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Molecular Mechanisms and Physiology Associated with the Blood–Brain Barrier
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Molecular Mechanisms and Physiology Associated with the Blood–Brain Barrier

A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Biology".

Deadline for manuscript submissions: closed (20 September 2024) | Viewed by 14293

Special Issue Editor

Dr. Anne Vejux

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Guest Editor
Equipe 5, Neurobiologie des Comportements Alimentaires/Neurobiology of Feeding Behaviours 9E, Boulevard Jeanne d'Arc, 21000 Dijon, France
Interests: oxysterols; very-long-chain fatty acids; lipid metabolism; diet; peroxisomes; biotherapies; inflammation; cancer; cell cycle and apoptosis; autophagy; biological membranes; oxidative damage; biomarkers; neurodegenerative diseases
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Special Issue Information

Dear Colleagues,

The blood–brain barrier (BBB) is a physical and metabolic barrier that isolates the brain from the rest of the body. It intervenes daily in the regulation of cerebral homeostasis. It was long considered that only small lipophilic molecules could passively diffuse through these successive layers of phospholipids to reach the brain tissue and influence neurotransmission or the reproduction of microorganisms, viruses, or tumor cells there. Different strategies have been implemented to reduce the size of molecules, make them more lipophilic, or to even deliver substances directly to the brain intrathecally. Some highly hydrophilic molecules can pass the BBB, while some lipophilic anticancer drugs do not cross; some molecules with identical physicochemical properties cannot pass the BBB so easily. There are transporters at the endothelial cell level, allowing the brain to cover its metabolic needs by taking up different elementary nutrients such as glucose or amino acids. In pharmacology, these transporters allow the passage of drugs such as levodopa. The study of these facilitated transport mechanisms opens interesting perspectives for the development of new drugs targeting the nervous system, which could take advantage of these access routes to cross the blood–brain barrier despite their hydrophilic character. These transporters could be the site of drug interactions or genetic polymorphisms. Geneticists are beginning to describe such polymorphisms, which could explain individual variations in response to certain drugs. There are also effective efflux pumps explaining drug resistance (e.g., p-glycoprotein). Selective endocytosis is also present, allowing the cerebral penetration of certain large molecules such as insulin, transferrin, or lipoproteins. Finally, there is cerebrospinal fluid which eliminates the molecules that have crossed the BBB. The BBB is also not uniform over the entire surface of the brain; in certain places it is looser (hypothalamus), which allows a passive and non-selective diffusion of molecules towards the cerebral parenchyma.

Gathering a better understanding of the cellular and molecular mechanisms involved in the processes of the passage of molecules/drugs/nutrients to the brain is essential. Many areas are thus targeted in this Special Issue, such as blood–brain barrier and neurodegenerative diseases, blood–brain barrier and cancer, and blood–brain barrier and diet.

Dr. Anne Vejux
Guest Editor

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Keywords

  • blood–brain barrier
  • neurodegenerative diseases
  • cancer
  • diet
  • pharmacology
  • transporters
  • receptors
  • microglial cells
  • tanycytes
  • fenestrated vessels
  • hypothalamus
  • plasticity

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Published Papers (6 papers)

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Research

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22 pages, 6281 KiB  
Article
17β-Estradiol Abrogates TNF-α-Induced Human Brain Vascular Pericyte Migration by Downregulating miR-638 via ER-β
by Lisa Kurmann, Giovanna Azzarito, Brigitte Leeners, Marinella Rosselli and Raghvendra K. Dubey
Int. J. Mol. Sci. 2024, 25(21), 11416; https://doi.org/10.3390/ijms252111416 - 24 Oct 2024
Cited by 1 | Viewed by 1429
Abstract
Pericytes (PCs) contribute to brain capillary/BBB integrity and PC migration is a hallmark for brain capillary leakage following pro-inflammatory insults. Estradiol promotes endothelial barrier integrity by inhibiting tumor necrosis factor-alpha (TNF-α)-induced PC migration. However, the underlying mechanisms remain unclear. Since micro-RNAs (miRs) regulate [...] Read more.
Pericytes (PCs) contribute to brain capillary/BBB integrity and PC migration is a hallmark for brain capillary leakage following pro-inflammatory insults. Estradiol promotes endothelial barrier integrity by inhibiting tumor necrosis factor-alpha (TNF-α)-induced PC migration. However, the underlying mechanisms remain unclear. Since micro-RNAs (miRs) regulate BBB integrity and increases in miR638 and TNF-α occur in pathological events associated with capillary leakage, we hypothesize that TNF-α mediates its capillary disruptive actions via miR638 and that estradiol blocks these actions. Using quantitative reverse transcription PCR, we first assessed the modulatory effects of TNF-α on miR638. The treatment of PCs with TNF-α significantly induced miR638. Moreover, transfection with miR638 mimic induced PC migration, whereas inhibitory miR638 (anti-miR) abrogated the pro-migratory actions of TNF-α, suggesting that TNF-α stimulates PC migration via miR638. At a molecular level, the pro-migratory effects of miR638 involved the phosphorylation of ERK1/2 but not Akt. Interestingly, estradiol downregulated the constitutive and TNF-α-stimulated expression of miR638 and inhibited the TNF-α-induced migration of PCs. In PCs treated with estrogen receptor (ER) ER-α, ER-β, and GPR30 agonists, a significant downregulation in miR638 expression was solely observed in response to DPN, an ER-β agonist. DPN inhibited the pro-migratory effects of TNF-α but not miR638. Additionally, the ectopic expression of miR638 prevented the inhibitory effects of DPN on TNF-α-induced PC migration, suggesting that interference in miR638 formation plays a key role in mediating the inhibitory actions of estradiol/DPN. In conclusion, these findings provide the first evidence that estradiol inhibits TNF-α-induced PC migration by specifically downregulating miR638 via ER-β and may protect the neurovascular unit during injury/stroke via this mechanism. Full article
(This article belongs to the Special Issue Molecular Mechanisms and Physiology Associated with the Blood–Brain Barrier)
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22 pages, 5741 KiB  
Article
Structural Features Influencing the Bioactive Conformation of Angiotensin II and Angiotensin A: Relationship between Receptor Desensitization, Addiction, and the Blood–Brain Barrier
by Graham J. Moore, Harry Ridway, Laura Kate Gadanec, Vasso Apostolopoulos, Anthony Zulli, Jordan Swiderski, Konstantinos Kelaidonis, Veroniki P. Vidali, Minos-Timotheos Matsoukas, Christos T. Chasapis and John M. Matsoukas
Int. J. Mol. Sci. 2024, 25(11), 5779; https://doi.org/10.3390/ijms25115779 - 26 May 2024
Cited by 2 | Viewed by 2058
Abstract
The N-terminal portion of the octapeptide angiotensin II (DRVYIHPF; AngII), a vasopressor peptide that favorably binds to, and activates, AngII type 1 receptor (AT1R), has an important role in maintaining bioactive conformation. It involves all three charged groups, namely (i) the [...] Read more.
The N-terminal portion of the octapeptide angiotensin II (DRVYIHPF; AngII), a vasopressor peptide that favorably binds to, and activates, AngII type 1 receptor (AT1R), has an important role in maintaining bioactive conformation. It involves all three charged groups, namely (i) the N-terminal amino group cation, (ii) the Asp sidechain anion and (iii) the Arg guanidino cation. Neutralization of any one of these three charged groups results in a substantial reduction (<5%) in bioactivity, implicating a specialized function for this cluster. In contrast, angiotensin A (ARVYIHPF; AngA) has reduced bioactivity at AT1R; however, replacement of Asp in AngII with sarcosine (N-methyl-glycine) not only restores bioactivity but increases the activity of agonist, antagonist, and inverse agonist analogues. A bend produced at the N-terminus by the introduction of the secondary amino acid sarcosine is thought to realign the functional groups that chaperone the C-terminal portion of AngII, allowing transfer of the negative charge originating at the C-terminus to be transferred to the Tyr hydroxyl-forming tyrosinate anion, which is required to activate the receptor and desensitizes the receptor (tachyphylaxis). Peptide (sarilesin) and nonpeptide (sartans) moieties, which are long-acting inverse agonists, appear to desensitize the receptor by a mechanism analogous to tachyphylaxis. Sartans/bisartans were found to bind to alpha adrenergic receptors resulting in structure-dependent desensitization or resensitization. These considerations have provided information on the mechanisms of receptor desensitization/tolerance and insights into possible avenues for treating addiction. In this regard sartans, which appear to cross the blood–brain barrier more readily than bisartans, are the preferred drug candidates. Full article
(This article belongs to the Special Issue Molecular Mechanisms and Physiology Associated with the Blood–Brain Barrier)
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18 pages, 1437 KiB  
Article
Identification of an Intravenous Injectable NK1 Receptor Antagonist for Use in Traumatic Brain Injury
by Robert Vink and Alan Nimmo
Int. J. Mol. Sci. 2024, 25(6), 3535; https://doi.org/10.3390/ijms25063535 - 21 Mar 2024
Cited by 2 | Viewed by 1729
Abstract
Traumatic brain injuries represent a leading cause of death and disability in the paediatric and adult populations. Moderate-to-severe injuries are associated with blood–brain barrier dysfunction, the development of cerebral oedema, and neuroinflammation. Antagonists of the tachykinin NK1 receptor have been proposed as potential [...] Read more.
Traumatic brain injuries represent a leading cause of death and disability in the paediatric and adult populations. Moderate-to-severe injuries are associated with blood–brain barrier dysfunction, the development of cerebral oedema, and neuroinflammation. Antagonists of the tachykinin NK1 receptor have been proposed as potential agents for the post-injury treatment of TBI. We report on the identification of EUC-001 as a potential clinical candidate for development as a novel TBI therapy. EUC-001 is a selective NK1 antagonist with a high affinity for the human NK1 receptor (Ki 5.75 × 10−10 M). It has sufficient aqueous solubility to enable intravenous administration, whilst still retaining good CNS penetration as evidenced by its ability to inhibit the gerbil foot-tapping response. Using an animal model of TBI, the post-injury administration of EUC-001 was shown to restore BBB function in a dose-dependent manner. EUC-001 was also able to ameliorate cerebral oedema. These effects were associated with a significant reduction in post-TBI mortality. In addition, EUC-001 was able to significantly reduce functional deficits, both motor and cognitive, that normally follow a severe injury. EUC-001 is proposed as an ideal candidate for clinical development for TBI. Full article
(This article belongs to the Special Issue Molecular Mechanisms and Physiology Associated with the Blood–Brain Barrier)
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8 pages, 884 KiB  
Communication
Vagus Nerve Stimulation Modulates Inflammation in Treatment-Resistant Depression Patients: A Pilot Study
by Paul Lespérance, Véronique Desbeaumes Jodoin, David Drouin, Frédéric Racicot, Jean-Philippe Miron, Christophe Longpré-Poirier, Marie-Pierre Fournier-Gosselin, Paméla Thebault, Réjean Lapointe, Nathalie Arbour and Jean-François Cailhier
Int. J. Mol. Sci. 2024, 25(5), 2679; https://doi.org/10.3390/ijms25052679 - 26 Feb 2024
Cited by 9 | Viewed by 3254
Abstract
Vagal neurostimulation (VNS) is used for the treatment of epilepsy and major medical-refractory depression. VNS has neuropsychiatric functions and systemic anti-inflammatory activity. The objective of this study is to measure the clinical efficacy and impact of VNS modulation in depressive patients. Six patients [...] Read more.
Vagal neurostimulation (VNS) is used for the treatment of epilepsy and major medical-refractory depression. VNS has neuropsychiatric functions and systemic anti-inflammatory activity. The objective of this study is to measure the clinical efficacy and impact of VNS modulation in depressive patients. Six patients with refractory depression were enrolled. Depression symptoms were assessed with the Montgomery–Asberg Depression Rating, and anxiety symptoms with the Hamilton Anxiety Rating Scale. Plasmas were harvested prospectively before the implantation of VNS (baseline) and up to 4 years or more after continuous therapy. Forty soluble molecules were measured in the plasma by multiplex assays. Following VNS, the reduction in the mean depression severity score was 59.9% and the response rate was 87%. Anxiety levels were also greatly reduced. IL-7, CXCL8, CCL2, CCL13, CCL17, CCL22, Flt-1 and VEGFc levels were significantly lowered, whereas bFGF levels were increased (p values ranging from 0.004 to 0.02). This exploratory study is the first to focus on the long-term efficacy of VNS and its consequences on inflammatory biomarkers. VNS may modulate inflammation via an increase in blood–brain barrier integrity and a reduction in inflammatory cell recruitment. This opens the door to new pathways involved in the treatment of refractory depression. Full article
(This article belongs to the Special Issue Molecular Mechanisms and Physiology Associated with the Blood–Brain Barrier)
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14 pages, 2979 KiB  
Article
Hyperinsulinemia Impairs Clathrin-Mediated Endocytosis of the Insulin Receptor and Activation of Endothelial Nitric Oxide Synthase in Brain Endothelial Cells
by Stephanie G. DiLucia, B. Jacob Kendrick and Catrina Sims-Robinson
Int. J. Mol. Sci. 2023, 24(19), 14670; https://doi.org/10.3390/ijms241914670 - 28 Sep 2023
Cited by 3 | Viewed by 1707
Abstract
Adequate perfusion of cerebral tissues, which is necessary for the preservation of optimal brain health, depends on insulin signaling within brain endothelial cells. Proper insulin signaling relies on the regulated internalization of insulin bound to the insulin receptor, a process which is disrupted [...] Read more.
Adequate perfusion of cerebral tissues, which is necessary for the preservation of optimal brain health, depends on insulin signaling within brain endothelial cells. Proper insulin signaling relies on the regulated internalization of insulin bound to the insulin receptor, a process which is disrupted by hyperinsulinemia via an unknown mechanism. Thus, the goal of this study was to characterize the impact of hyperinsulinemia on the regulation of molecular targets involved in cerebral blood flow and insulin receptor internalization into brain endothelial cells. The phosphorylation of molecular targets associated with cerebral blood flow and insulin receptor internalization was assessed in hyperinsulinemic brain endothelial cells. Insulin receptor uptake into cells was also examined in the setting of endocytosis blockade. Our data demonstrate that hyperinsulinemia impairs the activation of endothelial nitric oxide synthase. These data correspond with an impairment in clathrin-mediated endocytosis of the insulin receptor and dysregulated phosphorylation of key internalization effectors. We conclude that hyperinsulinemia alters the phosphorylation of molecular targets involved in clathrin-mediated endocytosis, disrupts signaling through the insulin receptor, and hinders the capacity for blood flow regulation by brain endothelial cells. Full article
(This article belongs to the Special Issue Molecular Mechanisms and Physiology Associated with the Blood–Brain Barrier)
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Review

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11 pages, 698 KiB  
Review
The Mechanisms of Altered Blood–Brain Barrier Permeability in CD19 CAR T–Cell Recipients
by Soniya N. Pinto and Giedre Krenciute
Int. J. Mol. Sci. 2024, 25(1), 644; https://doi.org/10.3390/ijms25010644 - 4 Jan 2024
Cited by 6 | Viewed by 2993
Abstract
Cluster of differentiation 19 (CD19) chimeric antigen receptor (CAR) T cells are a highly effective immunotherapy for relapsed and refractory B-cell malignancies, but their utility can be limited by the development of immune effector cell-associated neurotoxicity syndrome (ICANS). The recent discovery of CD19 [...] Read more.
Cluster of differentiation 19 (CD19) chimeric antigen receptor (CAR) T cells are a highly effective immunotherapy for relapsed and refractory B-cell malignancies, but their utility can be limited by the development of immune effector cell-associated neurotoxicity syndrome (ICANS). The recent discovery of CD19 expression on the pericytes in the blood–brain barrier (BBB) suggests an important off-target mechanism for ICANS development. In addition, the release of systemic cytokines stimulated by the engagement of CD19 with the CAR T cells can cause endothelial activation and decreased expression of tight junction molecules, further damaging the integrity of the BBB. Once within the brain microenvironment, cytokines trigger a cytokine-specific cascade of neuroinflammatory responses, which manifest clinically as a spectrum of neurological changes. Brain imaging is frequently negative or nonspecific, and treatment involves close neurologic monitoring, supportive care, interleukin antagonists, and steroids. The goal of this review is to inform readers about the normal development and microstructure of the BBB, its unique susceptibility to CD19 CAR T cells, the role of individual cytokines on specific elements of the brain’s microstructural environment, and the clinical and imaging manifestations of ICANS. Our review will link cellular pathophysiology with the clinical and radiological manifestations of a complex clinical entity. Full article
(This article belongs to the Special Issue Molecular Mechanisms and Physiology Associated with the Blood–Brain Barrier)
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