bims-blobar 2025-09-07 papers

bims-blobar

Biomed News

on Blood brain barrier repair

Issue of 2025–09–07
28 papers selected by
Nicolas Rebergue

Uridine treatment protects against blood-brain barrier disruption in a rat model of Li-pilocarpine-induced status epilepticus.
Influence of Alzheimer's associated Aβ oligomers and oxidative stress on blood-brain barrier dysfunction.
Nesfatin-1 ameliorates blood-brain barrier dysfunction in Alzheimer's disease by targeting VEGF-R1 and reducing cellular senescence in brain vascular endothelial cells.
Association between preoperative blood-brain barrier permeability and postoperative delirium in older patients undergoing cardiac surgery: a pilot study.
Unveiling the intricate dynamics of the interplay between triple-negative breast cancer cells and the blood-brain barrier endothelium.
High-dose acetaminophen does not acutely compromise blood-brain barrier permeability in mice.
Unifying Vascular Injury and Neurodegeneration: A Mechanistic Continuum in Cerebral Small Vessel Disease and Dementia.
Gut dysbiosis is associated with increased blood-brain barrier permeability and cognitive impairment in elderlies with coronary heart disease.
Protection against stroke-induced blood-brain barrier disruption by Guanxinning injection and its active-component combination via TLR4/NF-κB/MMP9-mediated neuroinflammation.
Multimodal Imaging of Blood-Brain Barrier Dysfunction in Parkinson's Disease: From Pathological Mechanisms to Therapeutic Opportunities.
Epigenetic Reactivation of CNS Endothelial Developmental Programs Triggers Adult Brain Angiogenesis, Promotes Post-Stroke Revascularization and Neuronal Regeneration.
The Effect of Tryptanthrin and Its Oxime on the Blood-Brain Barrier Permeability in Rats with Cerebral Infarction.
Exploring novel roles of lipid droplets and lipid metabolism in regulating inflammation and blood-brain barrier function in neurological diseases.
Early-life gut microbiome maturity regulates blood-brain barrier and cognitive development.
The missing link: TNF-α as a unifying mechanism in methamphetamine-induced neuronal dysfunction and blood-brain barrier compromise.
Serum ZO-1 and occludin levels in bipolar disorder patients.
Pathogenic breaches: how viruses compromise blood-tissue barriers.
Head-down position after reperfusion improves cerebral ischaemic injury in rat.
The contributions of aquaporin-4 to water exchange across the blood-brain barrier measured by filter-exchange imaging.
Sex- and age- differences in the expression of critical blood-brain barrier regulators: a physiological context.
Cerebral Organoids with Integrated Endothelial Networks Emulate the Neurovascular Unit and Mitigate Core Necrosis.
Effects of atorvastatin-loaded PEGylated liposomes delivered by magnetic stimulation for stroke treatment.
Selectin E upregulation upon forkhead box P1 loss augments neutrophil infiltration and brain damage in hypertensive intracerebral hemorrhage.
17β-trenbolone increases circulating myeloid-derived MMP8 in CSDS-induced mice and drives depressive tendencies to social threat.
Crossing Pathological Boundaries: Multi-Target Restoration of the Neurovascular Unit in Alzheimer's and Vascular Dementia-From Modern Therapeutics to Traditional Chinese Medicine.
Lipid-laden endothelial cells exhibit a transcriptomic signature linked to blood-brain barrier dysfunction, metabolic reprogramming and increased inflammation in the aging brain.
Artificial mesenchymal stem cell extracellular vesicles enhanced ischemic stroke treatment through targeted remodeling brain microvascular endothelial cells.
By inhibiting pyroptosis to reduce neuroinflammation, PEG-bHb may prevent the development of secondary injury after traumatic brain injury.

Front Neurosci. 2025 ;19 1635247

Uridine treatment protects against blood-brain barrier disruption in a rat model of Li-pilocarpine-induced status epilepticus.

Birnur Aydin, Busra Ocalan Esmerce, Aysen Cakir, Sueda Tuncak, Cansu Koc, Mehmet Cansev, Tulin Alkan.

   Introduction: Blood-brain barrier (BBB) disruption is one of the most striking changes triggered by status epilepticus, which deserves specific attention in terms of novel treatment approaches targeting epileptogenesis. Uridine is a pyrimidine nucleoside with neuroprotective, antiepileptic and antiepileptogenic effects; however, its mechanism of action is not fully characterized. In this study, we aimed to investigate the short-term outcomes of uridine treatment on status epilepticus-induced-BBB dysfunction in an animal model.
Methods: Status epilepticus was induced by lithium and pilocarpine administration in male Sprague-Dawley rats which were post-treated with intraperitoneal injection of saline or uridine (500 mg/kg b.w.; twice a day) for 2 days. Blood-brain barrier structural integrity was assessed by measuring expressions of endothelial tight junction proteins zonula occludens-1 (ZO-1) and occludin, matrix metalloproteinases (MMP-2 and MMP-9), aquaporin-4 (AQP4) water channel and its anchoring protein α1-syntrophin in hippocampal tissue 48 h after SE. Additionally, BBB permeability was determined by measuring brain edema and serum S100B levels.
Results: The data showed that uridine significantly prevented the reduction in ZO-1 and α1-syntrophin protein levels and attenuated serum S100B levels, indicating protective effects on BBB integrity and AQP4 polarization. In contrast, uridine enhanced brain water content in SE-induced rats, a finding that might be a result of maintained AQP4 polarization and enhanced cytotoxic edema.
Discussion: Together, our results showed for the first time that post-seizure treatment with uridine provides protection against BBB disruption in an experimental SE model; nevertheless, the long-term effects of this treatment warrant further investigation.

Keywords:  aquaporin-4; blood–brain barrier; brain edema; status epilepticus; uridine

DOI:  https://doi.org/10.3389/fnins.2025.1635247
Tissue Barriers. 2025 Sep 03. 2553927

Influence of Alzheimer's associated Aβ oligomers and oxidative stress on blood-brain barrier dysfunction.

Brittany E Watson, Mihyun L Waugh, Nolan J Foreman, Melissa A Moss.

  Blood-brain barrier (BBB) dysfunction is an early event observed in Alzheimer's disease (AD). Two characteristics of AD brain and brain vasculature contribute to BBB dysfunction: the accumulation of aggregated amyloid-β protein (Aβ) and an increase in oxidative stress. This work uses a BBB model of primary human brain microvascular endothelial cells to investigate the individual and synergistic influence of both pathogenic Aβ oligomers and oxidative stress on BBB transendothelial electrical resistance (TEER), an indicator of barrier integrity. Results indicate that nontoxic, physiological concentrations of Aβ oligomers reduce TEER, while Aβ monomer remains inert. Moreover, introducing mild oxidative stress, which alone does not influence monolayer integrity, exacerbates the effect of Aβ oligomers on TEER within this BBB model. These findings advance the understanding of BBB dysfunction in AD and point toward therapeutic strategies targeting this early event that contributes to a currently irreversible disease.

Keywords:  Alzheimer’s disease; amyloid-β; blood–brain barrier dysfunction; oxidative stress; transendothelial electrical resistance

DOI:  https://doi.org/10.1080/21688370.2025.2553927
Transl Psychiatry. 2025 Sep 03. 15(1): 341

Nesfatin-1 ameliorates blood-brain barrier dysfunction in Alzheimer's disease by targeting VEGF-R1 and reducing cellular senescence in brain vascular endothelial cells.

Biyue Zhang, Shumei Zhang, Zeming Guo, Chunzhan Hong, Futian Zhang, Huasong Lin.

Cellular senescence and associated endothelial permeability are crucial factors in the dysfunction of the blood-brain barrier (BBB) in neurodegenerative diseases, including Alzheimer's disease (AD). Nesfatin-1 (NF-1), a neuropeptide involved in regulating appetite and energy homeostasis, has not been extensively studied for its pathophysiological role in AD. In this study, we found that NF-1 treatment improved cellular senescence in brain vascular endothelial bEnd.3 cells by restoring the expression of hTERT and TERF2 against oligomerized Aβ1-42. Additionally, NF-1 reduced p53 and p21 protein levels in bEnd.3 cells exposed to oligomerized Aβ1-42. Notably, NF-1 reduced oligomerized Aβ1-42-induced endothelial monolayer permeability by maintaining transendothelial electric resistance (TEER) and the levels of tight junction proteins claudin 5 and ZO-1. Furthermore, NF-1 suppressed the expression of VEGF-R1 but not VEGF-R2 in bEnd.3 cells exposed to oligomerized Aβ1-42. Overexpression of VEGF-R1 negated the protective effects of NF-1 against oligomerized Aβ1-42-induced cellular senescence and increased endothelial monolayer permeability, indicating the involvement of VEGF-R1 in this process. Using a transgenic (Tg APPswe/PSEN1dE9) AD mouse model, we demonstrated that NF-1 administration lowered VEGF-R1 expression in the brain cortex of AD mice. Moreover, NF-1 mitigated BBB dysfunction and enhanced the expression of claudin 5 and ZO-1 in the brains of AD mice. Our results suggest that NF-1 may be a potential therapeutic strategy for treating AD.

DOI: https://doi.org/10.1038/s41398-025-03528-8
Aging Clin Exp Res. 2025 Aug 29. 37(1): 258

Association between preoperative blood-brain barrier permeability and postoperative delirium in older patients undergoing cardiac surgery: a pilot study.

Lichao Di, Peiying Huang, Yeju He, Jie Li, Yu Liu, Liwei Chi, Na Sun, Lining Huang.

   BACKGROUND: Postoperative delirium (POD) is a frequent and serious complication in older adults after cardiac surgery. Blood-brain barrier (BBB) dysfunction is implicated in cognitive decline, but its preoperative role in POD remains underexplored. This pilot study aimed to investigate the association between preoperative regional BBB permeability, assessed by dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI), and POD in older patients undergoing off-pump coronary artery bypass grafting (OPCABG).
METHODS: This prospective observational pilot study, registered in the Chinese Clinical Trial Registry (ChiCTR2200063774), included patients aged ≥ 65 years scheduled for OPCABG. Preoperative BBB permeability (quantified as Ktrans) in the hippocampus, thalamus, frontal lobe, and temporal lobe, along with regional brain volumes and Montreal Cognitive Assessment-Basic (MoCA-B) scores, were assessed. POD was diagnosed using the 3-Minute Diagnostic Confusion Assessment Method (3D-CAM) or CAM-ICU for 5 postoperative days. Univariable and multivariable logistic regression analyses were performed to identify predictors of POD. Correlations between Ktrans, volume, and POD severity (CAM-S) were examined.
RESULTS: Fifty patients (mean age 69.0 ± 3.3 years) were analyzed; 19 (38%) developed POD. In univariable analysis, higher preoperative Ktrans in the hippocampus (Odds Ratio [OR] 1.350, 95%CI 1.048-1.740, P = 0.020) and thalamus (OR 1.466, 95%CI 1.017-2.113, P = 0.040), lower MoCA-B scores (P = 0.020), and smaller hippocampal (OR 0.297, 95%CI 0.131-0.672, P = 0.004) and thalamic volumes (OR 0.304, 95%CI 0.121-0.766, P = 0.012) were associated with POD. However, in multivariable logistic regression including MoCA-B, Ktrans, and volumes, only lower MoCA-B scores (OR 0.697, 95%CI 0.513-0.947, P = 0.021) and smaller hippocampal volume (OR 0.322, 95%CI 0.105-0.992, P = 0.048) remained independent predictors of POD incidence. Preoperative hippocampal Ktrans correlated significantly with POD severity (CAM-S, r = 0.673, P = 0.002).
CONCLUSION: In this pilot study, while increased preoperative BBB permeability in the hippocampus and thalamus was associated with POD univariably, baseline cognitive function and hippocampal volume were stronger independent preoperative predictors of POD incidence after OPCABG. Higher preoperative hippocampal BBB permeability was associated with greater POD severity, suggesting a role for pre-existing BBB vulnerability in exacerbating delirium. These preliminary and exploratory findings warrant validation in larger, adequately powered cohorts and highlight the complex interplay of pre-existing brain vulnerabilities in POD development.
TRIAL REGISTRATION: Chinese Clinical Trial Registry (ChiCTR2200063774; registered on 09/16/2022).

Keywords:  Blood–brain barrier permeability; Cardiac surgery; Delirium; Dynamic contrast-enhanced MRI; Hippocampus; Ktrans; Neuropsychological tests; Older patients; Postoperative Delirium

DOI:  https://doi.org/10.1007/s40520-025-03140-2
Acta Neuropathol Commun. 2025 Aug 28. 13(1): 185

Unveiling the intricate dynamics of the interplay between triple-negative breast cancer cells and the blood-brain barrier endothelium.

Ana Rita Garcia, Ana Rita Vaz, Rui Malhó, Hugo M Botelho, Inês Figueira, Maria Alexandra Brito.

  Brain metastases (BM) critically reduce breast cancer (BC) patients' survival. Extravasation is pivotal for BM development, but the underlying events at the blood-brain barrier (BBB) remain elusive. We aimed to unravel the players and mechanisms governing BC cells (BCCs)-BBB interaction. For that, mixed cultures of human brain microvascular endothelial cells (HBMECs), mimicking the BBB, and brain-tropic triple-negative BCCs (MDA-MB-231 Br4), or non-brain-tropic (MDA-MB-231) or non-metastatic cells (MCF-7) were established. Temporal and spatial analysis of BCCs-BBB interactions (live-cell imaging automated microscopy), and assessments of endothelial-to-mesenchymal transition (EndMT) markers, transcription factors, cytoskeletal proteins, and morphology (immunocytochemistry) were performed. BBB integrity (permeability, transendothelial electrical resistance) and endothelial migration (wound-healing) were also assessed. Our results revealed that contrasting with non-metastatic and non-brain-tropic cells, BCCs quickly developed an invasive, migratory phenotype, characterized by invadopodium formation and reduced roundness. Spatial analysis showed different positioning of BCCs relative to the BBB endothelium over time, with 14% of BCCs transmigrated after 3 h, compromising BBB integrity through endothelial holes, reduced tightness, and increased permeability. Prior to transmigration, alterations in adhesion markers (E-selectin, ICAM-1, CD24, CD34, β3-integrin, Sialyl-Lewis X) were observed. EndMT was also evident by decreased endothelial (β-catenin and pan cytokeratin) and increased mesenchymal (vimentin, neuronal-cadherin, Slug, ZEB1) markers, elongation (RhoA, α-SMA), nuclear deformation, and migratory capacity. Caveolin-1 silencing in HBMEC decreased BCCs transmigration. This study reveals significant BBB phenotypic and structural changes, facilitating both paracellular and transcellular BCCs transmigration. These findings provide advanced understanding of BCCs trafficking across the BBB, aiding strategy development to prevent extravasation and BM.

Keywords:  Adhesion; Blood-brain barrier; Brain metastases; Brain microvascular endothelial cells; Endothelial-mesenchymal transition; Extravasation; Paracellular migration; Transcellular migration; Transmigration; Triple-negative breast cancer

DOI:  https://doi.org/10.1186/s40478-025-01985-2
Metab Brain Dis. 2025 Sep 03. 40(7): 258

High-dose acetaminophen does not acutely compromise blood-brain barrier permeability in mice.

Sumaih Zoubi, Dhavalkumar Patel, Yeseul Ahn, Ehsan Nozohouri, Heba Ewida, Ulrich Bickel.

  Acetaminophen is widely recognized for its safety as a pain reliever and fever reducer at recommended doses. However, in addition to the well-known hepatotoxic and nephrotoxic effects at overdoses recent animal studies in rats have raised the possibility that acetaminophen at a high dose of 500 mg/kg may lead to acute impairment of the blood-brain barrier (BBB). Because species differences in hepatic and renal toxicity of acetaminophen are present, we assessed here the effect of moderate and severe overdoses of acetaminophen (300 mg/kg and 600 mg/kg, respectively) after intraperitoneal administration in mice on BBB permeability. Using stable isotope-labeled [13C12]sucrose as a small molecule hydrophilic marker the brain uptake clearance Kin was measured. Our results showed no significant differences in BBB permeability between vehicle control and acetaminophen treated groups (Kin of the control group = 0.070 ± 0.025 µL min-1 g-1, Kin of the 300 mg/kg group = 0.059 ± 0.017 µL min-1 g-1, and Kin of the 600 mg/kg group = 0.066 ± 0.010 µL min-1 g-1, all values mean ± SD, n = 6) suggesting that even high doses of acetaminophen do not acutely compromise BBB permeability in mice. We did also not observe significant changes in tight junction proteins in brain. These findings support the notion that acetaminophen effects on the BBB may be species-specific among rodents.

Keywords:  Acetaminophen; Blood–brain barrier; LC-MS/MS; Permeability; [13C]sucrose

DOI:  https://doi.org/10.1007/s11011-025-01696-6
Eur J Neurosci. 2025 Sep;62(5): e70246

Unifying Vascular Injury and Neurodegeneration: A Mechanistic Continuum in Cerebral Small Vessel Disease and Dementia.

Chelsea Jin, Sonu Bhaskar.

  Cerebral small vessel disease (CSVD) is a major yet underappreciated driver of cognitive impairment and dementia, contributing to nearly half of all cases. Emerging evidence indicates that CSVD is not merely a coexisting vascular condition but an active amplifier of neurodegeneration, operating through a self-perpetuating cascade of microvascular injury, blood-brain barrier (BBB) breakdown, and glymphatic system dysfunction. In this hypothesis-driven review, we propose the Integrated Vascular-Neurodegenerative Continuum, a mechanistic model in which vascular pathology triggers and accelerates neurodegeneration via intersecting pathways, including chronic cerebral hypoperfusion, oxidative stress, and APOE ε4-associated endothelial vulnerability. We synthesize molecular, imaging, and genetic evidence supporting this continuum, highlighting novel diagnostic and therapeutic targets such as peak skeletonized mean diffusivity, dynamic contrast-enhanced magnetic resonance imaging-based BBB leakage quantification, and emerging agents like cilostazol and allopurinol. We also critically appraise the limitations of current diagnostic frameworks and advocate for integrative, multimodal approaches to risk stratification. This model offers a unifying framework that bridges cerebrovascular and neurodegenerative domains, offering a foundation for precision medicine strategies aimed at dementia prevention and treatment.

Keywords:  APOE ε4; blood–brain barrier; cerebral small vessel disease; glymphatic dysfunction; neurodegeneration; vascular dementia

DOI:  https://doi.org/10.1111/ejn.70246
Front Aging Neurosci. 2025 ;17 1640761

Gut dysbiosis is associated with increased blood-brain barrier permeability and cognitive impairment in elderlies with coronary heart disease.

Lichao Di, Peiying Huang, Yeju He, Na Sun, Liwei Chi, Lining Huang.

   Objective: The gut-brain axis is recognized as a critical pathway through which gut microbiota influences neurological health. However, the complex interplay between gut microbiota composition, blood-brain barrier (BBB) integrity, and cognitive function in elderly individuals with coronary heart disease (CHD) experiencing mild cognitive impairment (MCI) remains insufficiently elucidated. This study aimed to investigate these relationships in a cohort of 40 elderlies with CHD, comparing those with MCI to those with normal cognition (NC), focusing on microbial diversity, specific taxa alterations, BBB permeability, and their correlations with cognitive performance.
Methods: This preplanned secondary analysis utilized data from two prospective cohort studies, enrolling elderlies with CHD (≥60 years). Participants were categorized into NC (n = 20) and MCI (n = 20) groups based on standardized neuropsychological assessments. Fecal samples underwent 16S rRNA gene sequencing (V3-V4 region) to evaluate gut microbiota diversity and composition. BBB permeability was quantified using dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI), specifically measuring the volume transfer constant (Ktrans) in the hippocampus.
Results: Compared to the NC group, MCI patients exhibited significantly reduced gut microbial α-diversity (Chao1 index: p = 0.002; Shannon index: p = 0.009) and distinct β-diversity profiles (Bray-Curtis dissimilarity, PERMANOVA, p = 0.003). LEfSe analysis identified depletion of key short-chain fatty acid (SCFA)-producing taxa in the MCI group, including at the family level (Ruminococcaceae, p = 0.016; Rikenellaceae, p = 0.042; and Barnesiellaceae, p = 0.038) and genus level (Faecalibacterium, p = 0.003 and Oscillospira, p = 0.002). Hippocampal BBB permeability (Ktrans) was significantly elevated in MCI patients (6.04 ± 3.02 vs. 3.90 ± 1.03 × 10-3 min-1, p = 0.006) and inversely correlated with the relative abundance of Faecalibacterium (Spearman's r = -0.466, p = 0.002) and Oscillospira (Spearman's r = -0.322, p = 0.043). Conversely, these genera showed positive correlations with Montreal Cognitive Assessment-Basic (MoCA-B) scores (Faecalibacterium: r = 0.596, p < 0.001; Oscillospira: r = 0.369, p = 0.019).
Conclusion: Elderlies with CHD and MCI demonstrate significant gut dysbiosis, characterized by reduced microbial diversity and depletion of SCFA-producing taxa, notably butyrate producers. These microbial alterations are correlated with increased BBB permeability in the hippocampus and diminished cognitive function. These findings highlight the potential role of the gut-brain axis in the pathogenesis of cognitive decline in this vulnerable population and suggest that targeting gut microbiota could be a therapeutic avenue.

Keywords:  16S rRNA sequencing; DCE-MRI; blood–brain barrier; cognitive function; coronary heart disease; gut microbiota; gut-brain axis; mild cognitive impairment

DOI:  https://doi.org/10.3389/fnagi.2025.1640761
Phytomedicine. 2025 Aug 16. pii: S0944-7113(25)00801-3. [Epub ahead of print]147 157162

Protection against stroke-induced blood-brain barrier disruption by Guanxinning injection and its active-component combination via TLR4/NF-κB/MMP9-mediated neuroinflammation.

Siwen Fan, Hongying Du, Yixin Yao, Huanyi Wang, Min Zhang, Xuliu Shi, Jiankun Yan, Li Peng, Guangxu Xiao, Shuang He, Ming Lyu, Yan Zhu.

   BACKGROUND: The blood-brain barrier (BBB) is essential for central nervous system (CNS) homeostasis, yet neuroinflammatory mechanisms driving BBB disruption remain poorly understood.
PURPOSE: To explore the oxygen-glucose deprivation/reoxygenation (OGD/R)-induced BBB dysfunction and evaluate the therapeutic effects of Guanxinning injection (GXNI), a Danshen-Chuanxiong herbal combination, targeting neuroinflammatory pathways.
METHODS: A 3D-BBB organoid composed of human brain microvascular endothelial cells, human astrocytes, and primary human brain microvascular pericytes was constructed, and conditions for OGD/R that simulate ischemic stroke were established. Structure and function of the in vitro BBB were evaluated by morphology, paracellular permeability, and tight junction proteins ZO-1, claudin-5, and occludin expression. In vivo, infarct volume and BBB leakage were measured in a mid-cerebral artery occlusion-induced cerebral ischemia-reperfusion injury model. RNA-seq and network pharmacology analysis were used to identify key genes and pathways for ischemic BBB disruption. HPLC-MS was performed to identify and quantify active components. Molecular docking, SPR, and molecular dynamics were performed to predict and confirm the interaction of active compounds and target proteins.
RESULTS: A Danshen-Chuanxiong double herbal medicine, GXNI, mitigated these effects, restoring transport capacity, reducing oxidative stress (ROS), and enhancing basement membrane components (laminin, collagen IV). In vivo, GXNI alleviated cerebral ischemia-reperfusion injury (CIRI), decreasing BBB leakage, infarct volume, and neurological deficits. The pivotal role of TLR4/NF-κB/MMP9 neuroinflammatory axis for GXNI BBB protection was identified through transcriptomic analysis and validated via immunofluorescence in BBB spheroids. Molecular docking revealed Danshen-derived salvianolic acid B (SAB) as a high-affinity MMP9 binder, confirmed by quantitative binding assays. The SAB and Chuanxiong-derived senkyunolide I (SI) combination achieved more prominent upregulation of tight junction proteins and suppression of MMP9.
CONCLUSION: Our findings further confirm neuroinflammation as a central driver of ischemic BBB damage and demonstrate that GXNI preserves BBB integrity by targeting TLR4/NF-κB/MMP9 signaling in 3D models and CIRI mice, with SAB-SI synergistically contributing to enhanced therapeutic efficacy.

Keywords:  3D spheroids; Blood-brain barrier; Danshen-Chuanxiong herb pair; Ischemic stroke; MMP9; Neuroinflammation

DOI:  https://doi.org/10.1016/j.phymed.2025.157162
Eur J Neurosci. 2025 Sep;62(5): e70237

Multimodal Imaging of Blood-Brain Barrier Dysfunction in Parkinson's Disease: From Pathological Mechanisms to Therapeutic Opportunities.

Zihao Lu, Haolin Yin, Pan Xiang, Xuan Yi, Xiaohe Tian, Qiyong Gong.

In Parkinson's disease (PD), blood-brain barrier (BBB) dysfunction is shifting from being viewed as a passive marker of damage to a key pathological driver and potential therapeutic target. Its disruption involves mechanisms such as abnormal α-synuclein transport, tight junction breakdown, inflammatory activation, and vascular remodeling, all of which significantly disturb the neural microenvironment. Imaging technologies are playing an increasingly pivotal role in unraveling these complex processes. Based on current clinical and experimental evidence, this review outlines the major mechanisms of BBB disruption in PD and focuses on recent advances in multiscale imaging techniques for BBB research. It covers super-resolution microscopy, two-photon imaging, MRI, and PET, emphasizing their critical value in mechanistic investigation, functional assessment, and target localization. Multimodal imaging enables cross-scale integration-from nanoscopic to macroscopic levels and from laboratory research to clinical application-and holds promise for building a "mechanism-imaging-intervention" framework that may accelerate the translation from pathophysiological understanding to clinical intervention.

DOI: https://doi.org/10.1111/ejn.70237
bioRxiv. 2025 Aug 21. pii: 2025.08.15.670554. [Epub ahead of print]

Epigenetic Reactivation of CNS Endothelial Developmental Programs Triggers Adult Brain Angiogenesis, Promotes Post-Stroke Revascularization and Neuronal Regeneration.

Sithara Thomas, Cikesh Chandran, Lalit K Ahirwar, Arif O Harmanci, Shafeeque M Chathathayil, Nabil J Alkayed, Ari C Dienel, Spiros L Blackburn, Devin W McBride, Kumar T Peeyush.

Therapeutic angiogenesis is essential for regenerating brain tissue damaged by stroke, yet it remains an unmet clinical challenge. During brain development, pro-angiogenic genes drive the formation of vascular networks, with their expression tightly regulated in later stages. We found that in adult CNS endothelial cells (ECs), angiogenesis-related genes are epigenetically silenced through histone deacetylase 2 (HDAC2) and the polycomb repressive complex 2 (PRC2). Conditional deletion of Hdac2 in ECs reactivated pro-angiogenic signaling, including Wnt/β-catenin target genes, leading to functional neovascularization with preserved blood-brain barrier (BBB) integrity in the adult brain. In contrast, Ezh2 (PRC2 subunit) deletion reduced vessel density and compromised BBB function. Deletion of Hdac2 and Ezh2 immediately after transient ischemic stroke conferred vascular protection by modulating stroke-induced transcriptional programs in CNS ECs. In contrast, delayed deletion, initiated seven days post-stroke, after significant neuronal loss in the infarct region, induced robust revascularization and promoted post-stroke neurogenesis, with differentiation into both excitatory and inhibitory neurons. These findings highlight CNS EC HDAC2 as a promising therapeutic target for inducing adult brain angiogenesis, facilitating revascularization, and supporting neuronal regeneration following stroke.

DOI: https://doi.org/10.1101/2025.08.15.670554
Bull Exp Biol Med. 2025 Aug 29.

The Effect of Tryptanthrin and Its Oxime on the Blood-Brain Barrier Permeability in Rats with Cerebral Infarction.

G A Chernysheva, V I Smolyakova, M B Plotnikov, O I Aliev, O A Ulyakhina, A N Osipenko, A R Kovrizhina, A I Khlebnikov.

  A comparative study of the effect of tryptanthrin and its oxime (Tr-Ox) on the blood-brain barrier (BBB) permeability was conducted in male Wistar rats with cerebral infarction (CI) modeled by intraluminal occlusion of the middle cerebral artery. In 3, 48, and 72 h after CI, extravasation of Evans blue bound to serum albumin in the cerebral hemispheres was assessed 3 h after its intravenous administration (3 ml/kg, 2% solution). Tryptanthrin and Tr-Ox were injected intraperitoneally in a dose of 10 mg/kg on the 30th minute of ischemia and then daily for 2 days. There were no significant differences in the effects of these compounds 3 and 48 h after CI. In both experimental groups, the dye concentration in the left (affected) hemisphere significantly decreased after 3 and 48 h by 30-37 and 51-54%, respectively, in comparison with the control (CI without treatment); in the right hemisphere, dye concentration decreased by 34-39% after 48 h. After 72 h, 45% reduction in Evans blue extravasation in the affected hemisphere was found only in the Tr-Ox group. The ability of tryptanthrin and Tr-Ox to reduce the BBB permeability in the CI acute period is mainly due to the anti-inflammatory effect of these compounds. The protective effect of Tr-Ox, which can affect the JNK1/3 signaling pathway, was more prolonged.

Keywords:  blood–brain barrier; cerebral infarction; rats; tryptanthrin; tryptanthrin oxime

DOI:  https://doi.org/10.1007/s10517-025-06459-y
Front Neurosci. 2025 ;19 1603292

Exploring novel roles of lipid droplets and lipid metabolism in regulating inflammation and blood-brain barrier function in neurological diseases.

Luo Fu, Ting Luo, Zhongnan Hao, Yongli Pan, Wenqiang Xin, Lin Zhang, Zhuhong Lai, Haitao Zhang, Hua Liu, Wei Wei.

  The blood-brain barrier (BBB) is a critical structure that maintains the brain's homeostasis by regulating the transport of molecules and protecting it from harmful substances. However, in neurological diseases such as ischemic stroke, Alzheimer's disease, Parkinson's disease, and multiple sclerosis, the integrity and function of the BBB can be significantly compromised. In these conditions, BBB disruption leads to increased permeability, which facilitates neuroinflammation, exacerbates neuronal damage, and accelerates disease progression. Recent research has highlighted the potential of lipid-based carriers, including liposomes and lipid droplets (LDs), in modulating the BBB's integrity and function in various neurological diseases. Liposomes, with their ability to cross the BBB via mechanisms such as receptor-mediated transcytosis and carrier-mediated transport, are emerging as promising vehicles for the targeted delivery of therapeutic agents to the brain. These properties allow liposomes to effectively reduce infarct size and promote neuroprotection in ischemic stroke, as well as deliver drugs in the treatment of neurodegenerative diseases. Furthermore, LDs-dynamic regulators of lipid metabolism and cellular energy-play an essential role in maintaining cellular homeostasis, particularly during periods of stress when BBB function is compromised. These LDs help sustain cellular energy needs and modulate inflammatory responses, which are key factors in maintaining BBB integrity. Surface modifications of liposomes can further enhance their targeting efficiency, enabling them to selectively bind to specific brain cell types, including neurons, astrocytes, and microglia. This customization improves the precision of therapeutic delivery and supports the development of more tailored treatments. However, challenges such as immune responses, rapid clearance, and complement activation-related toxicity continue to hinder the broader application of liposomes and LDs in clinical settings. This review will focus on the roles of liposomes and LDs in regulating BBB integrity across a range of neurological diseases, discussing their potential for targeted drug delivery, neuroprotection, and the modulation of neuroinflammation. Additionally, we will explore the strategies being developed to address the limitations that currently restrict their clinical use.

Keywords:  blood–brain barrier; lipid droplets; liposomes; neurological disorders; neuroprotection

DOI:  https://doi.org/10.3389/fnins.2025.1603292
Gut Microbes. 2025 Dec;17(1): 2551879

Early-life gut microbiome maturity regulates blood-brain barrier and cognitive development.

Zachary M Zemmel, Xiaobing Fan, Yueyue Yu, Erica Markiewicz, Hsiu-Ming Tsai, Lei Lu, Jessica C Little, Ramanujam Ramaswamy, Bree Andrews, Erika C Claud, Jing Lu.

  The gut microbiome is an emerging factor in the neurobiology of disease. Blood-brain barrier (BBB) integrity is essential for proper brain function. However, the role the initial microbiome plays in BBB and brain development is unclear. In this study, we colonized germ-free pregnant mice with human full-term- or preterm-infant-derived gut microbiota, thereby establishing these communities in the resulting offspring. We discovered that mice harboring a full-term-associated microbiome exhibited stronger memory and learning capabilities and dramatically decreased early-life BBB permeability when compared to those with a prematurity-associated microbiome. Whole-brain single-cell RNA sequencing revealed downregulation of synaptic signaling genes in BBB cell types of mice with the prematurity-associated microbiome, indicating that microbiome maturity influences BBB transcriptional programs that support cognitive development. Comprehensive metagenomics and metabolomics uncovered bacterial populations and genomic pathways corresponding with decreased levels of circulating long-chain acylcarnitines and lysophosphatidylcholines in mice with the full-term-associated microbiome. Our findings highlight the microbiome as a therapeutic target for improving long-term neurodevelopmental outcomes due to its effect on the early-life BBB.

Keywords:  blood–brain barrier; gut–brain axis; host–microbe interactions; magnetic resonance imaging; metabolomics; neurodevelopmental impairment; shotgun metagenomics; single-cell RNA sequencing

DOI:  https://doi.org/10.1080/19490976.2025.2551879
J Neuroimmunol. 2025 Aug 26. pii: S0165-5728(25)00217-6. [Epub ahead of print]409 578736

The missing link: TNF-α as a unifying mechanism in methamphetamine-induced neuronal dysfunction and blood-brain barrier compromise.

Maria Carolina Machado da Silva, Antônio Carlos Pinheiro de Oliveira, Eduardo Candelario-Jalil, Habibeh Khoshbouei.

  Methamphetamine use disorder remains a significant public health concern, impacting neuronal function, immune responses, and vascular integrity. Of particular interest is methamphetamine's disruption of the blood-brain barrier (BBB), a key event that triggers neuroimmune dysfunction and the development of neurodegenerative conditions. While the systemic effects of methamphetamine are well-characterized, the mechanism(s) governing its dysregulation of BBB physiology remain poorly understood. Emerging evidence suggests that the methamphetamine-induced production of tumor necrosis factor (TNF), occurring both in the periphery and within the central nervous system, triggers a cascade of molecular events that compromises BBB permeability. This review provides a comprehensive overview of current findings on the cross interaction between methamphetamine and the BBB, with particular emphasis on the potential role of TNF in dysregulation of BBB permeability and dysfunction. By elucidating the complex interplay between methamphetamine, TNF, and the BBB, we aim to inform the development of targeted interventions and preventative strategies to mitigate methamphetamine-induced neurovascular and neuroimmune dysfunction.

Keywords:  Addiction; Blood-brain barrier; Cytokines; Methamphetamine; Neuroinflammation; TNF

DOI:  https://doi.org/10.1016/j.jneuroim.2025.578736
Eur Arch Psychiatry Clin Neurosci. 2025 Sep 01.

Serum ZO-1 and occludin levels in bipolar disorder patients.

Pınar Aydogan Avşar, Merve Akkuş.

  Bipolar disorder is a mental illness with a complex and multidimensional etiology. The blood-brain barrier (BBB) is a semi-permeable barrier between the central nervous system (CNS) and peripheral circulation that protects the CNS from external threats. The healthy functioning of the BBB is ensured by tight junctions (TJs) between cells. This research aims to investigate the serum levels of TJ proteins occludin and zonula occludens-1 protein (ZO-1) in bipolar disorder to elucidate etiopathogenesis. This study included 40 BD patients (20 manic episodes, 20 euthymic episodes) and 40 healthy controls. Serum occludin and ZO-1 values were obtained and compared between the two groups. The serum occludin and ZO-1 levels were significantly higher in the bipolar disorder patients. The analysis of covariance (ANCOVA) revealed a significant main effect of groups in the serum occludin and ZO-1 levels and an effect that was independent of age, gender, BMI, and smoking.BBB disruption and neuroinflammation may play a role in bipolar disorder etiopathogenesis. Occludin and ZO-1 may serve as potential biomarkers for BBB leakage in bipolar disorder. Further research may lead to additional pharmacological therapies targeting BBB for drug-resistant bipolar disorder patients.

Keywords:  BBB; Bipolar disorder; Brain-blood-barrier; Occludin; Tight junction proteins; ZO-1

DOI:  https://doi.org/10.1007/s00406-025-02097-7
Tissue Barriers. 2025 Aug 30. 2549020

Pathogenic breaches: how viruses compromise blood-tissue barriers.

Apoorva, Sunit K Singh.

  Blood-tissue barriers (BTBs) are highly specialized, selectively permeable surfaces that separate the circulatory system from delicate tissues and organs. Critical examples include the blood-brain barrier (BBB), blood-retinal barrier (BRB), blood-testis barrier (BTB), and other organ-specific barriers, including the alveolar-capillary interface in the lungs and the glomerular filtration barrier in the kidneys. These barriers regulate the bidirectional transport of nutrients, gases, and waste while restricting pathogens, toxins, and immune cells to maintain physiological balance. Nevertheless, viruses have evolved multiple strategies to circumvent or compromise these barriers, facilitating viral entry, evading immune surveillance, and establishing infection within protected compartments. Neurotropic viruses, including the West Nile virus and Japanese encephalitis virus, impair the blood-brain barrier by disrupting tight junction proteins and cytokine storms. In contrast, respiratory viruses such as influenza and SARS-CoV-2 affect the lung barrier, resulting in alveolar injury and systemic inflammation. Other viruses, such as the Zika virus, affect the BTB and placental barriers, presenting significant risks to fetal development and reproductive health. Such breaches facilitate viral spread, exacerbate tissue damage, and complicate therapeutic interventions. This review provides a comprehensive overview of blood-tissue barrier architecture, function, and mechanisms of viral disruption, highlighting their dual role in protection and susceptibility during viral infections. By elucidating interactions between viruses and blood-tissue barriers, this work highlights emerging research directions to mitigate viral pathogenesis and enhance treatment efficacy for barrier-associated diseases.

Keywords:  Cytokines; endothelial cells; junction proteins; viral receptors; viruses

DOI:  https://doi.org/10.1080/21688370.2025.2549020
Stroke Vasc Neurol. 2025 Sep 04. pii: svn-2025-004409. [Epub ahead of print]

Head-down position after reperfusion improves cerebral ischaemic injury in rat.

Qiong Wu, Nan-Nan Zhang, Ji-Ru Cai, Yi-Na Zhang, Hui-Sheng Chen.

   BACKGROUND AND AIMS: Preclinical and clinical studies found that head-down position (HDP) during ischaemic phase improved neurological function of acute ischaemic stroke, but the effect of HDP after reperfusion has never been investigated. This study aimed to investigate whether HDP after reperfusion can ameliorate cerebral ischaemic injury in rats.
METHODS: The middle cerebral artery occlusion/reperfusion (MCAO/R) model was established in rats, and different HDP interventions were performed. Survival rate, haemorrhage transformation rate, neurological deficit scores, infarct volume, weight loss and brain oedema were measured at 24 hours after surgery to explore the cerebroprotective effect of HDP. Immunohistochemistry, ELISA and western blot were used to determine the possible mechanisms.
RESULTS: Compared with MCAO/R group, HDP -20° immediately after reperfusion with 1 hour duration exerted a significant cerebroprotective effect including reducing brain infarction and oedema, and improving neurological impairment, with a favourable safety profile such as less haemorrhagic transformation and death. These protective effects were not observed under other HDP intervention conditions. Mechanistically, this HDP procedure may exert its effects by regulating microglial polarisation, inhibiting microglial activation and neuroinflammation, reducing brain oedema and blood-brain barrier (BBB) disruption, suppressing apoptosis and improving neurological function.
CONCLUSION: This is the first study to demonstrate the cerebroprotective effect of HDP -20° with 1 hour duration immediately after reperfusion in MCAO/R model rats, which involved inhibition of neuroinflammation and apoptosis as well as protection of BBB.

Keywords:  Cerebral Infarction

DOI:  https://doi.org/10.1136/svn-2025-004409
Magn Reson Med. 2025 Aug 29.

The contributions of aquaporin-4 to water exchange across the blood-brain barrier measured by filter-exchange imaging.

Zejun Wang, Shuyuan Tan, Keyu Lu, Qingcheng Li, Bingjie Jiao, Weiyun Li, Xuetao Wu, Lili Zhang, Linghui Zeng, Ruiliang Bai.

   PURPOSE: Water exchange across the blood-brain barrier (WEXBBB) is a promising biomarker for assessing the blood-brain barrier (BBB) integrity. However, the physiological mechanisms governing WEXBBB remain unclear. This study was conducted to investigate the contribution of Na+/K+-ATPase (NKA) on the luminal side of endothelial cells and aquaporin-4 (AQP4) to WEXBBB.
METHODS: WEXBBB was measured using filter-exchange imaging for BBB assessment (FEXI-BBB) on rats, and data were fitted using an adapted two-compartment crusher-compensated exchange rate (CCXR) model. Test-retest reliability of the vascular water efflux rate constant (kbo) was assessed. Ouabain and 2-(nicotinamide)-1,3,4-thiadiazole (TGN-020) were administered to inhibit NKA on the luminal side of endothelial cells and AQP4, respectively, to investigate their roles in WEXBBB measured by FEXI-BBB.
RESULTS: Fixing intravascular diffusivity in the two-compartment CCXR model significantly improved estimation accuracy and precision of kbo and other parameters. The test-retest experiment demonstrated that this method had good reproducibility in measuring kbo (intraclass correlation coefficient = 0.79). Administering TGN-020, which inhibits AQP4, significantly decreased kbo by 32% (kbo = 3.07 ± 0.81 s-1 vs. 2.09 ± 1.10 s-1, p < 0.05). However, the ouabain-treated group showed no significant change in kbo compared with that of the control group (2.51 ± 0.58 s-1 vs. 2.37 ± 1.02 s-1, p = 0.73) in the NKA inhibition experiment.
CONCLUSIONS: WEXBBB decreased by 32% after administering TGN-020, but no downward trend was noted after administering ouabain. Our findings indicate that AQP4 expression/function, but not NKA activity on the luminal side of endothelial cells, plays a significant role in regulating WEXBBB.

Keywords:  Na+/K+‐ATPase; aquaporin‐4; blood–brain barrier; filter‐exchange imaging; magnetic resonance imaging; water exchange across the blood–brain barrier.

DOI:  https://doi.org/10.1002/mrm.70049
Biol Sex Differ. 2025 Sep 02. 16(1): 67

Sex- and age- differences in the expression of critical blood-brain barrier regulators: a physiological context.

Xue Mi, Zi-Ling Ye, Xu-Jun Zhang, Xiao-Chun Chen, Xiao-Man Dai.

   BACKGROUND: Available evidence indicates that blood-brain-barrier (BBB) dysfunction exacerbates with the advancing age and is implicated in a variety of neurological diseases and that there are significant sex differences in these diseases. However, the sex differences and age-related changes in BBB structure and function are still unclear under physiological conditions.
METHODS: In this study, the mRNA was extracted from the cortical tissues and brain microvessels of male and female mice aged 3 months and 10 months to detect the expression of important BBB-related genes by qPCR.
RESULTS: Under physiological conditions, compared with age-matched male counterparts, female mice reported a significantly lower mRNA expression of tight junction-related genes (cldn5 and occludin), transporters (Glut1 and D-gp), pericyte marker (Pdgfrb), microvessel marker (Cd31), basement membrane component (Col4a2), glycocalyx-related genes (Hs3st1, Extl2, and Clgalt), vascular homeostasis-related genes (Hif1a, Ddit4, and Pik3ca), and some regulatory genes (Adm, Zfpm2 and Nr3c1). A similar outcome was found in the 10-month mice when compared with the 3-month counterparts.
CONCLUSION: This study systematically analyzes the expression characteristics of key BBB regulatory genes in different sexes and ages under physiological conditions and reveals a marked sex difference in the expression of BBB structure/function-related genes, which may persist with the advancing age. The findings may provide important theoretical insights into the pathogenesis of sex-and age-related neurological diseases.

Keywords:  Age; Blood-brain barrier; Brain microvessel; Glycocalyx; Pericytes; Sex difference

DOI:  https://doi.org/10.1186/s13293-025-00751-2
Adv Sci (Weinh). 2025 Aug 30. e07256

Cerebral Organoids with Integrated Endothelial Networks Emulate the Neurovascular Unit and Mitigate Core Necrosis.

Josep Fumadó Navarro, Siobhan Crilly, Wai Kit Chan, Shane Browne, John O Mason, Catalina Vallejo-Giraldo, Abhay Pandit, Mihai Lomora.

  Cerebral organoids (COs) are multicellular, self-organized, in vitro, 3D brain-like tissues used for developmental biology, disease modelling, and drug screening. However, their lack of vascularity renders them less physiologically accurate. Vascularization of COs remains challenging due to the different requirements between COs and vascular cells, limited vascular network penetration within the organoid, and the absence of luminal perfusion. Here, an encapsulation approach is devised in which human brain microvascular endothelial cells (HBMVECs) are delivered to developing COs from progressively degrading extracellular matrix (ECM)-based hydrogel droplets. By tuning this hydrogel concentration and media composition, an enhanced vascular-like network formation is observed, expanding within the organoid tissue. Using pathway inhibitors, a subset of the endothelial cells (ECs) is shown to originate from the CO itself, promoting network integration. Endothelial networks displayed blood-brain barrier (BBB) features, including astrocytic end-foot-like interactions, pericyte wrapping, and collagen-laminin basal lamina. Vascularized COs exhibited greater media internalization and up to three-fold lower apoptosis than non-vascularized COs. This comprehensive 3D neurovascular model is a promising platform for cerebrovascular research and drug testing applications.

Keywords:  angiogenesis; blood‐brain barrier; cerebral organoids; endothelial cells; perfusion; vascularization

DOI:  https://doi.org/10.1002/advs.202507256
Brain Stimul. 2025 Aug 28. pii: S1935-861X(25)00317-1. [Epub ahead of print]

Effects of atorvastatin-loaded PEGylated liposomes delivered by magnetic stimulation for stroke treatment.

Ji-Hye Kim, Ja-Hae Kim, Hafiz Ashfaq Ahmad, Hohyeon Kim, Nagareddy Raveena, Kang-Ho Choi, Jungwon Yoon, Yong-Yeon Jeong.

   BACKGROUND: Focused magnetic stimulation (MagStim) can temporarily and safely open the blood-brain barrier (BBB) for target delivery. We investigated whether opening the BBB with MagStim and delivering atorvastatin-loaded PEGylated liposomes (LipoStatin) would work synergistically for subacute post-stroke treatment.
METHODS: Two weeks after middle cerebral artery occlusion (MCAO), an injection of 15 mg/ml magnetic nanoparticles (MNPs) was performed, followed by 30 minutes of MagStim, in subacute stroke models. The procedure was conducted over a week, during which MagStim and MNPs were administered three times at two-day intervals, and LipoStatin (10 mg/kg) was injected immediately after each MagStim treatment. We investigated the motor function, BBB integrity, neuroinflammation, and neurogenesis three weeks after stroke (Sham vs. Control vs. LipoStatin vs. MagStim+LipoStatin).
RESULTS: The MagStim+LipoStatin group showed improved motor function compared to the Control (p = 0.007) group. The MagStim+LipoStatin group significantly reduced infarct volume and improved BBB integrity compared to the control and LipoStatin groups. In the MagStim+LipoStatin group, the expression of TNF-α was reduced (p = 0.020) compared to the LipoStatin group, and eNOS was enhanced (p = 0.037) compared to the Control group. Markers for neurogenesis were also considerably increased in the MagStim+LipoStatin group compared to the Control and LipoStatin groups (p < 0.0001).
CONCLUSIONS: Our study demonstrates the beneficial synergistic effects of MagStim and the target delivery of LipoStatin in subacute ischemic stroke. These findings underscore the need for future advancements in promising novel non-invasive MagStim methods and nanotherapeutic hybrid approaches for target drug delivery and treatment in post-stroke recovery.

Keywords:  BBB; LipoStatin; delivery; ischemic stroke; magnetic stimulation; nanoparticle

DOI:  https://doi.org/10.1016/j.brs.2025.08.024
Brain Res. 2025 Aug 26. pii: S0006-8993(25)00464-0. [Epub ahead of print]1866 149901

Selectin E upregulation upon forkhead box P1 loss augments neutrophil infiltration and brain damage in hypertensive intracerebral hemorrhage.

Naizhu Wang, Jingkun Wu, Zhaofei Song, Hongbin Wang, Yan Zhao.

  Hypertension in the brain may lead to hypertensive intracerebral hemorrhage (HICH), a devastating disease. This study, grounded on bioinformatics insights, aims to investigate the functions of Selectin E (SELE) and forkhead box P1 (FOXP1) in the progression of HICH. Increased SELE expression was detected in the striatum of a mouse model of HICH generated via angiotensin II and L-NAME treatments. Knockdown of SELE alleviated hemorrhage, neutrophil infiltration, and blood-brain barrier (BBB) rupture in the mouse brain. FOXP1, poorly expressed in the HICH mice, was found to repress SELE transcription by binding to its promoter region. Overexpression of FOXP1 resulted in analogous alleviating effects in the HICH mice; however, the effects were abrogated by the additional SELE overexpression. In vitro, human brain microvascular endothelial cells (HBMECs) were treated with thrombin to generate a cellular model of ICH, followed by co-culture with HL-60 cell-derived neutrophils. The FOXP1 overexpression reduced the adhesion of neutrophils, and it alleviated HBMEC apoptosis and permeability while enhancing angiogenesis. Still, these effects were counteracted by the SELE upregulation. In conclusion, this study demonstrates that SELE upregulation upon FOXP1 loss is associated with neutrophil infiltration and BBB rupture in HICH.

Keywords:  Blood-brain barrier rupture; Forkhead box P1; Hypertensive intracerebral hemorrhage; Neutrophil infiltration; Selectin E

DOI:  https://doi.org/10.1016/j.brainres.2025.149901
Environ Res. 2025 Aug 31. pii: S0013-9351(25)01985-1. [Epub ahead of print]285(Pt 5): 122733

17β-trenbolone increases circulating myeloid-derived MMP8 in CSDS-induced mice and drives depressive tendencies to social threat.

Xiang Zuo, Xiaochen Kuang, Ruimin Li, Yudi Zhao, Jingyi Tuo, Jinyu Qiu, Qili Zhao, Huijuan Bai, Xin Zhao, Xizeng Feng.

  Chronic psychosocial stress is a major risk factor for major depressive disorder (MDD). The impact of 17β-trenbolone (17-TB), an anabolic steroid and potential environmental endocrine disruptor, on stress responses and mood states in mammals is unclear. In this study, we explored how 17-TB interacts with chronic social defeat stress (CSDS) to drive neuroinflammatory cascades and behavioral abnormalities in mice. Utilizing a multidisciplinary cross-cutting approach integrating behavioral analysis, molecular biology, neuroimmunology, and electrophysiology, we ascertained that 17-TB exacerbated CSDS-induced mice peripheral inflammation by increasing IL-6, IL-1β, TNF-α, and myeloid-derived Matrix metalloproteinase 8 (MMP8). Furthermore, the study identified a concomitant downregulation of blood-brain barrier (BBB) tight junction proteins (ZO-1, Occludin), accompanied by an increase in BBB permeability. This led to degradation of the extracellular matrix (ECM) and altered neuronal excitability, evidenced by elevated EPSC amplitude/frequency and abnormal action potential firing, which were linked to heightened anxiety and depressive-like behaviors. Interestingly, 17-TB enhanced social dominance in CSDS-induced mice, associated with increased c-Fos+ expression in the medial prefrontal cortex (mPFC), indicating a disconnect between social competitiveness and emotional vulnerability. In conclusion, our study identified 17-TB as a neurotoxin that exacerbates stress-induced depression-like behaviors through BBB leakage, neuroinflammation, and ECM-driven synaptic dysfunction. The paradoxical social dominance highlights the ability of endocrine-disrupting chemicals (EDCs) to dysregulate neural circuits controlling emotional and social behavior. These findings underscore the imperative for a re-evaluation of EDC regulatory policy and the formulation of a therapeutic strategy that targets MMP8, a pivotal mediator of neuro-immune crosstalk in mood disorders.

Keywords:  Anxiety-depression; Blood-brain barrier; Environmental endocrine disruptor; Matrix metalloproteinase 8; Neuroinflammation; Social competition

DOI:  https://doi.org/10.1016/j.envres.2025.122733
Aging Dis. 2025 Sep 01.

Crossing Pathological Boundaries: Multi-Target Restoration of the Neurovascular Unit in Alzheimer's and Vascular Dementia-From Modern Therapeutics to Traditional Chinese Medicine.

Tengyu Zhao, Pengyu Pan, Ying Jia, Yuhan Zhou, Xinyue Zhang, Huibo Guan, Quan Li, Yanyan Zhou.

Alzheimer's disease (AD) and vascular dementia (VD) are the two most common forms of dementia, and they share common mechanisms, especially in regard to neurovascular dysfunction. There has been increasing evidence that the disruption of the neurovascular unit (NVU), which consists of endothelial cells, pericytes, astrocytes, microglia, neurons, and basement membrane, is one of the key early events in both AD and VD. The objective of this review is to summarize the structure and physiological function of the NVU, then discuss the pathological remodeling of the NVU in AD and VD and finally, show emerging evidence of multi-target approaches that restore the NVU and neurovascular protection. We begin with a description of the structure, and dietary regulatory roles of the NVU in cerebral homeostasis, especially related to Aβ, the blood-brain barrier (BBB), and neurovascular coupling (NVC). The NVU is then related to the pathological events that cause AD and VD, specifically to impaired Aβ clearance, inflammatory cascades, oxidative stress, and neurovascular uncoupling. Finally, the discussion focuses on a multi-target approach involving exercise, estrogen therapy, mesenchymal stem cells/exosomes, remote ischemic conditioning (RIC), and mindfulness meditation, and analyzes its implications for recovering NVU structure and function. We also discuss the concept of traditional Chinese medicine (TCM) approaches associated with NVU modulation with herbal formulas, traditional Chinese exercises and acupuncture, which has integrative pathways for MVU modulation. NVU dysfunction has a significant and converging impact on the development of both AD and VD. There is considerable support for multi-pathway neurovascular unit targeting, which should show a significant delay in cognitive decline. Incorporating multi-modal evidence from contemporary and traditional medical systems could offer new insights for individualized, neurovascular-targeted therapy for dementia.

DOI: https://doi.org/10.14336/AD.2025.0801
bioRxiv. 2025 Aug 28. pii: 2025.08.22.671845. [Epub ahead of print]

Lipid-laden endothelial cells exhibit a transcriptomic signature linked to blood-brain barrier dysfunction, metabolic reprogramming and increased inflammation in the aging brain.

Sarah Otu-Boakye, Duraipandy Natarajan, Bhuvana Plakkot, Ilakiya Raghavendiran, Tamas Kiss, Madhan Subramanian, Priya Balasubramanian.

Dysregulation in lipid metabolism is increasingly recognized as a key contributor to age-related diseases, including neurodegeneration and cerebrovascular dysfunction. While prior studies have largely focused on glial cells, the impact of lipid dysregulation on brain endothelial aging remains poorly understood. In this study, we conducted a secondary analysis of single-cell transcriptomic data from young and aged mouse brains, with a specific focus on endothelial cells (ECs). Our analyses revealed that aging promotes lipid droplet accumulation in brain ECs. These lipid-laden brain ECs exhibit a transcriptomic signature indicative of impaired blood-brain barrier function, increased cellular senescence, and inflammation in aging. Furthermore, lipid accumulation is associated with an altered metabolic phenotype characterized by increased fatty acid oxidation and decreased glycolysis, and impaired mitochondrial electron transport chain activity in the ECs of the aging brain. We have also validated lipid accumulation in aged ECs in vivo . Collectively, our findings indicate that lipid accumulation drives structural, functional, and metabolic impairments in the brain ECs, likely contributing to cerebrovascular aging. Understanding the mechanisms underlying lipid accumulation-induced endothelial dysfunction may offer novel therapeutic strategies for mitigating microvascular dysfunction and cognitive decline in aging.

DOI: https://doi.org/10.1101/2025.08.22.671845
Acta Pharm Sin B. 2025 Aug;15(8): 4248-4264

Artificial mesenchymal stem cell extracellular vesicles enhanced ischemic stroke treatment through targeted remodeling brain microvascular endothelial cells.

Shengnan Li, Wei Lv, Jiangna Xu, Jiaqing Yin, Yuqin Chen, Linfeng Liu, Xiang Cao, Wenjing Li, Zhen Li, Hua Chen, Hongliang Xin.

  Ischemic stroke is the leading cause of disability and mortality worldwide. The blood‒brain barrier (BBB) is the first line of defense after ischemic stroke. Disruption of the BBB induced by brain microvascular endothelial cells (BMECs) dysfunction is a key event that triggers secondary damage to the central nervous system, where blood-borne fluids and immune cells penetrate the brain parenchyma, causing cerebral edema and inflammatory response and further aggravating brain damage. Here, we develop a novel artificial mesenchymal stem cell (MSC) extracellular vesicles by integrating MSC membrane proteins into liposomal bilayers, which encapsulated miR-132-3p with protective effects on BMECs. The artificial extracellular vesicles (MSCo/miR-132-3p) had low immunogenicity to reduce non-specific clearance by the mononuclear phagocytosis system (MPS) and could target ischemia-injured BMECs. After internalization into the damaged BMECs, MSCo/miR-132-3p escaped the lysosomes via the HII phase transition of 1,2-dioleoyl-sn-glycero-3-phosphoethanolamine (DOPE) and decreased cellular reactive oxygen species (ROS) and apoptosis levels by regulating the RASA1/RAS/PI3K/AKT signaling pathway. In the transient middle cerebral artery occlusion (tMCAO) models, MSCo/miR-132-3p targeted impaired brain regions (approximately 9 times the accumulation of plain liposomes at 12 h), reduced cerebral vascular disruption, protected BBB integrity, and decreased infarct volume (from 44.95% to 6.99%).

Keywords:  Apoptosis; Artificial extracellular vesicles; Blood‒brain barrier; Cerebral vascular endothelial cells; Ischemic stroke therapy; Mesenchymal stem cell membrane proteins; Oxidative stress; miR-132-3p

DOI:  https://doi.org/10.1016/j.apsb.2025.06.009
Exp Neurol. 2025 Aug 27. pii: S0014-4886(25)00312-7. [Epub ahead of print] 115447

By inhibiting pyroptosis to reduce neuroinflammation, PEG-bHb may prevent the development of secondary injury after traumatic brain injury.

Qiang Zeng, Guoxing You, Weidan Li, Jianlei An, Zhiyong Huang, Xiaoyong Zhang, Hong Zhou, Yao Xiao, Ying Wang, Lian Zhao.

  Changes in severe pathological microenvironment of traumatic brain injury (TBI) have important implications for neurological repair, including oxidative stress and intense neuroinflammatory responses. Pyroptosis, a regulated cellular demise process characterized by membrane permeabilization, constitutes a primary contributor to post-traumatic brain injury induced neural inflammatory responses. Regulating the pyroptosis pathway may alleviate secondary brain injury. Polyethylene glycol-conjugated bovine hemoglobin (PEG-bHb) is a type of hemoglobin-based oxygen carriers (HBOCs) and is designed for oxygen delivery in transfusion therapy. PEG-bHb exhibits the capacity to bind and release oxygen, promoting oxygen supply in hypoxic tissues. In vivo studies have found that PEG-bHb can elevate regional oxygen saturation after TBI in prehospital stage, effectively inhibit pyroptosis, attenuate neuroinflammation and oxidative stress, and effectively attenuate the development of secondary brain injury. Furthermore, PEG-bHb has been demonstrated to protect the blood-brain barrier (BBB) by reducing the permeability of BBB and attenuating brain edema. PEG-bHb has been shown to enhance motor, learning, and memory abilities following TBI. Thus, PEG-bHb can act as a promising candidate for TBI treatment.

Keywords:  Hemoglobin-based oxygen carries; Mitochondrial dysfunction; Neuroinflammation; Oxidative stress; Pyroptosis; Traumatic brain injury

DOI:  https://doi.org/10.1016/j.expneurol.2025.115447