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Molecular Mechanisms and Regulation in Blood-Brain Barrier
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Molecular Mechanisms and Regulation in Blood-Brain Barrier

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: closed (30 January 2026) | Viewed by 11155

Special Issue Editor

Dr. Rajkumar Vutukuri

E-Mail Website
Guest Editor
Pharmazentrum Frankfurt, Goethe University, Frankfurt, Germany
Interests: angiogenesis; blood-brain barrier

Special Issue Information

Dear Colleagues,

The blood brain barrier (BBB) is a highly selective, multi-cellular permeability barrier that protects the brain from blood related substances as well as tightly regulate CNS homeostasis. Tightly organized microvascular endothelial cells are the principal constituent of BBB, supported by astrocytic end feet, pericytes neurons and extra cellular matrix, together referred to as neurovascular unit (NVU). Compromised BBB is prominent in stroke, encephalopathy, AD, and other neurodegenerative diseases. The current special issue of IJMS focuses on “Molecular Mechanisms and Regulation in Blood-Brain Barrier”, exploring the latest advances in understanding the cellular and molecular dynamics of the BBB. We invite articles and reviews investigating the role of tight junctions, NVU cell types and the molecular mechanisms pertaining to BBB, especially in the context of neurodegenerative and neuro-inflammatory diseases. Also, articles relating to emphasis on novel therapeutic strategies aimed at modulating BBB transport for enhanced drug delivery are encouraged. The special issue focuses on comprehensive insights on novel technologies developing BBB models that offer potential areas for clinical application and treating CNS diseases.

Dr. Rajkumar Vutukuri
Guest Editor

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 250 words) can be sent to the Editorial Office for assessment.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. International Journal of Molecular Sciences is an international peer-reviewed open access semimonthly journal published by MDPI.

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Keywords

  • blood brain barrier (BBB)
  • tight junctions
  • NVU cell types
  • neurodegenerative diseases
  • neuro-inflammation

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Published Papers (3 papers)

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Research

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17 pages, 3982 KB  
Article
NX210c Demonstrates Therapeutic Potential to Restore Blood–Brain Barrier in a QSP Model of Relapsing–Remitting Multiple Sclerosis
by Giulia Russo, Fianne Sips, Simona Catozzi, Pauline Bambury, Annette Janus, Mario Torchia, Valentina Di Salvatore, Luca Emili, Daniel Röshammar, Francesco Pappalardo and Yann Godfrin
Int. J. Mol. Sci. 2026, 27(3), 1349; https://doi.org/10.3390/ijms27031349 - 29 Jan 2026
Viewed by 332
Abstract
Blood–brain barrier (BBB) breakdown is a hallmark of several neurological disorders, including multiple sclerosis (MS). NX210c, a novel therapeutic peptide, has shown promise in restoring BBB integrity, in both preclinical and clinical settings, offering potential for use in MS populations and across various [...] Read more.
Blood–brain barrier (BBB) breakdown is a hallmark of several neurological disorders, including multiple sclerosis (MS). NX210c, a novel therapeutic peptide, has shown promise in restoring BBB integrity, in both preclinical and clinical settings, offering potential for use in MS populations and across various central nervous system conditions with overlapping mechanisms. In this study, we evaluated the therapeutic potential of NX210c in patients with relapsing–remitting MS (RRMS) using a previous quantitative systems pharmacology (QSP) model currently redesigned to capture the dynamic interplay between BBB integrity and immune system activity. We validated the QSP model using both preclinical and clinical datasets, and generated virtual populations representing healthy individuals and RRMS patients for in silico testing. NX210c was assessed as both a monotherapy and in combination with established MS treatments. Simulations predicted time course changes in key BBB integrity markers, including tight junction protein (TJP) expression and transendothelial electrical resistance (TEER), under various dosing regimens. NX210c treatment was associated with a significant attenuation of BBB degradation compared to untreated controls (~7–8% higher TJP expression and BBB electrical resistance). Furthermore, we investigated the long-term impact of NX210c on clinical outcomes such as relapse rates. Both 5 and 10 mg/kg doses (single cycle [thrice-weekly for 4 weeks]) induced improvement in disease activity in RRMS patients, as well as a 10 mg/kg dose (single or repeated 4-week cycles every 6 months) in highly active patients. Particularly when administered alongside one of five commonly used MS therapies (interferon β-1a, teriflunomide, cladribine, natalizumab, ocrelizumab), in the highly active subpopulation, the model on average predicted a reduction in relapse frequency in the 10 mg NX210c-treated group versus untreated group from four to no relapses over two years. These findings suggest that NX210c may enhance therapeutic efficacy in RRMS by promoting BBB restoration and modulating immune responses, offering a promising avenue for combination treatment strategies. Full article
(This article belongs to the Special Issue Molecular Mechanisms and Regulation in Blood-Brain Barrier)
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Review

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35 pages, 1987 KB  
Review
The Fluidic Connectome in Brain Disease: Integrating Aquaporin-4 Polarity with Multisystem Pathways in Neurodegeneration
by Felix-Mircea Brehar, Daniel Costea, Calin Petru Tataru, Mugurel Petrinel Rădoi, Alexandru Vlad Ciurea, Octavian Munteanu and Adrian Tulin
Int. J. Mol. Sci. 2025, 26(23), 11536; https://doi.org/10.3390/ijms262311536 - 28 Nov 2025
Viewed by 1827
Abstract
The way in which Aquaporin-4 (AQP4) is localized on the astrocytes’ surface—i.e., with AQP4 channels predominantly located on the endfeet of astrocytes near the blood vessels—represents an important structural element for maintaining brain fluid homeostasis. In addition to this structural function, AQP4 polarity [...] Read more.
The way in which Aquaporin-4 (AQP4) is localized on the astrocytes’ surface—i.e., with AQP4 channels predominantly located on the endfeet of astrocytes near the blood vessels—represents an important structural element for maintaining brain fluid homeostasis. In addition to this structural function, AQP4 polarity also facilitates glymphatic transport, the maintenance of the blood–brain barrier (BBB) functions, ion buffering, and neurotransmitter removal, and helps regulate neurovascular communications. The growing body of literature suggests that the loss of AQP4 polarity—a loss in the organization of AQP4 channels to the perivascular membrane—is associated with increased vascular, inflammatory, and metabolic disturbances in the context of many neurological diseases. As a result, this review attempts to synthesize both experimental and clinical studies to highlight that AQP4 depolarization often occurs in conjunction with early signs of neurodegeneration and neuroinflammation; however, we are aware that the loss of AQP4 polarity is only one factor in a complex pathophysiological environment. This review examines the molecular structure responsible for maintaining the polarity of AQP4—such as dystrophin–syntrophin complexes, orthogonal particle arrays, lipid microdomains, trafficking pathways, and transcriptional regulators—and describes how the vulnerability of these systems to various types of vascular stress, inflammatory signals, energy deficits, and mechanical injury can lead to a loss of AQP4 polarity. Furthermore, we will explore how a loss of AQP4 polarity can lead to the disruption of perivascular fluid movement, changes in blood–brain barrier morphology, enhanced neuroimmune activity, changes in ionic and metabolic balance, and disruptions in the global neural network synchronization. Importantly, we recognize that each of these disruptions will likely occur in concert with other disease-specific mechanisms. Alterations in AQP4 polarity have been observed in a variety of neurological disorders including Alzheimer’s disease, Parkinson’s disease, multiple sclerosis, traumatic brain injury, and glioma; however, we also observe that the same alterations in fluid regulation occur across all of these different diseases, but that no single upstream event accounts for the alteration in polarity. Ultimately, we will outline emerging therapeutic avenues to restore perivascular fluid transport, and will include molecular-based therapeutic agents designed to modify the anchoring of AQP4, methods designed to modulate the state of astrocytes, biomaterials-based drug delivery systems, and therapeutic methods that leverage dynamic modulation of the neurovascular interface. Future advances in multi-omic profiling, spatial proteomics, glymphatic imaging, and artificial intelligence will allow for earlier identification of AQP4 polarity disturbances and potentially allow for the development of more personalized treatment plans. Ultimately, by linking these concepts together, this review aims to frame AQP4 polarity as a modifiable aspect of the “fluidic connectome”, and highlight its importance in maintaining overall brain health across disease states. Full article
(This article belongs to the Special Issue Molecular Mechanisms and Regulation in Blood-Brain Barrier)
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30 pages, 1438 KB  
Review
Breaking the Barrier: The Role of Proinflammatory Cytokines in BBB Dysfunction
by Małgorzata Gryka-Marton, Anna D. Grabowska and Dariusz Szukiewicz
Int. J. Mol. Sci. 2025, 26(8), 3532; https://doi.org/10.3390/ijms26083532 - 9 Apr 2025
Cited by 35 | Viewed by 8391
Abstract
The BBB is created by a special system of brain microvascular endothelial cells (BMECs), pericytes (PCs), the capillary basement membrane, and the terminal branches (“end-feet”) of astrocytes (ACs). The key function of the BBB is to protect the central nervous system (CNS) from [...] Read more.
The BBB is created by a special system of brain microvascular endothelial cells (BMECs), pericytes (PCs), the capillary basement membrane, and the terminal branches (“end-feet”) of astrocytes (ACs). The key function of the BBB is to protect the central nervous system (CNS) from potentially harmful/toxic substances in the bloodstream by selectively controlling the entry of cells and molecules, including nutrients and components of the immune system. The loss of BBB integrity in response to neuroinflammation, as manifested by an increase in permeability, depends predominantly on the activity of proinflammatory cytokines. However, the pathomechanism of structural and functional changes in the BBB under the influence of individual cytokines is still poorly understood. This review summarizes the current state of knowledge on this topic, which is important from both pathophysiological and therapeutic points of view. The structures and functions of all components of the BBB are reviewed, with emphasis given to differences between this and other locations of the circulatory system. The protein composition of the interendothelial tight junctions in the context of regulating BBB permeability is presented, as is the role of pericyte–BMEC interactions in the exchange of metabolites, ions, and nucleic acids. Finally, the documented actions of proinflammatory cytokines within the BBB are discussed. Full article
(This article belongs to the Special Issue Molecular Mechanisms and Regulation in Blood-Brain Barrier)
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