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Activation of the Blood–Brain Barrier and Neurological Dysfunction

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

Deadline for manuscript submissions: 20 January 2025 | Viewed by 12831

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Special Issue Editor

Dr. Monique F. Stins

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Guest Editor

1. Associate Professor, Biomedical Research Institute of Southern California, Oceanside, CA, USA
2. Associate Professor, Adj. Department Molecular Microbiology and Immunology, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, USA
3. Associate Professor, Adj. Department Neurology, Johns Hopkins School of Medicine, Baltimore, MD, USA
Interests: blood–brain barrier, neuro-infectious diseases, e.g., cerebral malaria, Plasmodium, neurologic sequelae, heterogeneity of cerebral vasculature, differential pathology, white matter versus gray matter; neuronal dysfunction

Special Issue Information

Dear Colleagues,

The blood–brain barrier is situated at the interface of the central nervous system (CNS) and the periphery and protects the brain from undue influences, thus guaranteeing optimal neuronal functioning. However, many peripheral microbial diseases, including COVID19, bacteria, their toxic components, and organ activation, such as intestinal or kidney inflammation, influence the blood–brain barrier (BBB). This can result in the inflammation of the BBB endothelium with an increased release of chemokines and cytokines, an elevated presence of cell adhesion molecules, and alterations of the integrity of the BBB, leading to an influx of plasma components and/or immune cells into the brain.

Changes in the functionality of the BBB have been associated with various neurological conditions, such as epilepsy, amyotrophic lateral sclerosis, multiple sclerosis, neuro-infections, such as HIV infection, Lyme disease, cerebral malaria and COVID-19. Blunt force trauma induced by sports or accidents, stroke, tumors, sickle cell disorders and age-related neurological conditions such as Parkinson’s disease and Alzheimer’s disease also have components of BBB endothelial dysfunction. More recently, psychiatric disorders have also been associated with an altered BBB function.

Although the role of the BBB endothelium in these various disorders and conditions is receiving more and more attention, many gaps in our knowledge exist.

Neuroprotective treatments for these various neurological conditions are very limited. There is a great demand for novel neuroprotective approaches, and for strategies that improve drug delivery to the CNS. In addition, to better understand regional differences in the various neuropathologies, improved knowledge of BBB heterogeneity is needed. A better understanding of BBB heterogeneity may also aid in the improvement of pharmacological therapies and the more targeted delivery of neuroprotective drugs to the affected brain regions.

We welcome submissions to this Special Issue of IJMS that address the basic and clinical neuropathological disease processes and highlight their underlying biomolecular science.

Dr. Monique F. Stins
Guest Editor

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Keywords

blood–brain barrier
neuro-infectious diseases
cerebral malaria
Plasmodium
cerebral vasculature
vascular heterogeneity
white matter
gray matter

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Published Papers (6 papers)

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Research

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16 pages, 2325 KiB

Open AccessArticle

Inflammation and Elevated Osteopontin in Plasma and CSF in Cerebral Malaria Compared to Plasmodium-Negative Neurological Infections

by Monique F. Stins, Agnes Mtaja, Evans Mulendele, Daniel Mwimbe, Gabriel D. Pinilla-Monsalve, Mable Mutengo, Carlos A. Pardo and James Chipeta

Int. J. Mol. Sci. 2024, 25(17), 9620; https://doi.org/10.3390/ijms25179620 - 5 Sep 2024

Viewed by 513

Abstract

Cerebral malaria in young African children is associated with high mortality, and persisting neurological deficits often remain in survivors. Sequestered Plasmodium-infected red blood cells lead to cerebrovascular inflammation and subsequent neuroinflammation. Brain inflammation can play a role in the pathogenesis of neurologic sequelae. Therefore, we assessed a select set of proinflammatory analytes (IP10, IL23, MIP3α, GRO, MCP-1, and osteopontin in both the plasma and cerebrospinal fluid(CSF) of Zambian children with cerebral malaria and compared this with children with neurological symptoms that were negative for Plasmodium falciparum (non-cerebral malaria). Several similarities in plasma and CSF levels were found, as were some striking differences. We confirmed that IP10 levels were higher in the plasma of cerebral malaria patients, but this was not found in CSF. Levels of osteopontin were elevated in both the plasma and CSF of CM patients compared to the non-CM patients. These results show again a highly inflammatory environment in both groups but a different profile for CM when compared to non-cerebral malaria. Osteopontin may play an important role in neurological inflammation in CM and the resulting sequelae. Therefore, osteopontin could be a valid target for further biomarker research and potentially for therapeutic interventions in neuroinflammatory infections. Full article

(This article belongs to the Special Issue Activation of the Blood–Brain Barrier and Neurological Dysfunction)

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15 pages, 5642 KiB

Open AccessArticle

Endothelial Cell-Derived Soluble CD200 Determines the Ability of Immune Cells to Cross the Blood–Brain Barrier

by Myriam Pujol, Tautvydas Paskevicius, Alison Robinson, Simran Dhillon, Paul Eggleton, Alex S. Ferecskó, Nick Gutowski, Janet Holley, Miranda Smallwood, Jia Newcombe, Luis B. Agellon and Marek Michalak

Int. J. Mol. Sci. 2024, 25(17), 9262; https://doi.org/10.3390/ijms25179262 - 27 Aug 2024

Viewed by 3178

Abstract

The infiltration of immune cells into the central nervous system mediates the development of autoimmune neuroinflammatory diseases. We previously showed that the loss of either Fabp5 or calnexin causes resistance to the induction of experimental autoimmune encephalomyelitis (EAE) in mice, an animal model of multiple sclerosis (MS). Here we show that brain endothelial cells lacking either Fabp5 or calnexin have an increased abundance of cell surface CD200 and soluble CD200 (sCD200) as well as decreased T-cell adhesion. In a tissue culture model of the blood–brain barrier, antagonizing the interaction of CD200 and sCD200 with T-cell CD200 receptor (CD200R1) via anti-CD200 blocking antibodies or the RNAi-mediated inhibition of CD200 production by endothelial cells increased T-cell adhesion and transmigration across monolayers of endothelial cells. Our findings demonstrate that sCD200 produced by brain endothelial cells regulates immune cell trafficking through the blood–brain barrier and is primarily responsible for preventing activated T-cells from entering the brain. Full article

(This article belongs to the Special Issue Activation of the Blood–Brain Barrier and Neurological Dysfunction)

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11 pages, 695 KiB

Open AccessArticle

S100B Serum Levels in Chronic Heart Failure Patients: A Multifaceted Biomarker Linking Cardiac and Cognitive Dysfunction

by Jan Traub, Michael K. Schuhmann, Roxanne Sell, Stefan Frantz, Stefan Störk, Guido Stoll and Anna Frey

Int. J. Mol. Sci. 2024, 25(16), 9094; https://doi.org/10.3390/ijms25169094 - 22 Aug 2024

Viewed by 549

Abstract

S100 calcium-binding protein B (S100B) is a protein primarily known as a biomarker for central nervous system (CNS) injuries, reflecting blood–brain barrier (BBB) permeability and dysfunction. Recently, S100B has also been implicated in cardiovascular diseases, including heart failure (HF). Thus, we investigated serum levels of S100B in 146 chronic HF patients from the Cognition.Matters-HF study and their association with cardiac and cognitive dysfunction. The median S100B level was 33 pg/mL (IQR: 22–47 pg/mL). Higher S100B levels were linked to longer HF duration (p = 0.014) and increased left atrial volume index (p = 0.041), but also with a higher prevalence of mild cognitive impairment (p = 0.023) and lower visual/verbal memory scores (p = 0.006). In a multivariable model, NT-proBNP levels independently predicted S100B (T-value = 2.27, p = 0.026). S100B did not impact mortality (univariable HR (95% CI) 1.00 (0.99–1.01); p = 0.517; multivariable HR (95% CI) 1.01 (1.00–1.03); p = 0.142), likely due to its reflection of acute injury rather than long-term outcomes and the mild HF phenotype in our cohort. These findings underscore S100B’s value in comprehensive disease assessment, reflecting both cardiac dysfunction and potentially related BBB disruption. Full article

(This article belongs to the Special Issue Activation of the Blood–Brain Barrier and Neurological Dysfunction)

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16 pages, 2296 KiB

Open AccessArticle

Increased Permeability of the Blood–Brain Barrier in a Diabetic Mouse Model (Lepr^db^/db Mice)

by Musaad A. Alshammari, Abdulaziz O. Alshehri, Faleh Alqahtani, Mohammad R. Khan, Muhammed A. Bakhrebah, Fawaz Alasmari, Tahani K. Alshammari and Shakir D. Alsharari

Int. J. Mol. Sci. 2024, 25(14), 7768; https://doi.org/10.3390/ijms25147768 - 16 Jul 2024

Cited by 1 | Viewed by 861

Abstract

Type 2 Diabetes Mellitus (T2DM) is linked to multiple complications, including cognitive impairment, and the prevalence of memory-related neurodegenerative diseases is higher in T2DM patients. One possible theory is the alteration of the microvascular and macrovascular environment of the blood–brain barrier (BBB). In this study, we employed different approaches, including RT-PCR, functional pharmacokinetic studies using sodium fluorescein (NaFL), and confocal microscopy, to characterize the functional and molecular integrity of the BBB in a T2DM animal model, leptin receptor-deficient mutant mice (Lepr^db^/db mice). As a result, VCAM-1, ICAM-1, MMP-9, and S100b (BBB-related markers) dysregulation was observed in the Lepr^db^/db animal model compared to littermate wild-type mice. The brain concentration of sodium fluorescein (NaFL) increased significantly in Lepr^db/db untreated mice compared to insulin-treated mice. Therefore, the permeability of NaFL was higher in Lepr^db^/db control mice than in all remaining groups. Identifying the factors that increase the BBB in Lepr^db^/db mice will provide a better understanding of the BBB microvasculature and present previously undescribed findings of T2DM-related brain illnesses, filling knowledge gaps in this emerging field of research. Full article

(This article belongs to the Special Issue Activation of the Blood–Brain Barrier and Neurological Dysfunction)

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24 pages, 2627 KiB

Open AccessArticle

Anti-Inflammatory Action of Resveratrol in the Central Nervous System in Relation to Glucose Concentration—An In Vitro Study on a Blood–Brain Barrier Model

by Justyna Komorowska, Mateusz Wątroba, Małgorzata Bednarzak, Anna D. Grabowska and Dariusz Szukiewicz

Int. J. Mol. Sci. 2024, 25(6), 3110; https://doi.org/10.3390/ijms25063110 - 7 Mar 2024

Cited by 1 | Viewed by 1462

Abstract

Unbalanced blood glucose levels may cause inflammation within the central nervous system (CNS). This effect can be reversed by the action of a natural neuroprotective compound, resveratrol (RSV). The study aimed to investigate the anti-inflammatory effect of RSV on astrocyte cytokine profiles within an in vitro model of the blood–brain barrier (BBB) under varying glucose concentrations (2.2, 5.0, and 25.0 mmol/L), corresponding to hypo-, normo-, and hyperglycemia. The model included co-cultures of astrocytes (brain compartment, BC) and endothelial cells (microvascular compartment, MC), separated by 0.4 µm wide pores. Subsequent exposure to 0.2 μM LPS in the brain compartment (BC) and 50 μM RSV in the microvascular compartment (MC) of each well was carried out. Cytokine levels (IL-1 α, IL-1 β, IL-2, IL-4, IL-6, IL-8) in the BC were assessed using a Multi-Analyte ELISArray Kit before and after the addition of LPS and RSV. Statistical analysis was performed to determine significance levels. The results demonstrated that RSV reduced the concentration of all studied cytokines in the BC, regardless of glucose levels, with the most substantial decrease observed under normoglycemic conditions. Additionally, the concentration of RSV in the BC was highest under normoglycemic conditions compared to hypo- and hyperglycemia. These findings confirm that administration of RSV in the MC exerts anti-inflammatory effects within the BC, particularly under normoglycemia-simulating conditions. Further in vivo studies, including animal and human research, are warranted to elucidate the bioavailability of RSV within the central nervous system (CNS). Full article

(This article belongs to the Special Issue Activation of the Blood–Brain Barrier and Neurological Dysfunction)

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Review

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40 pages, 4629 KiB

Open AccessReview

Blood–Brain Barrier Breakdown in Neuroinflammation: Current In Vitro Models

by Sarah Brandl and Markus Reindl

Int. J. Mol. Sci. 2023, 24(16), 12699; https://doi.org/10.3390/ijms241612699 - 11 Aug 2023

Cited by 12 | Viewed by 5457

Abstract

The blood–brain barrier, which is formed by tightly interconnected microvascular endothelial cells, separates the brain from the peripheral circulation. Together with other central nervous system-resident cell types, including pericytes and astrocytes, the blood–brain barrier forms the neurovascular unit. Upon neuroinflammation, this barrier becomes leaky, allowing molecules and cells to enter the brain and to potentially harm the tissue of the central nervous system. Despite the significance of animal models in research, they may not always adequately reflect human pathophysiology. Therefore, human models are needed. This review will provide an overview of the blood–brain barrier in terms of both health and disease. It will describe all key elements of the in vitro models and will explore how different compositions can be utilized to effectively model a variety of neuroinflammatory conditions. Furthermore, it will explore the existing types of models that are used in basic research to study the respective pathologies thus far. Full article

(This article belongs to the Special Issue Activation of the Blood–Brain Barrier and Neurological Dysfunction)

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