminal membrane via a low affinity glutamate/aspartate transporter.…”

Section: Discussionmentioning

confidence: 99%

Comparison of a Rat Primary Cell-Based Blood-Brain Barrier Model With Epithelial and Brain Endothelial Cell Lines: Gene Expression and Drug Transport

Veszelka

Tóth

Walter

et al. 2018

Front. Mol. Neurosci.

103

127

View full text Add to dashboard Cite

Cell culture-based blood-brain barrier (BBB) models are useful tools for screening of CNS drug candidates. Cell sources for BBB models include primary brain endothelial cells or immortalized brain endothelial cell lines. Despite their well-known differences, epithelial cell lines are also used as surrogate models for testing neuropharmaceuticals. The aim of the present study was to compare the expression of selected BBB related genes including tight junction proteins, solute carriers (SLC), ABC transporters, metabolic enzymes and to describe the paracellular properties of nine different culture models. To establish a primary BBB model rat brain capillary endothelial cells were co-cultured with rat pericytes and astrocytes (EPA). As other BBB and surrogate models four brain endothelial cells lines, rat GP8 and RBE4 cells, and human hCMEC/D3 cells with or without lithium treatment (D3 and D3L), and four epithelial cell lines, native human intestinal Caco-2 and high P-glycoprotein expressing vinblastine-selected VB-Caco-2 cells, native MDCK and MDR1 transfected MDCK canine kidney cells were used. To test transporter functionality, the permeability of 12 molecules, glucopyranose, valproate, baclofen, gabapentin, probenecid, salicylate, rosuvastatin, pravastatin, atorvastatin, tacrine, donepezil, was also measured in the EPA and epithelial models. Among the junctional protein genes, the expression level of occludin was high in all models except the GP8 and RBE4 cells, and each model expressed a unique claudin pattern. Major BBB efflux (P-glycoprotein or ABCB1) and influx transporters (GLUT-1, LAT-1) were present in all models at mRNA levels. The transcript of BCRP (ABCG2) was not expressed in MDCK, GP8 and RBE4 cells. The absence of gene expression of important BBB efflux and influx transporters BCRP, MRP6, -9, MCT6, -8, PHT2, OATPs in one or both types of epithelial models suggests that Caco-2 or MDCK models are not suitable to test drug candidates which are substrates of these transporters. Brain endothelial cell lines GP8, RBE4, D3 and D3L did not form a restrictive paracellular barrier necessary for screening small molecular weight pharmacons. Therefore, among the tested culture models, the primary cell-based EPA model is suitable for the functional analysis of the BBB.

show abstract

“…Glutamate transporters located on brain capillary endothelial cells facilitate brain-to-blood efflux of glutamate and play a role in glutamate homeostasis. When glutamate concentrations are kept low in blood, this results in a larger concentration gradient of glutamate and enhances its brain-to-blood efflux [ 78 , 79 ]. Glutamate levels in the blood might be reduced via two enzymes: glutamate-oxaloacetate transaminase (GOT or AST) ( l -glutamate + oxaloacetate ⇌ α-ketoglutarate + l -aspartate) and glutamate-pyruvate transaminase (GPT or ALT) ( l -glutamate + pyruvate ⇌ α-ketoglutarate + l -alanine).…”

Section: Excitotoxicitymentioning

confidence: 99%

Revisiting Traumatic Brain Injury: From Molecular Mechanisms to Therapeutic Interventions

et al. 2020

View full text Add to dashboard Cite

Studying the complex molecular mechanisms involved in traumatic brain injury (TBI) is crucial for developing new therapies for TBI. Current treatments for TBI are primarily focused on patient stabilization and symptom mitigation. However, the field lacks defined therapies to prevent cell death, oxidative stress, and inflammatory cascades which lead to chronic pathology. Little can be done to treat the mechanical damage that occurs during the primary insult of a TBI; however, secondary injury mechanisms, such as inflammation, blood-brain barrier (BBB) breakdown, edema formation, excitotoxicity, oxidative stress, and cell death, can be targeted by therapeutic interventions. Elucidating the many mechanisms underlying secondary injury and studying targets of neuroprotective therapeutic agents is critical for developing new treatments. Therefore, we present a review on the molecular events following TBI from inflammation to programmed cell death and discuss current research and the latest therapeutic strategies to help understand TBI-mediated secondary injury.

show abstract

Glutamate Transporters in the Blood-Brain Barrier

Cited by 16 publications

References 107 publications

Distribution of the branched-chain α-ketoacid dehydrogenase complex E1α subunit and glutamate dehydrogenase in the human brain and their role in neuro-metabolism

Distribution of the branched-chain α-ketoacid dehydrogenase complex E1α subunit and glutamate dehydrogenase in the human brain and their role in neuro-metabolism

Comparison of a Rat Primary Cell-Based Blood-Brain Barrier Model With Epithelial and Brain Endothelial Cell Lines: Gene Expression and Drug Transport

Revisiting Traumatic Brain Injury: From Molecular Mechanisms to Therapeutic Interventions

Contact Info

Product

Resources

About