bims-blobar Biomed News
on Blood brain barrier repair
Issue of 2025–07–06
sixteen papers selected by
Nicolas Rebergue
  1. Group II metabotropic glutamate receptors modulate blood brain barrier function: direct and indirect effect through astrocytes and microglia.
  2. Rosmarinic acid attenuates blood-brain barrier dysfunction to improve cerebral ischemia/reperfusion injury in mice.
  3. Mechanism of Endothelial Cell Death in Cerebral Ischemic Stroke and Application of Protective Drugs.
  4. Effect of experimental hypoosmolar hyponatremia on the blood brain barrier and brain edema formation.
  5. ALDH2 Attenuates Blood-Brain Barrier Injury Induced by Cerebral Ischemia/Reperfusion via Alleviating ROS/NLRP3 Inflammasome Axis.
  6. Comprehensive immune ageing reveals TREM2/TIM3 myeloid cells drive brain immune evasion.
  7. Exosomal miR-24-3p participates in the progression of depression by regulating neuronal damage and blood-brain barrier dysfunction.
  8. MSCs engineered with secreted Klotho alleviate blood-brain barrier disruption and reduce neuroinflammation more effectively than MSCs in experimental autoimmune encephalomyelitis.
  9. Beyond Reperfusion: Adjunctive Therapies Targeting Inflammation, Edema, and BBB Dysfunction in Ischemic Stroke.
  10. Tryptophan-Rich Diet Improves High-Fat Diet-Induced Cognitive Dysfunction and Blood-Brain Barrier Disruption in C57BL/6 Mice through FFAR3 Activation.
  11. NR4A2 attenuates early brain injury after intracerebral hemorrhage by promoting M2 microglial polarization via TLR4/TRAF6/NF-κB pathway inhibition.
  12. 3BTRON: A Blood-Brain Barrier Recognition Network.
  13. The anti-depressive role of the Pei Yuan Kai Yu formula in cerebral small vessel disease based on gut microbiota.
  14. Blood‑brain barrier dysfunction in epilepsy: Mechanisms, therapeutic strategies and future orientation (Review).
  15. Retraction: ErbB4 preserves blood-brain barrier integrity via the YAP/PIK3CB pathway after subarachnoid haemorrhage in rats.
  16. Hypoxia preconditioned MSC exosomes attenuate high-altitude cerebral edema via the miR-125a-5p/RTEF-1 axis to protect vascular endothelial cells.
  1. Eur J Pharmacol. 2025 Jul 01. pii: S0014-2999(25)00647-8. [Epub ahead of print]1003 177893
    Group II metabotropic glutamate receptors modulate blood brain barrier function: direct and indirect effect through astrocytes and microglia.
    Giuseppe Costantino, Sara Merlo, Giorgia Serena Gullotta, Filippo Caraci, Ferdinando Nicoletti, Maria Angela Sortino, Simona Federica Spampinato.
      To keep brain homeostasis, the highly specialized endothelial cells that constitute the blood-brain barrier (BBB) are also supported by astrocytes and microglia. Glial influence on barrier properties may be controversial in inflammatory conditions as they can either stabilize or compromise BBB functions. The role played by metabotropic glutamate (mGlu) receptors 2 and 3 on BBB properties in inflammatory conditions has not been investigated, and we analyzed whether these receptors represent potential pharmacological targets. We used an in vitro BBB model, where human derived microvascular endothelial cells (TY-10) were cultured either alone or co-cultured with astrocytes (hAST) or in a triple co-culture with astrocytes and microglia (HMC3 cells). Barrier properties were assessed by evaluating transendothelial electrical resistance (TEER), barrier permeability, endothelial expression of junctional proteins and gene expression of inflammatory cytokines and chemokines. Tumor necrosis factor (TNF)α and Interferon (IFN)γ (T&I; 1 ng/ml each) were applied as an inflammatory stimulus in the presence of the mGlu2/3 receptors agonist, LY379268 and the mGlu2 receptor negative allosteric modulator, VU6001966. T&I impaired barrier properties in all experimental settings. In the monoculture model, T&I effect was only slightly counteracted by LY379268 that, instead, prevented T&I effects both in the endothelial/astrocytes co-cultures and in the triple-co-cultures. However, only in the presence of microglia VU6001966 significantly reduced LY379268 effect. Accordingly, LY379268 dampened T&I-induced expression of inflammatory cytokines in microglia cells, and again, co-treatment with VU6001966 contrasted this action. Thus, activation of mGlu2 and mGlu3 receptors preserves BBB functions acting directly on endothelial cells and contrasting the inflammatory response of astrocytes and microglia.
    Keywords:  Blood brain barrier; Cytokines; Microglia; Permeability; Tight junctions; mGlu receptors
    DOI:  https://doi.org/10.1016/j.ejphar.2025.177893
  2. Eur J Pharmacol. 2025 Jul 01. pii: S0014-2999(25)00636-3. [Epub ahead of print]1003 177882
    Rosmarinic acid attenuates blood-brain barrier dysfunction to improve cerebral ischemia/reperfusion injury in mice.
    Chao Guo, Jianbo Li, Yucheng Liao, Ying Yin, Zhongying Ma, Shan Liang, Wei Quan, Jingwen Wang.
       BACKGROUND: Cerebral ischemia/reperfusion (CI/R) has detrimental effects in cases of ischemic stroke. This notably triggers the blood-brain-barrier (BBB) to break. Known for its ability to provide neuroprotective benefits, rosmarinic acid (RosA) is a phenolic acid compound in the Lamiaceae family of plants. However, the relevance between the neuroprotective effect of RosA on CI/R and its direct protective effect on the BBB remains unclear. This study aimed to investigate how RosA regulates BBB integrity after CI/R injury and explore its underlying pharmacological mechanism in mice.
    METHODS: The mouse model of middle cerebral artery occlusion (MCAO) was established by subjecting the animals to 1 h of ischemia followed by a 24-h reperfusion period. Neurological scoring, infarct size, BBB permeability, histological examination, and biochemical parameters were subsequently assessed.
    RESULTS: Our study showed that RosA improved neurofunction and reduced infarct size by protecting BBB permeability, alleviating CI/R-induced neuronal loss and apoptosis. Molecular docking, molecular dynamics (MD) simulationand surface plasmon resonance (SPR) suggested that RosA may directly bind to matrix metalloproteinase-9 (MMP-9) and matrix metalloproteinase-2 (MMP-2). Furthermore, RosA significantly enhanced tight junction proteins, including zonula occludens-1 (ZO-1), occludin and claudin 5, while simultaneously decreasing the levels of MMP-9 and MMP-2 mRNA and proteins.
    CONCLUSION: Our findings reveal that RosA significantly mitigates CI/R-induced BBB disruption in middle cerebral artery occlusion (MCAO) mice by enhancing tight junction protein expression and down-regulating MMP-9 and MMP-2 levels.
    Keywords:  Blood-brain barrier; Cerebral ischemia/reperfusion; Molecular docking; Rosmarinic acid; Tight junction protein
    DOI:  https://doi.org/10.1016/j.ejphar.2025.177882
  3. Front Biosci (Landmark Ed). 2025 May 30. 30(6): 26034
    Mechanism of Endothelial Cell Death in Cerebral Ischemic Stroke and Application of Protective Drugs.
    Hongru Yi, Hui Huang, Qingwen Meng, Qibing Liu.
      Brain endothelial cells (BECs) are situated at the interface between the bloodstream and the brain, serving a crucial function in the development and maturation of the brain, particularly in upholding the integrity of the blood-brain barrier (BBB). Consequently, any modifications or gradual breakdown of the endothelium can significantly disrupt brain homeostasis. Ischemic stroke (IS), characterized by the progressive compromise of the BBB and increased BECs mortality, stands as a prominent global cause of mortality and disability. This review will utilize recent research to explore mechanisms underlying death.
    Keywords:  brain endothelial cells death; ischemic stroke; neuroprotective drugs
    DOI:  https://doi.org/10.31083/FBL26034
  4. Sci Rep. 2025 Jul 02. 15(1): 23361
    Effect of experimental hypoosmolar hyponatremia on the blood brain barrier and brain edema formation.
    Marta Aleksandrowicz, Przemysław Wencel, Mateusz Kciuk, Mariusz Popek, Łukasz Przykaza.
      The most frequent cause of hyponatremia is water retention due to the increase in blood levels of antidiuretic hormone (vasopressin, AVP). Hyponatremia is associated with neurological deficits, which are mainly linked to brain edema. Although the cytotoxic mechanism of brain edema in hyponatremia is commonly known, the role of a vasogenic mechanism is ambiguous. The present studies aimed to evaluate the effect of both acute and chronic hyponatremia on brain edema, blood-brain barrier (BBB) permeability, and mRNA expression of the tight junctions. Acute hyponatremia was induced for 5 h by subcutaneous (s.c.) injection of vasopressin or a synthetic analog of vasopressin-desmopressin (dDAVP) with intraperitoneal (i.p.) water loading in the amount of 11% body weight. Chronic hyponatremia was induced for 4 days with the help of AVP or dDAVP released continuously from subcutaneously implanted ALZET mini-osmotic pumps and a liquid diet. Because of the vascular action of vasopressin, either vasopressin or desmopressin was used to induce hyponatremia to assess whether the observed changes were characteristic of AVP-associated hyponatremia or hyponatremia alone. Brain water content was determined using the wet-dry method. BBB permeability was studied using sodium fluorescein. Gene expression of claudin-5, occludin, and zonula occludens (ZO-1) was assessed by real-time PCR (RT-PCR). Osmolarity, Na+, and Cl- concentrations were analyzed using the electrolyte and blood gas analyzer. Hypoosmotic acute hyponatremia led to increased brain water content and downregulation of tight junction gene expression, although leakage of the BBB was not observed. These results, except for the gene expression of claudin-5, were comparable in both groups with acute hyponatremia, regardless of whether AVP or dDAVP induced it. In chronic hyponatremia, irrespective of the mode of induction, there were no changes in the studied parameters. These results demonstrate a new insight into the nature of edema in acute hypoosmotic hyponatremia due to signs of vasogenic edema.
    Keywords:  BBB; Cytotoxic edema; Hyponatremia; Tight junctions; Vasogenic edema; Vasopressin
    DOI:  https://doi.org/10.1038/s41598-025-06320-2
  5. Neurochem Res. 2025 Jul 03. 50(4): 224
    ALDH2 Attenuates Blood-Brain Barrier Injury Induced by Cerebral Ischemia/Reperfusion via Alleviating ROS/NLRP3 Inflammasome Axis.
    Jie Gao, Liya Wang, Meng Qin, Yujiao Gao, Siyu Sun, Hao Wang, Qin Gao, Ying Yu.
      An important factor influencing the prognosis of ischemic stroke is impairment of the blood-brain barrier (BBB). Additionally, oxidative stress and inflammation contribute significantly to the breakdown of the BBB during ischemic stroke reperfusion. Strong evidence suggested that Aldehyde dehydrogenase 2 (ALDH2) may have protective properties and reduce oxidative stress and inflammatory reactions in neurological conditions. Therefore, in order to examine the impact of ALDH2 on BBB integrity after ischemia/reperfusion (I/R) damage, we constructed the cerebral artery occlusion/reperfusion (MCAO/R) model and the oxygen-glucose deprivation/reperfusion (OGD/R) model. According to our findings, ALDH2 activation enhanced cell viability in bEnd.3 cells treated with OGD/R and reduced infarct area and neurological impairments in MCAO/R animals. Furthermore, both in vitro and in vivo, ALDH2 suppressed inflammation-related factors IL-1β and IL-18, as well as oxidative stress and the expression of the NOD-like receptor thermal protein domain associated protein 3 (NLRP3) inflammasome. In addition, bEnd.3 cells exhibited a reduced reactive oxygen species (ROS) generation function of ALDH2. Moreover, we noticed that ALDH2 boosted the expression of the tight junctions (TJs) zonula occludens-1 (ZO-1) and Occludin to control BBB function. In summary, ALDH2 protected against cerebral I/R injury and BBB destruction, and this protection was related to the ROS/NLRP3 axis.
    Keywords:  ALDH2; Anti-inflammatory; Anti-oxidative stress; Blood-brain barrier; Cerebral ischemia/reperfusion
    DOI:  https://doi.org/10.1007/s11064-025-04472-1
  6. EBioMedicine. 2025 Jun 27. pii: S2352-3964(25)00277-4. [Epub ahead of print]118 105833
    Comprehensive immune ageing reveals TREM2/TIM3 myeloid cells drive brain immune evasion.
    Berta Segura-Collar, Lucia Mondejar-Ruescas, Denisse Alcivar-López, María Garranzo-Asensio, Pablo Mata-Martinez, Ramón Garcia-Escudero, Aurelio Hernández-Laín, Juan M Sepúlveda, Ángel Pérez Nuñez, Jesús Avila, Pilar Sánchez-Gómez, Ricardo Gargini.
       BACKGROUND: Ageing-dependent low-grade inflammation is a hallmark of central nervous system (CNS) diseases. Vascular and immune abnormalities are implicated in the progression of gliomas and occur in the early stages of Alzheimer's disease (AD); however, the mechanisms by which these alterations manifest in the brain parenchyma remain unclear.
    METHODS: Using RNAseq, scRNAseq, bioinformatics tools and a cohort of patients with glioma and Alzheimer's disease for validation of results, we have established an analysis of blood-brain barrier (BBB) dysfunction and neuron loss. A mouse model for glioblastoma pathology was also used that reversed BBB disruption and neuron loss, with the incorporation of the IDH mutation. Finally, we established a characterization of the relevant immune populations with an IHC analysis and transcriptional profile.
    FINDINGS: In this study, molecular analyses of the brain ecosystem revealed that blood-brain barrier dysfunction and neuronal synapse integrity exhibit significant threshold-dependent changes that correlate directly and inversely, respectively, with brain ageing (significant changes at 57 years) and the progression of AD and gliomas (survival of 1525 vs 4084 days for patients with High vs Low BBB dysfunction). Using human samples and mouse models, we identified immunoageing processes characterized by an imbalance between pro-inflammatory and anti-inflammatory signals. This dysregulation promotes the extravasation of monocyte-derived macrophages (85% increase of cells), particularly those with a suppressive phenotype, alongside an increase in inflammatory cytokine levels. Notably, our data show that vascular normalization in a glioma model can reverse neuronal loss and attenuate the aggressiveness of the tumours. Finally, tumour development can be prevented by reactivating the ageing immune system.
    INTERPRETATION: We propose that the ageing brain represents a common, BBB dysfunction-associated process driving chronic inflammation. This inflammation is regulated by TREM2+/TIM3+ suppressive myeloid cells, which play a central role in disease progression. Our findings suggest that targeting these pathways could offer therapeutic strategies to mitigate CNS pathologies linked to ageing, characterized by toxic neuroinflammation and myeloid dysfunction.
    FUNDING: This study was funded by ISCIII and co-funded by the European Union.
    Keywords:  Ageing; Alzheimer's disease; Glioblastoma; Immune evasion; TIM3; TREM2
    DOI:  https://doi.org/10.1016/j.ebiom.2025.105833
  7. World J Biol Psychiatry. 2025 Jul 01. 1-10
    Exosomal miR-24-3p participates in the progression of depression by regulating neuronal damage and blood-brain barrier dysfunction.
    Shoufen Yu, Xueyuan Yu, Junchang Liu, Muzhen Guan, Zhongheng Wang, Xiaosa Li.
       BACKGROUND: The blood-brain barrier (BBB) is essential for maintaining normal brain function and is involved in the progression of major depressive disorder (MDD). This study investigated the abnormal expression and regulatory role of miR-24-3p in neuronal injury and BBB dysfunction during MDD pathogenesis.
    METHODS: The expression of miR-24-3p was examined in serum samples from patients with MDD and from chronic unpredictable mild stress and lipopolysaccharide mouse models, as well as in hippocampal tissue from mice. A loss-of-function assay was conducted to explore the role of miR-24-3p in brain injury, assessing neuronal cell viability, apoptosis, inflammatory response, oxidative stress, and astrocyte activation. Exosomes were then isolated to evaluate the regulatory role and function of miR-24-3p in BBB dysfunction. Behavioural tests were performed to assess depressive-like behaviours in mice.
    RESULTS: miR-24-3p was significantly upregulated in MDD samples. Inhibiting miR-24-3p suppressed LPS-induced neuronal apoptosis and inflammation, while promoting the secretion of neurofunctional factors. Further analysis revealed that inhibiting exosomal miR-24-3p alleviated depressive-like behaviour in MDD model mice, reduced BBB permeability, and improved BBB function.
    CONCLUSION: miR-24-3p inhibition attenuated neuronal damage, reduced astrocyte activation, and enhanced BBB stability through exosome-mediated regulation, thereby alleviating neurobehavioural abnormalities and the progression of MDD.
    Keywords:  blood–brain barrier; exosome; major depressive disorder; miR-24-3p; neuronal injury
    DOI:  https://doi.org/10.1080/15622975.2025.2522794
  8. Stem Cell Res Ther. 2025 Jul 01. 16(1): 346
    MSCs engineered with secreted Klotho alleviate blood-brain barrier disruption and reduce neuroinflammation more effectively than MSCs in experimental autoimmune encephalomyelitis.
    Narges Maleki, Maryam Rezapour Kalkhorann, Mohammad Sajad Sajad Emami Aleagha, Amir Emami, Abdolamir Allameh.
       BACKGROUND: The anti-aging protein, Klotho, has been shown to exert neuroprotective effects in neurodegenerative disorders. This study was designed to evaluate the effects of MSCs engineered with secreted Klotho (SKL-MSCs) on neuroinflammation in experimental autoimmune encephalomyelitis (EAE) mouse model and to investigate underlying molecular mechanisms.
    METHODS: EAE was induced in female C57BL/6 mice, and animals were then randomized to receive PBS, MSCs, or SKL-MSCs at the onset of disease. BBB permeability assay was performed. The mRNA and protein expression of inflammatory factors was detected in the brain of animals by real-time PCR and immunohistochemistry, respectively. The mRNA and protein expression of BBB-associated factors was detected in the brain of animals by real-time PCR and Western blotting, respectively.
    RESULTS: The results showed that SKL-MSCs slowed EAE progression and attenuated the disease severity more effectively than MSCs. SKL-MSCs also decreased the expression of TNF-α, IFN-γ, and IL-17 but increased the expression of IL-10 more potently than MSCs in the brain of EAE animals. Furthermore, SKL-MSCs reduced BBB permeability more significantly than MSCs, which was accompanied by decreased levels of BBB-associated factors, ICAM-1, VCAM-1, MMP-9, and CCL2, in the brain of EAE animals. However, in mice treated with MSCs, the reduction in the expression of BBB-associated factors was limited to ICAM-1 and MMP-9.
    CONCLUSIONS: Our study highlighted the significantly greater therapeutic power of SKL-MSCs compared with MSCs in attenuating EAE disease severity and reducing neuroinflammation, which might be mediated through a more marked reduction in the BBB permeability and BBB-associated factors expression levels in the brain of animals.
    Keywords:  Blood–brain barrier; EAE model; Klotho; Mesenchymal stem cells; Multiple sclerosis; Neuroinflammation
    DOI:  https://doi.org/10.1186/s13287-025-04428-w
  9. Cerebrovasc Dis. 2025 Jul 03. 1-14
    Beyond Reperfusion: Adjunctive Therapies Targeting Inflammation, Edema, and BBB Dysfunction in Ischemic Stroke.
    Alexander Weiss, Yuchuan Ding.
       BACKGROUND: Stroke remains a leading cause of disability and death worldwide. While reperfusion therapies such as tissue plasminogen activator (tPA) and mechanical thrombectomy have significantly improved stroke management, their effectiveness is limited by ischemia/reperfusion (I/R) injury, which disrupts the blood-brain barrier, increases neuroinflammation, and exacerbates secondary neuronal damage. Consequently, there is an urgent need for adjunctive therapies that specifically target these secondary injury mechanisms.
    SUMMARY: This review explores novel therapeutic strategies aimed at mitigating neuroinflammation, post-stroke edema, and BBB permeability. Key approaches discussed include anti-inflammatory therapies targeting tumor necrosis factor-alpha (TNF-α), interleukin-6 (IL-6), and matrix metalloproteinases (MMPs); neuromodulation by vagus nerve stimulation (VNS); and the inhibition of edema-related molecules such as sulfonylurea receptor 1 (SUR1), aquaporin-4 (AQP4), and both systemic and peripheral hypothermic cooling. While these therapies show promise in preclinical models, their clinical translation is hindered by challenges such as systemic immunosuppression, susceptibility to infection, and limited therapeutic windows. Among these therapies assessed, SUR1 inhibition and Remote Administration of Hypothermia (RAH) are promising candidates for improving stroke outcomes.
    KEY MESSAGES: Secondary injury from BBB disruption, inflammation, and edema remains a major barrier to optimal stroke recovery. Pharmacologic, neuromodulatory, and molecular-targeting strategies- including TNF-a, IL-6, MMP inhibition, VNS, and hypothermia, each offer distinct therapeutic mechanisms, but face critical clinical translation barriers Among emerging therapies, Remote administration of hypothermia (RAH) and SUR1 inhibition represent novel interventions that address many of the translational challenges of other therapies by addressing key mechanisms of neuroinflammation and edema with favorable safety profiles.
    DOI:  https://doi.org/10.1159/000547092
  10. J Agric Food Chem. 2025 Jul 02.
    Tryptophan-Rich Diet Improves High-Fat Diet-Induced Cognitive Dysfunction and Blood-Brain Barrier Disruption in C57BL/6 Mice through FFAR3 Activation.
    Cailong Pan, Jie Wang, Zhenyun Mao, Xue Jiang, Yajie Xu, Yong Zhang, Lu Chen, Zhi-Yuan Zhang, Xiaoliang Wang.
      Increasing evidence indicates that high-fat diets (HFDs) are strongly associated with cognitive deficits. Tryptophan (Trp), an essential amino acid, has been implicated in regulating metabolic and neurological pathways, but its role in mitigating HFD-induced cognitive dysfunction remains insufficiently explored. We hypothesized that enhancing Trp availability (0.1 or 0.5%) could protect the brain from HFD-induced impairments by preserving blood-brain barrier (BBB) integrity and neuronal function. HFD-fed mice exhibited deficits in Morris water maze, fear conditioning, and novel object recognition tests, accompanied by decreased tight junction proteins claudin-1 and occludin. Trp supplementation restored these indices to levels comparable to normal diet mice. Indole-3-propionic acid (IPA), a Trp metabolite, was identified as a mediator underlying these protective effects. IPA administration replicated cognitive improvements and BBB preservation. Transcriptomic analyses revealed both IPA and Trp converge on pathways regulating neuronal health and BBB function, including PPAR signaling, extracellular matrix organization, and adherens junction regulation. Mechanistically, IPA activated free fatty acid receptor 3 (FFAR3) in brain endothelial cells, reducing paracellular permeability and restoring tight junction protein expression. These results highlight a Trp-rich diet as a therapeutic strategy to mitigate HFD-induced cognitive decline through IPA-mediated FFAR3 activation.
    Keywords:  blood−brain barrier; cognitive dysfunction; free fatty acid receptor 3; high-fat diet; indole-3-propionic acid; tryptophan
    DOI:  https://doi.org/10.1021/acs.jafc.5c05217
  11. Cell Mol Life Sci. 2025 Jun 28. 82(1): 262
    NR4A2 attenuates early brain injury after intracerebral hemorrhage by promoting M2 microglial polarization via TLR4/TRAF6/NF-κB pathway inhibition.
    Di Hu, Cheng Huang, Ling Tang, Jiawen Lei, Jiaqi Wang, Wenzheng Hu, Minshan Chen, Siyuan Song, Lin Lu, Pingyi Xu.
      In the early stage of intracerebral hemorrhage (ICH), rebleeding occurs when blood from the initial hematoma permeates the surrounding brain parenchyma through the disrupted blood-brain barrier (BBB), exacerbating brain injury. Neuroinflammation is a critical driver of the pathological processes underlying this phenomenon. Research on microglia near early hematomas revealed that promoting the transition of microglia to the M2 phenotype could mitigate perihematomal inflammatory damage. Recent studies have shown that the nuclear receptor-related 1 protein (NR4A2) can regulate microglial function and inhibit inflammation. However, the functions of NR4A2 in the development of ICH are still unclear. In this study, we explored the potential protective effect and mechanism of NR4A2 in ICH models. Our results demonstrated that the expression of NR4A2 was significantly decreased in both ICH rats and cell models. Increasing NR4A2 activity could effectively decrease the hematoma volume, improve the neurological prognosis and alleviate perihematomal BBB damage. In vivo and in vitro experiments revealed that NR4A2 inhibited perihematomal inflammatory damage by driving microglial polarization toward the anti-inflammatory M2 phenotype. Mechanistically, NR4A2 targeted TLR4 and inhibited the TRAF6/NF-κB pathway, thereby promoting M2 microglial polarization, reducing inflammatory cell extravasation and maintaining the integrity of the BBB. Conversely, the protective effects of NR4A2 were negated when CRX-527 (a TLR4 agonist) was introduced. These findings suggest that NR4A2 represents a promising therapeutic target for ICH.
    Keywords:  Blood–brain barrier; Microglial polarization; NR4A2; Neuroinflammation; TLR4; TRAF6/NF-κB
    DOI:  https://doi.org/10.1007/s00018-025-05755-0
  12. Commun Biol. 2025 Jul 04. 8(1): 1001
    3BTRON: A Blood-Brain Barrier Recognition Network.
    Nan Fletcher-Lloyd, Isabel Bravo-Ferrer, Katrine Gaasdal-Bech, Blanca Díaz Castro, Payam Barnaghi.
      The blood-brain barrier (BBB) plays a crucial role in maintaining brain homeostasis. During ageing, the BBB undergoes structural alterations. Electron microscopy (EM) is the gold standard for studying the structural alterations of the brain vasculature. However, analysis of EM images is time-intensive and can be prone to selection bias, limiting our understanding of the structural effect of ageing on the BBB. Here, we introduce 3BTRON, a deep learning framework for the automated analysis of electron microscopy images of the BBB. Using age as a readout, we trained and validated our model on a unique dataset (n = 359). We show that the proposed model could confidently identify the BBB of aged mouse brains from young mouse brains across three different brain regions, achieving a sensitivity of 77.8% and specificity of 80.0% post-stratification when predicting on unseen data. Additionally, feature importance methods revealed the spatial features of each image that contributed most to the predictions. These findings demonstrate a new data-driven approach to analysing age-related changes in the architecture of the BBB.
    DOI:  https://doi.org/10.1038/s42003-025-08453-6
  13. Front Pharmacol. 2025 ;16 1510250
    The anti-depressive role of the Pei Yuan Kai Yu formula in cerebral small vessel disease based on gut microbiota.
    Lixuan Yang, Yutian Ao, Yannan Li, Baoan Dai, Junnan Li, Wenzhe Duan, Kaiqiang Dong, Zhenyun Han, Rongjuan Guo.
       Background: Cerebral small vessel disease (CSVD), characterized by pathological changes in brain vessels, is a common cause of death in the elderly and often accompanied by depression, which significantly affects patients' quality of life and rehabilitation; understanding its pathogenesis and developing innovative therapies are urgently needed, especially considering the role of the blood - brain barrier impairment and the gut - microbiota - gut - brain axis in this complex condition.
    Methods: Dahl/SS rats were fed a diet containing 8% NaCl and were subjected to chronic unpredictable mild stress (CUMS) stimulation for 4 weeks. PY (1.407 g/kg/day) was administered intragastrically to evaluate its role in CSVD with depression. Pseudo germ-free rats were colonized with gut microbiota from high-salt-fed rats exposed to CUMS, followed by PY administration.
    Results: In rats with CSVD and depression, PY significantly increased body weight; alleviated depression-like behaviors; and decreased the levels of inflammatory cytokines such as TNF-α, IL-1β, and IL-6 in both serum and hippocampus. Additionally, PY reversed inflammation-induced nerve damage; reduced the overexpression of microglia in the hippocampus; decreased the levels of hippocampal VEGF and MMP-9, and increased the levels of hippocampal occludin, ZO-1, and claudin-5. Moreover, PY improved the composition of gut microbiota and enhanced microbial diversity. PY induced characteristic changes in the microbiome, which were associated with inflammation, endothelial dysfunction, and depressive-like behaviors. These significant metabolites were identified and were found closely related to inflammation, endothelial cell dysfunction, and depression-like behaviors.
    Conclusion: In conclusion, PY acts as an antidepressant to slow down the progression of CSVD by inhibiting microglial activation, reducing inflammation and ameliorating endothelial dysfunction. It exerts its effect, at least in part, by enhancing microbiota-mediated metabolism in vivo.
    Keywords:  Pei Yuan Kai Yu formula; cerebral small vessel disease; depression; gut microbiota; inflammation; microglia
    DOI:  https://doi.org/10.3389/fphar.2025.1510250
  14. Int J Mol Med. 2025 Sep;pii: 136. [Epub ahead of print]56(3):
    Blood‑brain barrier dysfunction in epilepsy: Mechanisms, therapeutic strategies and future orientation (Review).
    Na Huang, Yawen Huang, Zhenyuan Deng, Shuya Qi, Wei Zhang, Yuanyuan Liu, Guohe Tan.
      The blood‑brain barrier (BBB) is a crucial structure for maintaining homeostasis within the central nervous system, and its integrity plays a pivotal role in the onset and progression of epilepsy. Epileptic seizures can disrupt the molecular architecture of the BBB, including the loss of tight junction proteins, activation of matrix metalloproteinases and dysfunction of supporting cells. Various pathological changes, such as transmembrane transport disorders, upregulation of platelet‑derived growth factor receptor β and vascular endothelial growth factor signalling pathways, and activation of astrocytes and microglia, accompany these alterations. These modifications exacerbate the entry of toxic molecules (such as albumin) into the brain parenchyma, triggering neuroinflammation and neuronal damage, thereby establishing a vicious cycle of epilepsy, BBB disruption and recurrent epilepsy. Consequently, repairing or protecting the BBB is a novel strategy for controlling epileptic seizures and treating drug‑resistant epilepsy. Consequently, compared with current treatment approaches that primarily focus on suppressing neuronal excitability, repairing or protecting the BBB is a novel strategy for controlling epileptic seizures and treating drug‑resistant epilepsy. Drugs such as botulinum, levetiracetam and angiotensin receptor blockers show the potential for BBB protection. The development of nanomaterials can enhance drug concentrations in affected areas, thereby offering new avenues for refractory epilepsy. The present study systematically reviews the critical role of the BBB in the pathogenesis of epilepsy, untangles the complex association between BBB dysfunction and the course of the disease, aims to deepen our understanding of the molecular mechanisms underlying BBB damage, and explores new approaches for epilepsy prevention and treatment from a BBB perspective. This review provides a theoretical foundation and research direction for the development of diagnostic and treatment strategies that are safer and more effective than current standard therapies.
    Keywords:  antiepileptic therapy; blood‑brain barrier; epilepsy; nano‑drug delivery system; neuroinflammation; tight junction proteins
    DOI:  https://doi.org/10.3892/ijmm.2025.5577
  15. Front Neurosci. 2025 ;19 1642419
    Retraction: ErbB4 preserves blood-brain barrier integrity via the YAP/PIK3CB pathway after subarachnoid haemorrhage in rats.
    Frontiers Editorial Office
      [This retracts the article DOI: 10.3389/fnins.2018.00492.].
    DOI:  https://doi.org/10.3389/fnins.2025.1642419
  16. Bioact Mater. 2025 Oct;52 541-563
    Hypoxia preconditioned MSC exosomes attenuate high-altitude cerebral edema via the miR-125a-5p/RTEF-1 axis to protect vascular endothelial cells.
    Jia-Chen Zuo, Jun Liang, Nan Hu, Bin Yao, Qi-Jian Zhang, Xiao-Li Zeng, Ling-Jie Zhang, Xu Zhang, Zhe-Han Chang, Chong Chen, Xin-Jian Yan, Wen-Wei Shao, Ping Zhu, Xiao-Hong Li.
      Vasogenic edema, caused by the disruption of the blood-brain barrier (BBB), is a significant pathological factor in high-altitude cerebral edema (HACE). Due to the rapid progression and high mortality rate of HACE, prophylactic treatment is important. Mesenchymal stem cell exosomes (MSC-EXO) are increasingly being used in tissue injury repair, and research suggests that appropriate conditioning can enhance the targeted efficacy of exosome therapy. Our in vitro experiments revealed that hypoxia preconditioned MSC-EXO (H-EXO) significantly outperformed normoxic MSC-EXO (N-EXO) in multiple protective aspects. Specifically, H-EXO demonstrated enhanced capacity to mitigate hypoxia-induced aberrant angiogenesis, maintain vascular endothelial cell viability, and suppress ROS accumulation and apoptotic signaling under hypoxic stress. Mechanistic investigation identified miR-125a-5p cargo in H-EXO as a key mediator of RTEF-1 targeted inhibition during hypoxic exposure. In corresponding in vivo studies, H-EXO administration effectively attenuated HACE-induced pathological angiogenesis while maintaining crucial vascular homeostasis markers. The therapeutic effects manifested through three principal aspects: 1) downregulation of RTEF-1/VEGF hyperexpression, 2) modulation of VE-cadherin, SMA, and PDGFRα + β expression to preserve BBB integrity, and 3) concurrent protection of neurovascular functions against HACE-induced damage. This investigation elucidates the miR-125a-5p/RTEF-1 axis as the central mechanism through which hypoxic preconditioning enhances MSC-EXO's endothelial protective properties. Our findings establish H-EXO's multimodal therapeutic potential, demonstrating its capacity to simultaneously inhibit pathological angiogenesis, restore BBB function, and protect neural tissue under hypoxic stress conditions. The study elucidates key mechanisms underlying clinical prevention and management of HACE by delineating H-EXO's preventive mechanisms against hypoxia-induced cerebrovascular injury.
    Keywords:  High-altitude cerebral edema; Hypoxia preconditioned exosomes; Neurological recovery; Vascular endothelial cells; miR-125a-5p
    DOI:  https://doi.org/10.1016/j.bioactmat.2025.06.018
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