bims-blobar 2025-08-03 papers

bims-blobar

Biomed News

on Blood brain barrier repair

Issue of 2025–08–03
twenty-two papers selected by
Nicolas Rebergue

Identification and Characterization of a Translational Mouse Model for Blood-Brain Barrier Leakage in Cerebral Small Vessel Disease.
Blood-Brain barrier disruption in long COVID and cognitive correlates: A cross-sectional MRI study.
Oligodendrocyte precursor cell transplantation attenuates inflammation after ischemic stroke in mice.
Nutritional Modulation of Impaired Blood-Brain Barrier Integrity and Function in Major Depression.
Quercetin Protects Blood-Brain Barrier Integrity and Maintains Microvascular Permeability Following Traumatic Brain Injury.
Intestinal ischemia-reperfusion and blood-brain barrier compromise: pathways to cognitive dysfunction.
Differential Regulation of Proteins Related to the Blood-Brain Barrier in Stress-Resilient and Stress-Susceptible Mice.
Kisspeptin-10 Protects Against HIV-1 Tat-Induced Blood-Brain Barrier Dysfunction and Neuroinflammation via RhoA/ROCK Pathway: Implications for HAND Therapy.
Emerging biomarkers and frontier therapies: unveiling the role of endothelial dysfunction in cerebral small vessel disease.
Sevoflurane reduces brain edema and improves blood-brain barrier by downregulating CaMKII to inhibit TMEM16A after cerebral ischemia injury both in vivo and in vitro.
Meningeal enhancement following traumatic brain injury: a mini review.
IRF7 in peripheral monocytes drives BBB disruption in anti-NMDAR encephalitis.
Restricted fetal blood brain barrier permeability in a preclinical model of autism induced by Group B Streptococcus maternal immune activation.
Elucidating molecular pathogenesis and developing targeted therapeutic interventions for cerebrovascular endothelial cell-mediated vascular dementia.
Impact of Myocardial Infarction on Cerebral Homeostasis: Exploring the Protective Role of Estrogen.
Pathogenesis of brain injury in cerebral malaria: emerging mechanisms and implications for intervention.
Brain pericytes derived from human pluripotent stem cells retain vascular and phagocytic functions under hypoxia.
Umbilical Cord Blood Endothelial Progenitor Cells Modulate Neurovascular Unit Damage in a Neonatal Rat Model of Hypoxia Ischemia.
Obesity and Cognitive Function: Leptin Role Through Blood-Brain Barrier and Hippocampus.
Mechanism of the protective effect of 2,3,5,4'-Tetrahydroxy stilbene-2-O-β-D-glucoside on MPTP-induced Parkinson's disease mice.
Sphk2 in ischemic stroke pathogenesis: Roles, mechanisms, and regulation strategies.
Multi-Faceted Role of Histone Methyltransferase Enhancer of Zeste 2 (EZH2) in Neuroinflammation and Emerging Targeting Options.

Int J Mol Sci. 2025 Jul 12. pii: 6706. [Epub ahead of print]26(14):

Identification and Characterization of a Translational Mouse Model for Blood-Brain Barrier Leakage in Cerebral Small Vessel Disease.

Ruxue Jia, Gemma Solé-Guardia, Vivienne Verweij, Jessica M Snabel, Bram Geenen, Anil Man Tuladhar, Robert Kleemann, Amanda J Kiliaan, Maximilian Wiesmann.

  Blood-brain barrier (BBB) dysfunction is a hallmark of cerebral small vessel disease (cSVD). This study aimed to identify a mouse model that replicates BBB impairment and shares key cSVD risk factors. Transgenic db/db and LDLr-/-.Leiden mice, both prone to obesity and hypertension, were compared to C57BL/6J controls. BBB leakage was assessed using DCE-MRI and sodium fluorescein (NaFl); cerebral blood flow (CBF) by MRI. Dyslipidemia and vascular inflammation were measured by plasma tests. Tight junction integrity, endothelial dysfunction (glucose transporter 1, GLUT-1) and neuroinflammation were evaluated with immunohistochemistry and PCR. Both transgenic models developed an obese phenotype with hyperinsulinemia, but only LDLr-/-.Leiden mice showed human-like dyslipidemia. When fed a high-fat diet (HFD) or HFD plus cholesterol, LDLr-/-.Leiden mice showed reduced CBF, endothelial dysfunction (lowered GLUT-1), elevated vascular inflammation (ICAM-1, VCAM-1, S-selectin), and BBB leakage, as evidenced by DCE-MRI and NaFl, together with reduced ZO-1 and claudin-5 expression. Contrastingly, db/db mice showed endothelial dysfunction without BBB leakage. Neuroinflammation (IBA-1, GFAP) was observed only in LDLr-/-.Leiden groups, consistent with BBB disruption. These findings indicate that LDLr-/-.Leiden mice, but not db/db mice, are a promising translational model for studying BBB dysfunction in cSVD, offering insights into disease mechanisms and a platform for therapeutic development.

Keywords:  blood–brain barrier dysfunction; cerebral small vessel disease (cSVD); dynamic contrast-enhanced MRI (DCE-MRI); endothelial dysfunction; neuroinflammation

DOI:  https://doi.org/10.3390/ijms26146706
Brain Behav Immun. 2025 Jul 28. pii: S0889-1591(25)00293-4. [Epub ahead of print]

Blood-Brain barrier disruption in long COVID and cognitive correlates: A cross-sectional MRI study.

Leah H Rubin, Wen Shi, Alba Azola, Aparna Bhattacharyya, Raha M Dastgheyb, Jiani Wu, Christina Della Penna, Hannah Parker, Isabel Santiuste, Ana Ehrenspeck, Jennifer M Coughlin, Tracy D Vannorsdall, Hanzhang Lu, Rebecca Veenhuis.

  Disruption of the blood-brain barrier (BBB) may contribute to neuropsychiatric symptoms observed in Long COVID (LC). Using a non-contrast magnetic resonance imaging (MRI) technique, we investigated BBB permeability in individuals with LC and its relationship to cognitive function. We hypothesized that LC individuals would show greater BBB permeability than recovered individuals, and that higher permeability would correlate with poorer cognition. Ninety-seven participants meeting the 2024 NASEM definition of LC with at least one neuropsychiatric symptom and 31 recovered controls completed an MRI scan and cognitive testing. BBB permeability was assessed using water-extraction-with-phase-contrast-arterial-spin-tagging (WEPCAST) MRI, which estimates the permeability-surface-area product (PS) of arterially labeled water entering the brain. Cognitive performance was summarized into eight factor scores derived from principal components analysis. Compared to controls, the LC group was older (M = 47 vs. 39 years, P = 0.003), less educated (P = 0.02), more likely female (P = 0.04), and had higher hospitalization rates for COVID-19 (P = 0.02). PS was significantly elevated in the LC group after adjusting for age and sex (B = 18.59, SE = 6.11, β = 0.28, P = 0.003). No significant group differences were found in cerebral blood flow, extraction fraction (E), or brain volume. Within the LC group, higher PS was associated with poorer motor function, but not with other cognitive domains. These findings indicate subtle but persistent BBB disruption in LC individuals over two years post-infection, with a potential link to motor dysfunction. This supports prior evidence of BBB changes following severe COVID-19 and suggests that BBB integrity may be a long-term biomarker of neuropsychiatric complications in LC.

Keywords:  Blood brain barrier; COVID-19; Cognition; Long COVID

DOI:  https://doi.org/10.1016/j.bbi.2025.07.024
Front Neurol. 2025 ;16 1583982

Oligodendrocyte precursor cell transplantation attenuates inflammation after ischemic stroke in mice.

Li-Ping Wang, Chang Liu, Yuanyuan Ma, Aijuan Yan, Guo-Yuan Yang, Xinkai Qu, Wenshi Wei.

   Background: Disruption of blood-brain barrier and neuroinflammation are critical pathological features in the acute phase of ischemic stroke. This study investigates whether oligodendrocyte precursor cell transplantation can downregulate inflammation to attenuate blood-brain barrier disruption following ischemic brain injury.
Methods: Adult male Institute of Cancer Research mice (n = 60) underwent transient middle cerebral artery occlusion. Post ischemic assault, these mice received a stereotactic injection of oligodendrocyte precursor cells (6 × 105). Neurobehavioral outcomes, infarct volume, inflammatory cytokines, myeloperoxidase, and tight junction protein levels were measured following ischemia.
Results: Oligodendrocyte precursor cell transplantation reduced infarct volume, alleviated anxiety and depression, and promoted neurological recovery after ischemic stroke. Compared to the control group, oligodendrocyte precursor cell treated mice exhibited reduced levels of inflammatory cytokines IL-1β, IL-6, and TNF-α, reduced neutrophil infiltration, and diminished loss of tight junction protein. Oligodendrocyte precursor cells alleviated inflammation by increasing β-catenin expression. The administration of β-catenin inhibitor blocked the beneficial effects of oligodendrocyte precursor cell transplantation on neuroinflammation and blood-brain barrier permeability.
Conclusion: This study demonstrates that oligodendrocyte precursor cell transplantation attenuates neuroinflammation and protectes blood-brain barrier in the acute phase of ischemic stroke. Our findings indicate that oligodendrocyte precursor cell transplantation is a promising therapeutic approach for ischemic stroke.

Keywords:  blood–brain barrier; inflammation; ischemic stroke; oligodendrocyte precursor cell; transplantation

DOI:  https://doi.org/10.3389/fneur.2025.1583982
Int J Mol Sci. 2025 Jul 18. pii: 6917. [Epub ahead of print]26(14):

Nutritional Modulation of Impaired Blood-Brain Barrier Integrity and Function in Major Depression.

Miroslav Adzic, Iva Lukic, Milos Mitic, Ester Francija Zerajic, Emilija Glavonic, Milan Jovanovic, Sanja Ivkovic.

  Major Depressive Disorder (MDD) is increasingly linked to disruptions in blood-brain barrier (BBB) integrity, contributing to neuroinflammation and impaired brain homeostasis. While traditional antidepressant therapies often fail to achieve full remission, growing evidence suggests that specific dietary compounds may offer novel avenues for restoring BBB function and improving mental health outcomes. This review explores the potential of selected nutrients-omega-3 fatty acids, vitamin D, sulforaphane, fucoidan, and urolithins-to modulate BBB integrity through anti-inflammatory, antioxidant, and transporter-regulatory mechanisms. These compounds act by reinforcing tight junctions, reducing matrix metalloproteinase activity, and modulating efflux transporters such as P-glycoprotein. Although current evidence is largely preclinical, the mechanistic insights provided in this review support the rationale for integrating nutritional strategies into the management of MDD. Future clinical studies are needed to validate these findings and develop biomarker-driven approaches for targeting the BBB in nutritional interventions for psychiatric disorders.

Keywords:  blood-brain barrier; dietary interventions; major depressive disorder; neuroinflammation; nutrition

DOI:  https://doi.org/10.3390/ijms26146917
Neurocrit Care. 2025 Jul 30.

Quercetin Protects Blood-Brain Barrier Integrity and Maintains Microvascular Permeability Following Traumatic Brain Injury.

Bobby D Robinson, Antonia Yeager, Angela Lomas, Gabriela Seplovich, Chinchusha Anasooya Shaji, Katie Wiggins-Dohlvik, Jason H Huang, Claire L Isbell, Binu Tharakan.

   BACKGROUND: Cerebral edema is a consequential outcome of traumatic brain injury (TBI) and may lead to intracranial hypertension, necessitating urgent medical attention. One of the primary causes of cerebral edema is microvascular hyperpermeability, characterized by excessive leakage of intravascular fluid and proteins via blood-brain barrier (BBB) dysregulation. Prolonged activation of reactive oxygen species (ROS) formation and inflammatory pathways due to BBB hyperpermeability results in poor patient outcomes. The primary goal of this study was to ascertain if quercetin, a bioflavonoid plant pigment, would protect against BBB breakdown and hyperpermeability in the acute context following TBI.
METHODS: We used a mixed in vitro and in vivo model to test the effects of quercetin pretreatment on endothelial cell tight junctions in murine models of TBI and stress-induced hyperpermeability. Hydrogen peroxide (H2O2), a key contributor of secondary injuries following TBI, was used as an inducer of oxidative stress in cerebral endothelial cells in vitro. BBB tight junction/cytoskeletal integrity was assessed using immunofluorescence of junctional proteins zonula occludens-1, β-catenin, and vascular endothelial-cadherin, alongside filamentous actin labeling and a monolayer permeability assay. Intracellular ROS and H2O2 levels were determined using fluorescent probes. In vivo experiments consisted of intravital microscopy of brain pial vasculature in a mouse model of TBI.
RESULTS: The results demonstrate that quercetin (100 μM; 1 h) attenuated H2O2 (100 μM; 2 h)-induced monolayer hyperpermeability and ROS formation significantly and decreased the loss of tight junction and cytoskeletal integrity. Quercetin treatment (50 mg/kg) after injury decreased TBI-induced vascular hyperpermeability significantly compared to sham. These results indicate that quercetin provides BBB protection by decreasing oxidative stress-induced loss of tight junction/cytoskeletal integrity, ultimately resulting in decreased microvascular hyperpermeability.
CONCLUSIONS: The data suggest that quercetin may be a viable therapeutic option for preventing or managing cerebral oedema acutely following TBI.

Keywords:   F-actin; Antioxidant; Blood–brain barrier dysfunction; Brain microvascular endothelial cells; Endogenous antioxidants; Immunofluorescence; Microvascular hyperpermeability; Quercetin; Reactive oxygen species; Tight junction proteins; Traumatic brain injury; VE-cadherin; Zonula occludens-1

DOI:  https://doi.org/10.1007/s12028-025-02315-z
Front Neurosci. 2025 ;19 1597170

Intestinal ischemia-reperfusion and blood-brain barrier compromise: pathways to cognitive dysfunction.

Opeyemi Hammed, Oladele Afolabi, Richard Ajike, Oluwaseun Hezekiah, Babatunde Alabi, David Ajao, Waidi Saka, Olubunmi Oyekunle, Bamidele Olusola.

  Intestinal ischemia-reperfusion (I/R) injury, a disorder occurring from interruption of blood flow to the intestines followed by its restoration, causes a cascade of events leading to systemic consequences, including cognitive impairment. This study analyses the complicated link between intestinal I/R damage and blood-brain barrier (BBB) compromise, highlighting essential processes such as systemic inflammation, gut microbiota dysbiosis, oxidative stress, vagus nerve activation, and altered gut microbial metabolite production. During I/R injury, the weakened gut barrier permits the translocation of microbial products and inflammatory mediators into the circulation, beginning systemic inflammation that disrupts the BBB and exacerbates neuronal damage. Furthermore, gut microbiota dysbiosis and altered gut microbial metabolite synthesis, such as short-chain fatty acids (SCFAs), can impact neuronal signaling and cognitive processes. By delineating these pathways, this study seeks to provide a comprehensive knowledge of the intricate interplay between intestinal I/R injury, BBB integrity, and cognitive function, opening the way for potential therapeutic approaches.

Keywords:  blood–brain barrier; cognitive dysfunction; gut microbial metabolites; gut microbiota dysbiosis; intestinal ischemia–reperfusion injury; systemic inflammation

DOI:  https://doi.org/10.3389/fnins.2025.1597170
J Neurochem. 2025 Aug;169(8): e70172

Differential Regulation of Proteins Related to the Blood-Brain Barrier in Stress-Resilient and Stress-Susceptible Mice.

Joanna Solich, Agata Faron-Górecka, Magdalena Kolasa, Paulina Pabian, Agata Korlatowicz-Pasieka, Marta Dziedzicka-Wasylewska.

  Stress is considered a primary contributor to mood disorders, such as depression. Therefore, preclinical research encompasses the biochemical and molecular aspects of stress. In the present study, we investigated the effects of restraint stress (RS) on three strains of mice with varying susceptibility to RS: transgenic mice lacking the gene encoding the noradrenergic transporter (NET-KO) and Swiss SWR/J, both displaying a stress-resilient phenotype, and C57Bl/6J (WT), which is stress-susceptible. In silico analysis of a group of microRNAs (miRNAs) differentiating these phenotypes indicated that their target mRNAs encode various proteins that are involved in maintaining the integrity of the blood-brain barrier (BBB). Further analyses using Custom TaqMan Gene Expression Array Cards revealed alterations in these mRNAs in four brain regions of mice subjected to RS. Protein levels were examined with immunohistofluorescence and indicated changes in the levels of two key proteins, claudin-5 (CLDN5) and caveolin-1 (CAV1), and their co-localization with the endothelial cell marker CD31 protein. Additionally, we used fluorescein sodium salt to examine BBB permeability in the mouse strains and found higher permeability in stress-susceptible animals. The most intriguing finding was the differential expression of Cav1 mRNA and protein levels in the brain regions of stress-resilient mice compared to the stress-susceptible strain. This suggests that CAV1 may play an important role in the BBB of stress-resilient individuals under stress conditions.

Keywords:  blood–brain barrier; mRNA; mice; permeability; proteins; resilience; stress

DOI:  https://doi.org/10.1111/jnc.70172
Neurotoxicology. 2025 Jul 23. pii: S0161-813X(25)00097-X. [Epub ahead of print]

Kisspeptin-10 Protects Against HIV-1 Tat-Induced Blood-Brain Barrier Dysfunction and Neuroinflammation via RhoA/ROCK Pathway: Implications for HAND Therapy.

Chao Cheng, Dong Xiong, Fengwei Zheng, Tianze Wang, Weixin Li.

  This study investigated the effects of Kisspeptin-10 (Kp-10) on HIV-1 Tat-induced blood-brain barrier (BBB) permeability and oxidative stress using both in vivo and in vitro models. In vivo, one hour after intraperitoneal administration of 50 nmol/kg (DSS)*6-Kp-10, mice were intravenously injected with HIV-1 Tat (100μg/kg). Markers of oxidative stress, inflammatory cytokines, and BBB integrity were then evaluated. In vitro, bEnd.3 cells were treated with HIV-1 Tat and Kp-10, and endothelial permeability, Claudin-5 expression, and RhoA/ROCK signaling were assessed. HIV-1 Tat increased oxidative stress in the cortical tissue of mice, as evidenced by elevated malondialdehyde (MDA) and reduced levels of catalase (CAT) activity, glutathione peroxidase (GSH-Px) activity, and total antioxidant capacity (T-AOC). These effects were attenuated by Kp-10 administration. Additionally, Kp-10 suppressed the expression of pro-inflammatory cytokines, including interleukin-6 (IL-6), monocyte chemoattractant protein-1 (MCP-1), and tumor necrosis factor-alpha (TNF-α), in response to HIV-1 Tat. Notably, Kp-10 mitigated HIV-1 Tat-induced BBB dysfunction by upregulating Claudin-5 expression in the cortical tissue of mice. In vitro, bEnd.3 cells were treated with HIV-1 Tat in the presence of Kp-10 at various concentrations. Our results demonstrated that Kp-10 prevented HIV-1 Tat-induced increases in trans-endothelial permeability and reductions in transepithelial electrical resistance (TEER) by upregulating Claudin-5 expression. Furthermore, Kp-10 inhibited the activation of the RhoA/Rho-associated protein kinase (RhoA/ROCK) signaling pathway in bEnd.3 cells. Overexpression of the RhoA-GTP Q63L mutant abolished the protective effects of Kp-10, suggesting that these effects are mediated through the RhoA/ROCK axis. These findings suggest that Kp-10 might be a potential therapeutic agent for HIV-associated neurocognitive disorders (HAND).

Keywords:  Claudin-5; HIV-1 transactivator protein; Kisspeptin-10; RhoA; blood-brain barrier

DOI:  https://doi.org/10.1016/j.neuro.2025.07.008
Front Neurol. 2025 ;16 1615883

Emerging biomarkers and frontier therapies: unveiling the role of endothelial dysfunction in cerebral small vessel disease.

Kedi Sun, Hui Liu.

  Cerebral small vessel disease (cSVD), a major contributor to stroke, cognitive decline, and vascular dementia, accounts for around 25% of ischemic strokes and significantly impacts age-related neurological disability. Despite its clinical significance, the underlying mechanisms of cSVD remain incompletely understood, and therapeutic options are limited. Mounting evidence has pinpointed endothelial dysfunction as a central driver in cSVD pathogenesis, which disrupts blood-brain barrier (BBB) integrity, impairs cerebral blood flow autoregulation, and promotes neuroinflammation. The vascular endothelium, serving as a dynamic interface between blood and brain parenchyma, plays a crucial role in maintaining vascular homeostasis through functions like nitric oxide (NO)-mediated vasodilation, anti-thrombotic signaling, and immune regulation. In cSVD, chronic endothelial injury triggered by factors such as hypertension, oxidative stress, or genetic predisposition leads to microvascular rarefaction, pericyte loss, and gliosis, ultimately resulting in characteristic manifestations like white matter hyperintensities, lacunar infarcts, and cerebral microbleeds. Our review stands out by comprehensively integrating the latest research on emerging biomarkers and frontier therapeutic strategies specifically related to the cSVD-endothelium interplay. Recent breakthroughs in biomarker discovery, including novel circulating endothelial microparticles subtypes and advanced neuroimaging-derived biomarkers, offer unprecedented insights into endothelial health in cSVD. These biomarkers not only aid in early diagnosis but also enable more accurate risk stratification and monitoring of therapeutic responses. Concurrently, this review delves into the latest preclinical and clinical trial progress of innovative therapeutic strategies targeting endothelial repair. By bridging mechanistic insights with clinical translation, this review aims to highlight novel pathways for early intervention and personalized management of cSVD, thereby advancing the field beyond previous reviews that mainly focused on established knowledge. Relevant studies were retrieved from databases such as PubMed and Web of Science, covering the period up to 2025, to synthesize the latest evidence on endothelial dysfunction in cSVD. This review not only synthesizes current knowledge on endothelial dysfunction in cSVD but also critically evaluates the diagnostic and prognostic utility of emerging endothelial biomarkers and discusses recent therapeutic innovations, providing a more forward-looking perspective for researchers and clinicians.

Keywords:  blood–brain barrier; cerebral small vessel disease (CSVD); emerging biomarkers; endothelial cells (ECs); endothelial dysfunction

DOI:  https://doi.org/10.3389/fneur.2025.1615883
Brain Res Bull. 2025 Jul 24. pii: S0361-9230(25)00291-6. [Epub ahead of print]229 111479

Sevoflurane reduces brain edema and improves blood-brain barrier by downregulating CaMKII to inhibit TMEM16A after cerebral ischemia injury both in vivo and in vitro.

Jingbin Zhang, Yuhe Tian, Ruixue Wang, Xinlei Qin, Quntao Li, Ketao Ma, Junqiang Si, Dong Zhao, Yan Li, Jiangwen Yin.

  This study aimed to investigate whether sevoflurane could reduce brain edema and protect blood-brain barrier (BBB) after cerebral-ischemia injury in vivo and in vitro via calmodulin-dependent protein kinase II (CaMKII)/ transmembrane protein 16A (TMEM16A) pathway. Adult male Sprague-Dawley rats and the brain slices were respectively subjected to middle cerebral artery occlusion (MCAO) in vivo and oxygen-glucose deprivation (OGD) in vitro. Sevoflurane was intervened through a combination of pre-treatment and post-treatment in entire process. TMEM16A overexpression and knockdown was performed by adeno-associated virus. And using agonist and inhibitor affected CaMKII. Neurologic function, ultrastructure, brain water content and the integrity of blood-brain barrier were assessed. Protein levels were investigated by immunofluorescence and western blot. TMEM16A and AQP4 levels, brain water content, leakage of BBB increased in MCAO group. Claudin5 and ZO-1 levels decreased and neurological damage was aggravated after MCAO injury. Sevoflurane reduced brain edema, improved neurological function and protected BBB after MCAO by increasing Claudin5 and ZO-1 levels and decreasing TMEM16A and AQP4 levels. The effect of sevoflurane was weakened by overexpression of TMEM16A and enhanced by knockout of its expression. And when using the inhibitor KN-93, CaMKII level increased while TMEM16A level decreased, enhancing the neuroprotective effect of sevoflurane. Conversely, the effect of sevoflurane was weakened after using the agonist CALP1. Similarly, these manifestations were also observed after OGD injury. In brief, our findings suggest sevoflurane could reduce brain edema, and protect the BBB after cerebral ischemia-reperfusion injury which are related to the downregulation of CaMKII to inhibit TMEM16A.

Keywords:  blood-brain barrier; brain edema; calmodulin-dependent protein kinase II; cerebral ischemia; sevoflurane; transmembrane protein 16 A

DOI:  https://doi.org/10.1016/j.brainresbull.2025.111479
Front Neurol. 2025 ;16 1617126

Meningeal enhancement following traumatic brain injury: a mini review.

Alejandro Arbona-Lampaya, Alejandro Odeh-Couvertier, Ricardo Sánchez Jiménez, Eduardo Labat Álvarez.

  Traumatic brain injury (TBI) is a significant cause of neurological morbidity, often leading to blood-brain barrier (BBB) dysfunction and secondary injury mechanisms. Recent advancements in neuroimaging have highlighted traumatic meningeal enhancement (TME) on contrast-enhanced fluid-attenuated inversion recovery (FLAIR) MRI as a promising biomarker for detecting BBB disruption following TBI. TME, which is hypothesized to arise from vascular injury and inflammatory cascades that compromise the blood-meningeal barrier, has been associated with both acute trauma and long-term neurovascular dysfunction. Its presence, particularly when linked to subdural hematomas and delayed contrast extravasation, not only reflects the immediate severity of the injury but may also indicate chronic neuroinflammatory processes and persistent cognitive deficits. In this review, we gather current evidence on the pathophysiology of TME including its associations with vascular permeability, subdural hematoma, and prolonged inflammatory responses. We explore its potential as a biomarker for injury severity and prognosis in TBI patients. Finally, we further discuss the critical need for standardized imaging protocols and longitudinal studies to determine the clinical implications of persistent TME.

Keywords:  blood–brain barrier disruption; imaging biomarkers; subdural hematoma; traumatic brain injury; traumatic meningeal enhancement

DOI:  https://doi.org/10.3389/fneur.2025.1617126
Brain Behav Immun. 2025 Jul 28. pii: S0889-1591(25)00294-6. [Epub ahead of print]129 960-974

IRF7 in peripheral monocytes drives BBB disruption in anti-NMDAR encephalitis.

Qihui Li, Li Xiao, Jianfang Li, Yu Huang, Shishi Shen, Huilu Li, Fuhua Peng, Huichang He, Shen Huang, Jian Sun, Wei Qiu, Wei Cai, Yaqing Shu.

  Anti-N-methyl-D-aspartate receptor (NMDAR) encephalitis is a severe neurological disorder characterized by the presence of autoantibodies against the NMDAR and blood-brain barrier (BBB) disruption. This study investigates the involvement of monocytes and interferon regulatory factor 7 (IRF7) in BBB leakage of this disease. In anti-NMDAR encephalitis patients, the circulating monocytes count was positively correlated with BBB disruption, besides, IRF7 was activated in these cells. In peripheral blood and brain of our anti-NMDAR encephalitis mouse model, increased monocytes and elevated IRF7 expression within these cells were found. Additionally, in the blood and brain of this model, the quantity of monocytes and their IRF7 expression level were positively correlated with behavioral deficits. IRF7-KO mice were subjected to anti-NMDAR encephalitis modeling and exhibited milder disease severity and reduced BBB disruption compared to their WT counterparts. Bone marrow derived macrophages (BMDMs) from IRF7-KO mice showed diminished capacity to disrupt BBB compared with BMDMs from WT mice in in vitro study. Our findings suggest that IRF7 plays a critical role in the pathogenesis of anti-NMDAR encephalitis by modulating monocyte's capacity to disrupt BBB. Targeting IRF7 may offer a novel therapeutic strategy for this devastating neurological condition.

Keywords:  Anti-NMDAR encephalitis; Blood-brain barrier; Interferon regulatory factor 7; Monocytes; Neuroinflammation

DOI:  https://doi.org/10.1016/j.bbi.2025.07.026
J Dev Orig Health Dis. 2025 Aug 01. 16 e30

Restricted fetal blood brain barrier permeability in a preclinical model of autism induced by Group B Streptococcus maternal immune activation.

Margaux Digonnet, Mathilde Chevin, Nadia Alfaidy, Tiphaine Raia-Barjat, Antoine Giraud, Guillaume Sébire.

  Clinical and preclinical data about perinatal inflammation show its implication in brain injuries leading to autism spectrum disorder (ASD). For instance, Group B Streptococcus (GBS) chorioamnionitis generates autistic manifestations in the progeny. However, the precise way(s) how chorioamnionitis exerts its noxious effect on the central nervous system remains to be define. The pathogen-induced inflammatory response effects on the permeability of the blood brain barrier (BBB) have been documented in the mature brain. No study deals with the effect of GBS-induced chorioamnionitis, on the fetal BBB, even though it is one of the most common infection affecting the fetal environment. Given that dysfunctions of several key cells and molecules from the BBB seem to be involved in the pathogenesis of ASD from genetic and/or environmental origins, we hypothesized that pathogen-induced chorioamnionitis affects structurally and functionally the BBB. We used a well-established preclinical model of GBS chorioamnionitis leading to ASD phenotype in male offspring. We document a significant decrease of albumin permeability of the BBB in the white and gray matters of fetuses exposed versus unexposed to GBS chorioamnionitis. In line with this result, a significant increase in the expression of claudin-5 - component of tight junctions of the BBB - is detected in endothelial cells from BBB exposed to chorioamnionitis. Altogether, our results show that beyond genetic determinants, environmental factors such as bacterial infections affect the integrity of the BBB and might be involved in the fetal programming of ASD.

Keywords:  ASD; BBB; GBS; chorioamnionitis; claudin-5

DOI:  https://doi.org/10.1017/S2040174425100147
Front Aging Neurosci. 2025 ;17 1623050

Elucidating molecular pathogenesis and developing targeted therapeutic interventions for cerebrovascular endothelial cell-mediated vascular dementia.

Yanrong Yang, Hua Chen, Qibing Liu, Yang Niu, Chunyang Mao, Rui Wang.

  Vascular dementia (VaD) ranks as the second most prevalent subtype of dementia, surpassed only by Alzheimer's disease (AD). The maintenance of neurological function and cerebral homeostasis critically depends on precisely regulated blood flow within the intricately organized cerebrovascular network. Disruptions in cerebral hemodynamics may impair neurovascular homeostasis, thereby inducing pathophysiological cascades characterized by oxidative stress, neuroinflammation, and neuronal degeneration. Emerging evidence identifies cerebrovascular dysregulation and impaired neurovascular coupling (NVC) as primary pathogenic mechanisms underlying VaD, emphasizing the necessity to elucidate their complex interplay. Cerebrovascular endothelial cells exhibit remarkable heterogeneity, serving dual roles as both architectural components of the blood-brain barrier (BBB) and functional regulators of NVC. Furthermore, pericytes residing abluminal on capillary endothelia demonstrate critical involvement in hemodynamic modulation through contractile regulation of microvascular tone, while concurrently maintaining BBB integrity through dynamic paracrine signaling. This study examines cerebrovascular endothelial-neuronal interactions within the neurovascular unit (NVU) framework, analyzing their bidirectional regulatory mechanisms and therapeutic potential in cognitive dysfunction remediation. The pathophysiological progression of VaD manifests through multiple interdependent pathways, including cerebral hypoperfusion, oxidative stress cascades, neuroinflammatory responses, mitochondrial dysregulation, and electrolyte homeostasis perturbations. Through three interventional axes: (1) BBB fortification strategies; (2) cerebral hemodynamic optimization and NVC enhancement; (3) nanotherapeutic platforms integrating endothelial-specific molecular targets we systematically evaluate endothelial-centric therapeutic paradigms. This multi-modal approach proposes novel mechanistic insights and clinical translation frameworks for VaD management.

Keywords:  cerebrovascular endothelial cells; molecular mechanisms; neurovascular coupling; treatment and strategy; vascular dementia

DOI:  https://doi.org/10.3389/fnagi.2025.1623050
J Cardiovasc Aging. 2025 Jun;pii: 13. [Epub ahead of print]5(2):

Impact of Myocardial Infarction on Cerebral Homeostasis: Exploring the Protective Role of Estrogen.

Lana El-Samadi, Rana Zahreddine, Joanna A Ziade, Alaa El Ghawi, Ghadir Amin, George W Booz, Fouad A Zouein.

  Myocardial infarction (MI), commonly known as a heart attack, results from the rupture of atherosclerotic plaques in coronary arteries, which triggers a series of pathological events including cardiomyocyte death, thrombus formation, and systemic inflammation. These pathological events lead to significant structural and functional changes in the heart, potentially precipitating heart failure. The ramifications of MI extend beyond cardiac dysfunction and impact cerebral health. Accordingly, this review examines the cerebral implications of MI, focusing on how systemic inflammation and reduced cardiac output post-MI affect cerebral blood flow (CBF) and brain function. MI-induced changes in cardiac output can lead to cerebral hypoperfusion, while neuroinflammation and increased blood-brain barrier (BBB) permeability contribute to cognitive decline and neuronal damage, with potential links to Alzheimer's disease (AD). Furthermore, the review explores the role of estrogen in modulating cardiovascular and cerebral health, particularly in post-menopausal women who exhibit distinct cardiovascular risk profiles. Estrogen protects the heart by regulating local renin-angiotensin-aldosterone systems (RAAS) and has significant impacts on brain function. Declining estrogen levels during menopause exacerbate neuroinflammation and cognitive deficits, highlighting the importance of estrogen in maintaining cerebrovascular function. Experimental studies on estrogen replacement therapies, including 17β-estradiol and selective estrogen receptor modulators (SERMs), show potential in mitigating these detrimental effects, enhancing neurogenesis, and improving cognitive outcomes. Estrogen therapy is crucial in preventing cognitive decline and reducing amyloid plaque formation in Alzheimer's models. This review underscores the potential benefits of estrogen therapy in promoting brain recovery post-MI and improving functional outcomes.

Keywords:  17β-estradiol; AD; MI; blood-brain barrier; cerebral hypoperfusion; cognitive decline; heart failure; inflammation; menopause

DOI:  https://doi.org/10.20517/jca.2025.02
Curr Opin Infect Dis. 2025 Jul 22.

Pathogenesis of brain injury in cerebral malaria: emerging mechanisms and implications for intervention.

Dibyadyuti Datta, Chandy C John.

   PURPOSE OF REVIEW: Cerebral malaria (CM) in children has high mortality and leads to substantial long-term cognitive impairment. We review recent advances in defining the pathogenesis of brain injury in pediatric cerebral malaria.
RECENT FINDINGS: The cascade of events leading to brain injury in pediatric CM includes blood-brain barrier (BBB) impairment due to local hypoxemia, ischemia, and endothelial activation after sequestration of infected erythrocytes; and oxidative stress after release of free heme. Tumor necrosis factor alpha (TNF-α), reactive oxygen species, CD8+ T cells and parasite toxins can then cross the impaired BBB and through activation of central nervous system immune responses and direct cytotoxicity lead to neuronal injury. Acute kidney injury and hyperuricemia may worsen BBB impairment and cerebral edema. Cytotoxic or vasogenic edema, abnormal blood flow states, and increased microvascular hemoglobin are present in pediatric CM, but their relationship to brain injury is not yet fully defined.
SUMMARY: New studies of CM in children, including neuroimaging and electrophysiology studies, along with novel in vitro BBB model studies and ongoing experimental CM studies, show promise in improving our understanding of brain injury in CM and identifying interventions to decrease this injury.

Keywords:  brain injury; cerebral malaria; children; neuronal injury; pathogenesis

DOI:  https://doi.org/10.1097/QCO.0000000000001133
Stem Cells. 2025 Jul 30. pii: sxaf055. [Epub ahead of print]

Brain pericytes derived from human pluripotent stem cells retain vascular and phagocytic functions under hypoxia.

Mingzi Zhang, Youbin Kim, Allison Bosworth, Julia T C W, Lina R Nih, Kassandra Kisler, Abhay P Sagare, Ruslan Rust.

  The integrity and function of the blood-brain barrier (BBB) are largely regulated by pericytes. Pericyte deficiency leads to BBB breakdown and neurological dysfunction in major neurological disorders including stroke and Alzheimer's disease (AD). Transplantation of pericytes derived from induced pluripotent stem cells (iPSC-PC) has been shown to restore the BBB and improve functional recovery in mouse models of stroke and pericyte deficiency. However, the molecular profile and functional properties of iPSC-PC under hypoxic conditions, similar to those found in ischemic and neurodegenerative diseases remain largely unexplored. Here, we demonstrate that iPSC-PC under severe hypoxia retain essential functional properties, including key molecular markers, proliferation rates, and the ability to migrate to host brain vessels via function-associated PDGFRB-PDGF-BB signaling. Additionally, we show that iPSC-PC exhibit similar clearance of amyloid beta (Aβ) neurotoxins from AD mouse brain sections under both normoxic and hypoxic conditions. These findings suggest that iPSC-PC functions are largely resilient to hypoxia, highlighting their potential as a promising cell source for treating ischemic and neurodegenerative disorders.

Keywords:  Cell therapy; ischemia,s stroke; mural cells; neurodegeneration

DOI:  https://doi.org/10.1093/stmcls/sxaf055
Stem Cell Rev Rep. 2025 Jul 31.

Umbilical Cord Blood Endothelial Progenitor Cells Modulate Neurovascular Unit Damage in a Neonatal Rat Model of Hypoxia Ischemia.

Tayla R Penny, Yen Pham, Amy E Sutherland, Graham Jenkin, Tamara Yawno, Suzanne L Miller, Courtney A McDonald.

   INTRODUCTION: Neonatal hypoxia ischemia (HI) causes injury to the blood brain barrier (BBB), which in turn is associated with widespread cell loss. Cell therapies are currently being investigated for use in perinatal neuroprotection and umbilical cord blood (UCB) endothelial progenitor cells (EPCs; CD133+) have been previously shown to reduce gross neuropathology associated with HI; however, no study has investigated the effect of EPC treatment on the vulnerable BBB. Therefore, in this study, we investigated the effect of EPC treatment on BBB integrity in a neonatal rat model of HI.
METHODS: HI brain injury was induced in postnatal day (PND) 7 rat pups via permanent ligation of the left carotid artery, followed by a 180-minute hypoxic challenge at 8% O2. At 24 h post-insult, 2 × 105 EPCs were administered via intraperitoneal injection. At 7 days post-HI, brains and choroid plexuses were collected for immunohistochemistry or molecular analyses.
RESULTS: Neonatal HI resulted in neuropathology, with a significant increase in left hemisphere tissue loss. This was associated with microglial activation, astrogliosis and increased expression of Aquaporin 4 in the somatosensory cortex, and EPC administration significantly reduced these outcomes. Assessment of the BBB revealed GLUT1 and claudin-5 expression were significantly increased in HI animals compared to sham, and treatment with EPCs reduced these to sham control levels.
CONCLUSION: EPCs are a promising treatment option for neonatal HI as they modulate BBB changes. However, further studies are needed to understand early effects of EPC treatment and how EPC therapy modulates BBB dysfunction post HI brain injury.

Keywords:  Cell therapy; Cerebral palsy; Neuroprotection; Perinatal brain injury; Stem cells

DOI:  https://doi.org/10.1007/s12015-025-10939-z
Mol Neurobiol. 2025 Aug 01.

Obesity and Cognitive Function: Leptin Role Through Blood-Brain Barrier and Hippocampus.

Ebtesam Abdullah Al-Suhaimi, Abdullah A AlRubaish, Hanan A Aldossary, Mohamed A Homeida, Adeeb Shehzad, Abdelgadir M Homeida.

  The signal transduction and communication between adipose tissue-secreted adipokines and the central nervous system (CNS) are increasingly recognized for their role in metabolic and neurological regulation. This crosstalk contributes to the vulnerability of individuals with obesity to developing cognitive impairment. However, the detailed underlying molecular mechanisms through which obesity-induced peripheral changes influence blood-brain barrier (BBB) and CNS function remain under investigation. Among the key mediators of this interaction are signaling molecules (adipokines) secreted by white adipose tissue that regulate various physiological processes, including energy homeostasis, neural integrity, and immune responses. Obesity is associated with dysregulated leptin secretion due to adipose tissue dysfunction, contributing to metabolic abnormalities and hippocampal synaptic disturbances-factors that increase the risk of comorbid conditions, cognitive decline, and neurodegenerative disorders such as Alzheimer's disease. Additionally, obesity increases inflammatory molecules such as RAGE, LRP1, cytokines (IL-6 and TNF-α), leptin, insulin, and free fatty acids, which perturb amyloid-β degradation and promote accumulation in the brain while impairing brain-to-blood clearance. An electronic search was performed using Web of Science, Scopus, and PubMed to collect English-language articles published from 2010 to 2025 related to the role of leptin in obesity and neurodegenerative diseases. This study underpins recent literature on the mechanisms by which obesity-induced modulation of leptin signaling impacts cognitive decline, BBB dysfunction, and the pathogenesis of Alzheimer's disease. Thus, understanding leptin-driven mechanisms and developing targeted strategies, including leptin sensitization and BBB-protective interventions, could serve as effective therapeutic approaches to managing cognitive impairment associated with obesity.

Keywords:  Blood–brain barrier; Cognitive; Hippocampal; Leptin; Neuroinflammation; Obesity

DOI:  https://doi.org/10.1007/s12035-025-05262-0
Histol Histopathol. 2025 Jul 16. 18968

Mechanism of the protective effect of 2,3,5,4'-Tetrahydroxy stilbene-2-O-β-D-glucoside on MPTP-induced Parkinson's disease mice.

Gang Wu, Xiaolin Dong, Qingyun Li, Yanping Li, Furong Jin, Jingting Lu, Chengda Han, Lianbing Lin.

BACKGROUND AND PURPOSE: Parkinson's disease (PD) is a common neurodegenerative disorder with a complex pathogenesis. 2,3,5,4'-Tetrahydroxy stilbene-2-O-β-D-glucoside (TSG) is one of the main active components of Polygonum multiflorum Thunb., which has therapeutic effects in various neurodegenerative diseases. The aim of this study was to explore the influence of TSG on the PD process.
METHODS: The PD mouse model was constructed via the use of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). The PD process was evaluated via behavioral tests, HE staining, immunohistochemistry, and immunofluorescence. The levels of related proteins and inflammatory factors were detected via western blotting and ELISA. The effect of TSG on the intestinal flora of MPTP-induced PD mice was evaluated through 16S rDNA sequencing.
RESULTS: TSG intervention can significantly alleviate motor dysfunction in PD mice, increase the number of TH-positive neurons in the substantia nigra, inhibit the accumulation of α-syn and glial cell activation, reduce the expression of the tumor necrosis factor-α (TNF-α), interleukin (IL)-1β, IL-6, iNOS, and COX2 proteins in the substantia nigra and colon, inhibit neuroinflammation and intestinal inflammation, decrease the levels of LPS, LBP, TNF-α, IL-1β, and IL-6 in the serum, suppress systemic inflammation, reduce damage to the blood-brain barrier (BBB) and intestinal barrier in PD mice, and restore species diversity and abundance of the intestinal flora in PD mice to a certain extent.
CONCLUSION: TSG can improve motor coordination ability, systemic and neuroinflammatory levels, BBB injury, intestinal barrier injury, and the intestinal flora composition of PD mice, suggesting that TSG has a protective effect on MPTP-induced PD mice.

DOI: https://doi.org/10.14670/HH-18-968
Ageing Res Rev. 2025 Jul 25. pii: S1568-1637(25)00190-4. [Epub ahead of print]111 102844

Sphk2 in ischemic stroke pathogenesis: Roles, mechanisms, and regulation strategies.

Mengzhao Feng, Qi Qin, Kaiyuan Zhang, Fang Wang, Dengpan Song, Mengyuan Li, Yuan An, Zhihua Li, Fuyou Guo.

  Ischemic stroke, a leading cause of mortality and long-term disability worldwide, is characterized by acute cerebral artery occlusion leading to neuronal death and functional deficits. Despite advances in reperfusion therapies, the lack of effective neuroprotective agents underscores the need for novel therapeutic strategies targeting secondary injury mechanisms. Sphingosine kinase 2 (Sphk2) has emerged as a pivotal regulator in ischemic stroke pathogenesis, mitigating blood-brain barrier leakage, neuroinflammation, and neuronal survival through its downstream metabolite, sphingosine-1-phosphate. This review comprehensively examines the roles and mechanisms of Sphk2 in ischemic stroke, highlighting its potential in anti-inflammation and neuroprotection. We discuss current therapeutic approaches targeting Sphk2, including pharmacological activation, natural compounds and gene therapy. Future directions focus on developing Sphk2-specific agonists, optimizing delivery strategies, and exploring cell type-specific adeno-associated virus vectors and engineered exosomes modulation to maximize therapeutic efficacy while minimizing off-target effects. By synthesizing current knowledge and identifying gaps, this review provides a roadmap for harnessing Sphk2 as a therapeutic target to improve stroke outcomes.

Keywords:  Adeno-associated virus; Blood-brain barrier; Nanotechnology; Neuroinflammation; Sphingosine kinase 2; Sphingosine-1-phosphate; Stroke

DOI:  https://doi.org/10.1016/j.arr.2025.102844
Biology (Basel). 2025 Jun 23. pii: 749. [Epub ahead of print]14(7):

Multi-Faceted Role of Histone Methyltransferase Enhancer of Zeste 2 (EZH2) in Neuroinflammation and Emerging Targeting Options.

Sotirios Moraitis, Christina Piperi.

  Neuroinflammation, a complex nervous system response to brain injury and other pathological stimuli, exhibits a common denominator role in the pathogenesis of neurological disorders and their progression. Among several regulators of neuroinflammation, epigenetic mechanisms with particular emphasis on histone methylation have a prominent role by altering the expression of specific genes involved in the onset and progression of neuroinflammation. The Enhancer of Zeste 2 (EZH2) histone lysine methyltransferase is a multi-faceted and context-dependent regulator of immune response and neural cell function, significantly involved in the underlying mechanisms of neuroinflammation, such as inflammatory gene expression, astrocyte function, microglial activation, BBB integrity, and interactions with non-coding RNAs. Herein, we explore the intricate implication of EZH2 activity in the onset of neuroinflammation and associated pathological conditions, and discuss its potential as a therapeutic target. Currently available EZH2 inhibitors with neuroprotective effects are also addressed in an effort to reveal novel strategies for managing neuroinflammatory conditions, and potentially improving neurological health.

Keywords:  DZNep; EPZ-6438; EZH2 inhibitors; H3K27me3; epigenetic; histone methylation; neuroinflammation

DOI:  https://doi.org/10.3390/biology14070749