bims-blobar Biomed News
on Blood brain barrier repair
Issue of 2025–11–09
seventeen papers selected by
Nicolas Rebergue
  1. Nicotinamide mononucleotide rescues Di-n-butyl phthalate induced blood-brain barrier damage via NAD+/Sirt1/FOXO1a pathway activation.
  2. Metformin's protection against blood-brain barrier disruption and neuronal dysfunction under oxygen-glucose deprivation and tobacco smoke and e-vape chemical exposure.
  3. [Development of human iPS cells-derived brain microvascular endothelial cells].
  4. Proteomic subtyping of Alzheimer's disease CSF links blood-brain barrier dysfunction to reduced levels of tau and synaptic biomarkers.
  5. An iPSC-derived model for drug screening in cerebral small vessel disease.
  6. Blood-Brain Barrier Leakage: A New Imaging Biomarker of Cerebral Amyloid Angiopathy?
  7. Mechanisms of high-density lipoprotein in regulating blood-brain barrier function: insights and implications.
  8. Non-Contrast Assessment of Blood-Brain Barrier Permeability to Water: Improved Signal Modeling and Data Acquisition.
  9. Inflammation and Cognitive Decline: A Population-Based Cohort Study Among Aging Adults With Atrial Fibrillation.
  10. Soluble Epoxide Hydrolase Inhibition Confers Neuroprotection via PPAR-α Activation During Intracerebral Hemorrhage.
  11. Apigenin regulates CCR5/JAK1/STAT1/MMPs signaling to alleviate secondary brain injury after intracerebral hemorrhage and its enhanced delivery via targeted nanoparticles.
  12. Targeting hypercoagulability in ischemic stroke modulates fibrin-driven microglial polarization via JAK-STAT pathway.
  13. Endothelial ephrin-B2 knockdown increases post-traumatic disruption of the blood-spinal cord barrier following spinal cord injury.
  14. Pathophysiological Divergence Between Vascular and Post-Stroke Dementia: Bridging Human and Experimental Perspectives.
  15. Low-frequency electroacupuncture attenuates methamphetamine-induced depressive-like behaviors and cognitive impairment via modulating neuroinflammation.
  16. In Vivo Imaging of Blood-Brain Barrier Leakage Using a Contrast Agent in Patients With Cerebral Amyloid Angiopathy: An Exploratory Study.
  17. Gut microbiota modulates CNS barrier function in murine model for multiple sclerosis.
  1. Ecotoxicol Environ Saf. 2025 Oct 15. pii: S0147-6513(25)01635-5. [Epub ahead of print]305 119290
    Nicotinamide mononucleotide rescues Di-n-butyl phthalate induced blood-brain barrier damage via NAD+/Sirt1/FOXO1a pathway activation.
    Renjie Liu, Jiahui Feng, Yanqing Song, Haoyuan Yin, Zhongxi Yang, Yuhao Zhao, Jinan Ma, Xuan Chen, Huan Gao.
       BACKGROUND: Di-n-butyl phthalate (DBP), a pervasive environmental contaminant, is associated with neurotoxicity and cognitive deficits. However, its impact on blood-brain barrier (BBB) integrity and the underlying mechanisms, particularly involving nicotinamide adenine dinucleotide (NAD⁺) metabolism, remain poorly understood.
    AIMS: This study first investigated whether DBP impairs BBB integrity via NAD⁺ depletion and suppression of the Sirtuin 1 (Sirt1)/Forkhead box O1a (FOXO1a) pathway. Moreover, we further explored the therapeutic potential of nicotinamide mononucleotide (NMN), an NAD⁺ precursor, to counteract this damage.
    METHODOLOGIES: C57BL/6 mice were exposed to environmentally relevant doses of DBP to simulate human exposure. BBB integrity, neuroinflammation, and cognitive function were assessed using Evans blue dye, histopathology, ELISA, and behavioral tests. Transcriptomic analysis of cortical tissues identified dysregulated pathways. Human brain microvascular endothelial cells (HBMECs) were used to validate the mechanisms in vitro, with interventions involving NMN and the Sirt1 inhibitor EX-527.
    RESULTS: DBP exposure could significantly enhance BBB permeability, elevate the expression of pro-inflammatory cytokines, and decrease the levels of tight junction proteins. Transcriptomic analyses further revealed coordinated dysregulation of mitochondrial dysfunction and the Sirt1/FOXO1a signaling pathway. NMN supplementation effectively restored NAD+ concentrations, reactivated the Sirt1/FOXO1a pathway and mitigated BBB damage, thereby enhancing cognitive performance. The therapeutic benefits of NMN were abolished by EX-527 in HBMECs, confirming the critical role of Sirt1 in mediating therapeutic outcomes.
    CONCLUSION: DBP disrupts BBB integrity and cognitive function through NAD+ depletion-driven suppression of the Sirt1/FOXO1a pathway. NMN counteracts these effects, suggesting its potential as a therapeutic agent against environmental neurotoxins.
    Keywords:  Blood-brain barrier permeability; Environmental neurotoxicity; Mitochondrial dysfunction; Neuroinflammation; Phthalate exposure
    DOI:  https://doi.org/10.1016/j.ecoenv.2025.119290
  2. Fluids Barriers CNS. 2025 Nov 03. 22(1): 110
    Metformin's protection against blood-brain barrier disruption and neuronal dysfunction under oxygen-glucose deprivation and tobacco smoke and e-vape chemical exposure.
    Khondker Ayesha Akter, Sejal Sharma, Sejal Rajesh Jadhav, Yong Zhang, Thomas J Abbruscato.
       BACKGROUND: According to our previous findings, the integrity of the blood-brain barrier (BBB) is affected by tobacco smoke (TSe) and electronic cigarette (ECe) exposure, and metformin (MF) can counter these detrimental effects. It is unknown, therefore, if MF protects against neuronal dysfunction after BBB damage caused by either TSe or ECe alone or combined exposure (TSe and ECe) in stroke cases. Additionally, MF's ability to enter the ischemic brain during ischemic stroke is unknown. The purpose of this effort is to address these questions.
    METHODS: A well-established bEnd3/astrocyte co-culture in vitro BBB model was utilized to conduct permeability studies. Normoxia and hypoxia using oxygen-glucose deprivation (OGD) conditions were used to mimic the in vitro stroke conditions. Western blot (WB) and immunofluorescence analysis were performed for relevant molecular targets. Additionally, mitochondrial dysfunction was assessed using Seahorse Mito-stress analysis using primary neurons. Also, tMCAO was performed in C57BL/6 J mice to create ischemic injury. To quantify MF in the mouse brain, a highly sensitive LC-MS/MS technique was used.
    RESULTS: According to our findings, a decrease in transendothelial electric resistance (TEER) values and increased permeability coefficient (PC) for sodium fluorescein were observed in the OGD/R condition alone or when combined with TSe, ECe, or mixed exposure compared to the control group. MF pretreatment, however, protected the BBB from losing barrier properties by increasing the TEER and decreasing PC values. Altered expression of tight junction (TJ) proteins was observed following TSe and ECe exposure paired with OGD compared to the control and OGD alone. However, MF was capable of offsetting the majority of these adverse effects by differentially upregulating ZO-1, occludin, and claudin-5 expression. Altered neuronal mitochondrial dynamics and decreased OCR were observed after OGD alone or in combination with TSe or ECe, however, MF pretreatment significantly increased several indices of mitochondrial functions, especially basal respiration, ATP production, and non-mitochondrial O2 consumption.
    CONCLUSION: Our findings demonstrate that MF pretreatment could be an effective countermeasure following OGD exposure in conjunction with TSe and ECe exposure, which is often linked to the deterioration of the BBB and possibly mitochondrial function.
    Keywords:  BBB; Electronic cigarette; Mitochondrial dysfunction; Stroke; Tobacco smoke
    DOI:  https://doi.org/10.1186/s12987-025-00719-9
  3. Nihon Yakurigaku Zasshi. 2025 ;160(6): 404-410
    [Development of human iPS cells-derived brain microvascular endothelial cells].
    Tadahiro Hashita.
      Brain microvascular endothelial cells (BMECs) are the central cellular components of the blood-brain barrier (BBB) that protect the central nervous system. The characteristic functions of the BBB, such as its strong barrier properties and selective regulation of molecular transport into the brain, are largely mediated by BMECs. Human induced pluripotent stem cell-derived BMECs (iBMECs) have garnered attention because of their robust tight junction integrity and transporter activity, distinguishing them from cells used in conventional BBB models. In recent years, iBMECs have shown great promise for drug discovery and disease modeling, particularly through integration with organ-on-a-chip technologies and the use of disease-specific iPS cells to construct disease-mimicking BBB models. This article provides an overview of the current state and future prospects of iBMECs, highlighting advances in differentiation techniques, cellular characteristics, and their emerging applications.
    DOI:  https://doi.org/10.1254/fpj.25043
  4. Alzheimers Dement. 2025 Nov;21(11): e70830
    Proteomic subtyping of Alzheimer's disease CSF links blood-brain barrier dysfunction to reduced levels of tau and synaptic biomarkers.
    Madison C Bangs, Joshna Gadhavi, E Kathleen Carter, Lingyan Ping, Duc M Duong, Eric B Dammer, Fang Wu, Anantharaman Shantaraman, Edward J Fox, Erik C B Johnson, James J Lah, Allan I Levey, Nicholas T Seyfried.
       INTRODUCTION: Alzheimer's disease (AD) shows clinical and molecular heterogeneity shaped by demographic and genetic factors.
    METHODS: To resolve this heterogeneity, we performed a network-based proteomic analysis of cerebrospinal fluid (CSF) from 431 individuals, including 111 African Americans, to identify protein co-expression modules and define AD subtypes.
    RESULTS: Ten co-expression modules reflecting diverse pathways and cell types were identified, many linked to demographics and AD biomarkers. One subtype, enriched in African Americans and males, showed low CSF tau, elevated plasma proteins, and reduced synaptic proteins, features consistent with blood-brain barrier (BBB) dysfunction. This subtype also showed the highest levels of thrombin activity, capable of cleaving tau. Introducing plasma into CSF ex vivo recapitulated the BBB subtype signature, supporting a causal role for plasma proteases in tau and synaptic protein depletion.
    CONCLUSION: These findings link BBB dysfunction and plasma proteases to CSF tau loss and highlight the need for diversity in AD-biomarker research.
    HIGHLIGHTS: Race and sex correlate with key AD proteomic network modules. We identify six proteomic subtypes with distinct demographic and AD biomarker profiles. Subtype 3 demonstrates an A+/T- phenotype and a profile suggestive of BBB dysfunction. Low CSF tau and neuronal proteins may stem from infiltrating plasma protease cleavage. Plasma spike-in experiments show decreased endogenous CSF tau and neuronal proteins.
    Keywords:  blood–brain barrier; central nervous system; diagnosis; nervous system; nervous system diseases; neurobiology; neurodegenerative; neurodegenerative tauopathies; neurology; prognosis
    DOI:  https://doi.org/10.1002/alz.70830
  5. J Cereb Blood Flow Metab. 2025 Nov 07. 271678X251389379
    An iPSC-derived model for drug screening in cerebral small vessel disease.
    Alessandra Granata, Maha Al-Thani, Mary Goodwin-Trotman, David M Smith, Tom Van Agtmael, Hugh S Markus.
      Despite the enormous health importance of cerebral small vessel disease (cSVD) there are few treatments available. A major limitation in screening new therapies is a lack of clinically relevant disease models. Induced pluripotent stem cell (iPSC) technology allows creation of in vitro models of the vascular unit, which is found to be affected in cSVD. Here we derived iPSC from skin biopsies obtained from patients with two of the most common monogenic forms of cSVD, HTRA1 mutations and COL4A1/2 mutations. iPSCs were differentiated into brain endothelial-like cells and mural cells and co-cultured in a transwell system to replicate the vascular unit. iPSC models derived from the two distinctive forms of monogenic cSVD demonstrated a common molecular phenotype characterised by tight junction defects, elevated actin stress fiber expression and mural cell loss, increased blood-brain barrier (BBB) permeability and elevated matrix metalloproteinase (MMP) levels. Moreover, the model was successfully optimised to a 96-well format to screen 13 MMP inhibitors, three of which effectively restored permeability to control levels. Our findings provide evidence that MMP inhibition could serve as a potential therapeutic strategy for cSVD as well as present a robust model to screen drugs in cSVD.
    Keywords:  Cerebral small vessel disease; drug screening; induced pluripotent stem cells; matrix metalloproteinases; vascular dementia
    DOI:  https://doi.org/10.1177/0271678X251389379
  6. Neurology. 2025 Nov 25. 105(10): e214422
    Blood-Brain Barrier Leakage: A New Imaging Biomarker of Cerebral Amyloid Angiopathy?
    Jean-Claude Baron.
      
    DOI:  https://doi.org/10.1212/WNL.0000000000214422
  7. Fluids Barriers CNS. 2025 Nov 05. 22(1): 113
    Mechanisms of high-density lipoprotein in regulating blood-brain barrier function: insights and implications.
    Pengxi Zhu, Liyao Xiao, Yijie Wang.
      
    Keywords:  Apolipoprotein; Blood-brain barrier; Cholesterol metabolism; Glial cell polarization; Glymphatic system; High-density lipoprotein; Neurodegenerative diseases; Pericyte; Sphingosine-1-phosphate axis
    DOI:  https://doi.org/10.1186/s12987-025-00721-1
  8. Magn Reson Med. 2025 Nov 02.
    Non-Contrast Assessment of Blood-Brain Barrier Permeability to Water: Improved Signal Modeling and Data Acquisition.
    Wen Shi, Jiani Wu, Yifan Gou, Jie Song, Zhiyi Hu, Zihan Wang, Dengrong Jiang, Rebecca Veenhuis, Leah Rubin, Yulin Ge, Zixuan Lin, Hanzhang Lu.
       PURPOSE: Water-extraction-with-phase-contrast-arterial-spin-tagging (WEPCAST) MRI is a non-contrast method to estimate the blood-brain barrier (BBB) permeability to water. Similar to other arterial-spin-labeling (ASL) based techniques, signal-to-noise ratio is a limitation. This study aims to enhance its reliability via theoretical and experimental improvements.
    METHODS: We propose a generalized-venous-signal (GVS) model to describe the signal evolution of WEPCAST MRI, with which the control and labeled signals can be utilized to simultaneously estimate the water extraction fraction (E) and venous transit time (VTT). We conducted studies to test its feasibility and inter-visit reproducibility. We further made an experimental improvement by adding a 1-min blood T1 scan and investigating its benefit in reducing inter-subject variations.
    RESULTS: When applying the GVS model-based method at different locations along the superior sagittal sinus (SSS), VTT increased from anterior to posterior segments while E remained constant, consistent with known physiology. BBB permeability-surface-area-product (PS) revealed a significantly lower CoV of 5.0% ± 4.1% when using the GVS method, in comparison with 8.9% ± 6.5% using the peak-detection method (p = 0.002). Blood T1 was found to be 1725.7 ± 37.2 ms in males and 1799.2 ± 122.4 ms in females. After including subject-specific blood T1 in the parametric estimation, inter-subject CoV in PS was found to be 6.8%, compared with a CoV of 14.2% when using an assumed blood T1 (p = 0.004). VTT estimated from WEPCAST was consistent with that measured with a dedicated sequence (R = 0.757, p = 0.011).
    CONCLUSION: The reliability of WEPCAST MRI for the measurement of BBB permeability can be improved by incorporating GVS model and individual blood T1.
    Keywords:  WEPCAST MRI; blood–brain barrier; cerebral venous system; permeability; venous transit time
    DOI:  https://doi.org/10.1002/mrm.70168
  9. J Am Heart Assoc. 2025 Nov 04. 14(21): e039636
    Inflammation and Cognitive Decline: A Population-Based Cohort Study Among Aging Adults With Atrial Fibrillation.
    Danielle Marion, Zhe Li, Austyn Roseborough, Shawn N Whitehead, Ellen E Freeman, David H Birnie, Fanny M Elahi, Vladimir Hachinski, Mary Cushman, Jodi D Edwards.
       BACKGROUND: Despite associations between atrial fibrillation (AF) and cognitive decline independent of stroke, pathways underlying this relationship remain unclear. Inflammatory markers, such as CRP (C-reactive protein), are associated with blood-brain barrier (BBB) permeability, potentially leading to neuroinflammation and neurodegeneration. We estimated associations of CRP with cognitive impairment and death in aging adults with AF.
    METHODS: Adults aged ≥45 years with prevalent AF and no cognitive impairment were identified from the REGARDS (Reasons for Geographic and Racial Differences in Stroke) cohort (N=30 239). Plasma CRP was measured at baseline and cognitive status measured annually using the Six-Item Screener. Competing risks Cox proportional hazards regression was used to estimate cause-specific hazard for cognitive impairment (Six-Item Screener score ≤3). Cognitive trajectories were identified using latent class growth models and adjusted binomial logistic regression used to estimate associations between CRP and cognitive trajectories, with interactions by sex.
    RESULTS: Among 2109 participants, 285 developed cognitive impairment and 786 died over a median 9-year follow-up. A doubling of baseline CRP levels was associated with increased death (hazard ratio [HR], 1.13 [95% CI, 1.08-1.19]) but not incident cognitive impairment (HR, 0.98 [95% CI, 0.91-1.04]). Latent class analyses identified 2 unique cognitive trajectories: 91% had a stable trajectory, while 9% showed progressive decline. Sex-specific models showed a 9% increased odds of progressive cognitive decline in men (odds ratio, 1.09 [95% CI, 1.01-1.17]) but not women (odds ratio, 1.04 [95% CI, 0.97-1.12]).
    CONCLUSIONS: Higher CRP was associated with cognitive impairment in aging men with AF, highlighting inflammation-mediated blood-brain barrier dysfunction as a potential pathway linking AF to cognitive decline.
    Keywords:  atrial fibrillation; blood–brain barrier permeability; cognitive decline
    DOI:  https://doi.org/10.1161/JAHA.124.039636
  10. J Neurosci Res. 2025 Nov;103(11): e70092
    Soluble Epoxide Hydrolase Inhibition Confers Neuroprotection via PPAR-α Activation During Intracerebral Hemorrhage.
    Ari Misael Martínez-Torres, Cynthia Navarro-Mabarak, Julio Morán.
      Epoxyeicosatrienoic acids (EETs), are known to possess potent anti-inflammatory and antioxidant neuroprotective properties. However, the molecular mechanisms responsible for these effects are not well understood. In this work, we aimed to evaluate the neuroprotective role of EETs in a hemorrhagic stroke model and the possible involvement of PPAR-α activation in this neuroprotection. Hemorrhagic damage was induced in mice through the intracerebral administration of collagenase VII in the striatum. The neuroprotective effect of EETs was tested in mice by pre-treatments of 2 h with TPPU, an inhibitor of the EETs metabolism. TPPU was administered intraperitoneally at a dose of 0.5, 1.0, or 2 mg/kg. Brain damage was evaluated based on measurements of motor activity, hematoma volume, brain water content, and blood-brain barrier (BBB) permeability. Additionally, the levels of enzymes involved in the oxidative stress balance, such as NADPH oxidase 2 (NOX-2) and superoxide dismutase (SOD), were determined by Western blot analysis. Our results showed that EETs exert neuroprotective effects by significantly decreasing all parameters related to brain damage, improving motor function and promoting an antioxidant state, as evidenced by increased levels of SOD and reduced levels of NOX enzymes. Subsequently, PPAR-α involvement was evaluated through the administration of GW6471, a PPAR-α antagonist. Pre-treating mice with GW6471 for 30 min, reverted all neuroprotective effects, including the observed changes in SOD and NOX levels. Our results demonstrate that EETs confer neuroprotection in hemorrhagic brain injury, and this effect is dependent on PPAR-α activation.
    Keywords:  TPPU; epoxyeicosatrienoic acids (EETs); intracerebral hemorrhage; neuroprotection; soluble epoxide hydrolase (sEH)
    DOI:  https://doi.org/10.1002/jnr.70092
  11. J Nanobiotechnology. 2025 Nov 03. 23(1): 696
    Apigenin regulates CCR5/JAK1/STAT1/MMPs signaling to alleviate secondary brain injury after intracerebral hemorrhage and its enhanced delivery via targeted nanoparticles.
    Jia-Wei Wu, Yi-Ting Zhou, Bing-Xin Wang, Li-Ping Shen, Xu-Qi Zhang, Zhi-Yong Du, Peng Wang, Xiao-Jie Lu, Zeng-Li Miao, Xu-Dong Zhao.
      Intracerebral hemorrhage (ICH), a severe cerebrovascular disorder with high mortality, leads to secondary brain injury (SBI) primarily through neuroinflammation and blood-brain barrier (BBB) disruption. Among the pathological cascades, excessive activation of macrophages and the CCR5/JAK1/STAT1/MMPs signaling pathway play pivotal roles in amplifying neuronal damage. Apigenin (API), a natural flavonoid with anti-inflammatory and neuroprotective properties, has emerged as a promising therapeutic candidate to counteract these processes. In this study, we developed apigenin-loaded PLGA nanoparticles functionalized with DSPE-PEG2000-RVG29 and DSPE-PEG2000-folic acid (RVG/FA-NPs@API) to achieve targeted delivery to inflammatory macrophages and investigated their therapeutic effects against SBI after ICH. In a murine ICH model, API administration significantly improved neurological outcomes, reduced cerebral edema, suppressed neuronal apoptosis, and preserved BBB integrity. Mechanistically, API bound covalently to JAK1 at Cys1052, inhibiting its phosphorylation and subsequently downregulating the CCR5/JAK1/STAT1/MMPs cascade. Furthermore, RVG/FA-NPs@API demonstrated excellent stability, efficient brain-targeting, and superior biocompatibility, achieving enhanced therapeutic efficacy compared with free API. These findings highlight a novel strategy for targeted immunomodulation and provide translational insights into nanoparticle-assisted delivery of natural compounds for the treatment of ICH-induced SBI.
    Keywords:  Apigenin; Intracerebral hemorrhage; Molecular dynamics simulation; Network pharmacology; Neuroprotection; PLGA nanoparticles
    DOI:  https://doi.org/10.1186/s12951-025-03748-6
  12. J Neuroinflammation. 2025 Nov 04. 22(1): 258
    Targeting hypercoagulability in ischemic stroke modulates fibrin-driven microglial polarization via JAK-STAT pathway.
    Siyu Guan, Taoyuan Lu, Lei Li, Yong Zhang, Chuan Huang, Chen Li, Bowen Li, Jiayi Hu, Chunxiao Wan.
      Ischemic stroke is a leading cause of mortality and disability worldwide, yet its pathophysiological mechanisms remain poorly understood. In this study, we analyzed the coagulation function in 60 patients with acute ischemic stroke and found that their blood was in a hypercoagulable state. We confirmed this hematological change using a middle cerebral artery occlusion/reperfusion (MCAO/r) mouse model and improved the hypercoagulable state with the synthetic peptide Arg-Gly-Asp-Cys (RGDC), which inhibits platelet aggregation and fibrinogen binding. Interestingly, in MCAO/r mice, RGDC treatment led to enhanced neurological function, reduced blood-brain barrier (BBB) disruption, and alleviated neuroinflammation. Further analysis revealed that fibrin, the end product of coagulation, binds to ITGB2 on primary microglia and activates the JAK-STAT signaling pathway, influencing microglial polarization. These results establish a novel link between the hypercoagulable state and microglial function, offering a promising therapeutic approach to reduce neuroinflammation, improve neurological function and enhance outcomes in ischemic stroke by targeting coagulation pathways.
    Keywords:  Fibrin; Hypercoagulable state; ITGB2; Ischemic stroke; Microglia
    DOI:  https://doi.org/10.1186/s12974-025-03582-5
  13. Neurobiol Dis. 2025 Oct 30. pii: S0969-9961(25)00385-7. [Epub ahead of print]217 107168
    Endothelial ephrin-B2 knockdown increases post-traumatic disruption of the blood-spinal cord barrier following spinal cord injury.
    Katharina Kersting, Emily J von Bronewski, Laurens T Roolfs, Lea Meyer, Lilly Waldmann, Melina Nieminen-Kelhä, Irina Kremenetskaia, Anja Nitzsche, Andre Rex, Harald Prüß, Ralf Adams, Frank L Heppner, Michael G Fehlings, Peter Vajkoczy, Vanessa Hubertus.
       OBJECTIVES: Traumatic Spinal Cord Injury (SCI) disrupts the Blood-Spinal Cord Barrier (BSCB), amplifying injury processes. Targeted therapies require deeper insight into underlying mechanisms. Endothelial Ephrin-B2, a guidance molecule regulating cell adhesion and repulsion, might influence the BSCB, but its role after SCI remains unknown. This study investigates Ephrin-B2 in endothelial cells (ECs) and its influence on BSCB integrity in a mouse SCI model up to 28 days.
    METHODS: Transgenic mice with tamoxifen-inducible EC-specific Ephrin-B2 knockdown (efnb2iΔEC, n = 79) and Cre-negative littermates (efnb2lox/lox, n = 71) received serial tamoxifen injections. Animals underwent thoracic clip-compression injury (Th6/7, 60s, 5 g, n = 128) or Sham injury (laminectomy, n = 22). At postoperative days 1, 3, 7, 14 and 28 in vivo analysis included neurological assessment (Basso Mouse Scale, Tally Subscore, CatWalkTM automated gait analysis) and 7 T MRI (T2 Turbo Rare). Ex vivo analysis included Evans Blue assay (n = 5 per group/timepoint), vessel perfusion, and immunohistochemistry (n = 4 per group/timepoint) examining vessel density (CD31, FITC-Lectin), pericyte coverage (CD31, Desmin, PDGFR-beta), and junction proteins (Claudin-5, VE-Cadherin).
    RESULTS: efnb2iΔEC mice showed increased BSCB disruption during the acute phase (1d: p = 0.0117; 3d: p = 0.0153) accompanied by a trend for increased edema on day 1 after SCI (p = 0.0712). Vascular and junctional markers revealed posttraumatic impairment with regeneration after day 7, without significant inter-group differences (p > 0.05). Neurological recovery however was not influenced by EC-specific Ephrin-B2 knockdown (p > 0.05).
    CONCLUSIONS: Endothelial Ephrin-B2 is crucial for BSCB resilience after SCI. Its EC- specific knockdown aggravates barrier disruption and influences edema volume, suggesting Ephrin-B2 as a potential therapeutic target for acute SCI.
    Keywords:  Blood-spinal cord barrier; Cell-cell-communication; Ephrin-B2; Spinal cord injury; Spinal cord regeneration; Vascular regeneration
    DOI:  https://doi.org/10.1016/j.nbd.2025.107168
  14. J Integr Neurosci. 2025 Oct 29. 24(10): 45565
    Pathophysiological Divergence Between Vascular and Post-Stroke Dementia: Bridging Human and Experimental Perspectives.
    Ji Hyeon Ahn, Myoung Cheol Shin, Dae Won Kim, Ki-Yeon Yoo, Moo-Ho Won.
      Vascular dementia (VaD) and post-stroke dementia (PSD) are two leading subtypes of vascular cognitive impairment (VCI), each arising from distinct cerebrovascular pathologies. VaD typically results from chronic cerebral hypoperfusion and small vessel disease, leading to progressive executive dysfunction and white matter degradation. In contrast, PSD occurs following acute ischemic events and is frequently associated with hippocampal damage and episodic memory deficits. This review delineates the pathophysiological divergence between VaD and PSD by integrating findings from human clinical studies and preclinical animal models. While rodent models of chronic hypoperfusion replicate key features of VaD, such as oligodendrocyte injury and myelin loss, transient ischemia models-particularly middle cerebral artery occlusion-capture hallmark PSD features, including excitotoxic neuronal death, blood-brain barrier disruption, and glial activation. Emerging research also highlights the involvement of neurovascular unit dysfunction, inflammation-driven neurodegeneration, and region-specific synaptic alterations. Recognizing these mechanistic differences is critical for advancing diagnostic precision, identifying therapeutic windows, and improving translational relevance. Furthermore, the review underscores the need for aged and comorbid animal models, integration of human biomarker studies, and implementation of novel therapies targeting endothelial function, glial reactivity, and cognitive plasticity. Through this comparative approach, we propose a unified framework to guide future investigations and interventions across the spectrum of VCI.
    Keywords:  chronic hypoperfusion; cognitive impairment; ischemia-reperfusion; neuroinflammation; neurovascular unit; post-stroke dementia; translational models; vascular dementia
    DOI:  https://doi.org/10.31083/JIN45565
  15. Front Neurol. 2025 ;16 1652065
    Low-frequency electroacupuncture attenuates methamphetamine-induced depressive-like behaviors and cognitive impairment via modulating neuroinflammation.
    Jingyi Zhang, Rongji Hui, Jiabao Xu, Ludi Zhang, Bing Xie, Chunling Ma, Yi Li, Yueli Zou, Di Wen, Xiujun Yu.
       Introduction: Methamphetamine (METH) abuse primarily affects the central nervous system (CNS), leading to CNS damage and contributing to depressive-like behaviors, cognitive impairment, and other neuropsychiatric disorders. Electroacupuncture (EA) has shown promise in treating mental disorders linked to CNS damage, yet the effects of EA on METH-induced depressive-like behaviors and cognitive impairment and it's underlying therapeutic mechanisms remain largely unclear.
    Methods: In this study, a mouse model of METH-induced neuropsychiatric dysfunction was established by administering high-dose METH under elevated ambient temperature. EA was applied at different frequencies to the Zusanli (ST36) acupoint for 7 days post-METH administration.
    Results: Behavioral tests revealed that low-frequency EA significantly alleviated depressive-like behaviors and cognitive impairment. Additionally, EA restored blood-brain barrier (BBB) integrity, as evidenced by Western blotting (WB) and Evans blue staining. Neuronal injury was attenuated, as shown by Nissl and hematoxylin and eosin (HE) staining. Further investigations into neuroinflammation revealed that EA suppressed microglial activation in the hippocampus, decreased the expression of IL-6 and TNF-α, and inhibited the NF-κB/NLRP3 signaling pathway.
    Discussion: The present study suggested that EA alleviates METH-induced depressive-like behaviors and cognitive impairment by modulating neuroinflammation, particularly through the inhibition of microglial activation and pro-inflammatory cytokine release. EA may represent a promising non-pharmacological strategy for the treatment of METH-associated neuropsychiatric disorders.
    Keywords:  cognitive impairment; depressive-like behaviors; electroacupuncture; methamphetamine; neuroinflammation
    DOI:  https://doi.org/10.3389/fneur.2025.1652065
  16. Neurology. 2025 Nov 25. 105(10): e214336
    In Vivo Imaging of Blood-Brain Barrier Leakage Using a Contrast Agent in Patients With Cerebral Amyloid Angiopathy: An Exploratory Study.
    Hilde van den Brink, Mariel G Kozberg, Nazanin Makkinejad, John E Kirsch, Michael J Thrippleton, Thijs W van Harten, Sabine Voigt, Whitney M Freeze, Matthias J P Van Osch, Anand Viswanathan, Susanne J van Veluw.
       BACKGROUND AND OBJECTIVES: Blood-brain barrier (BBB) leakage may be an early step in the pathophysiology of cerebral amyloid angiopathy (CAA), possibly preceding hemorrhages. This exploratory study measured BBB leakage in vivo at the level of the leptomeningeal and small parenchymal vessels in patients with probable CAA. We hypothesized that BBB leakage from leptomeningeal and cortical small vessels would be higher in patients with CAA compared with controls and that leakage would be associated with hemorrhagic manifestations of CAA, that is, cortical superficial siderosis (cSS) and lobar cerebral microbleeds (CMBs).
    METHODS: Patients with probable CAA without previous intracerebral hemorrhage and non-CAA patients with mild cognitive impairment from the memory clinic were recruited in this prospective observational exploratory study. Participants underwent 3T brain MRI with injection of a gadolinium-based contrast agent (Dotarem). Leakage from leptomeningeal vessels was assessed on postcontrast vs precontrast T2-fluid-attenuated inversion recovery as either focal or sulcal CSF enhancements. Dynamic contrast-enhanced scans were analyzed to quantify permeability-surface area product (PS): a measure of leakage from parenchymal small vessels.
    RESULTS: Fourteen patients with CAA (mean age 67.7 ± 9.0 years; 57% female) and 7 non-CAA patients with mild cognitive impairment (mean age 70.1 ± 6.5 years; 29% female) were recruited. Focal CSF enhancements were observed similarly often in patients with CAA (7 [50%]) and non-CAA controls (4 [57%], p = 0.98), whereas sulcal CSF enhancements were only seen in patients with CAA (5 [36%] vs 0 [0%]). In patients with CAA, focal and sulcal CSF enhancement counts were associated with higher cSS volume (B = 2.61, p = 0.003; B = 1.02, p = 0.02), but not with CMBs. PS was numerically higher in the cortex in patients with CAA (5.08 ± 4.02 × 10-4 min-1) than in non-CAA controls (1.29 ± 4.08 × 10-4 min-1, p = 0.07), but it was not associated with CMB count or cSS volume (p > 0.67).
    DISCUSSION: Leakage of gadolinium-based contrast agent through the BBB can be measured in vivo in CAA from the leptomeningeal vessels, and findings point to likely leakage from cortical small vessels as well. Leakage from leptomeningeal vessels was associated with cSS. Studies with follow-up data need to determine whether these measures could serve as a predictive biomarker in CAA.
    DOI:  https://doi.org/10.1212/WNL.0000000000214336
  17. Fluids Barriers CNS. 2025 Nov 07. 22(1): 114
    Gut microbiota modulates CNS barrier function in murine model for multiple sclerosis.
    Junhua Xie, Marlies Burgelman, Pieter Dujardin, Jonas Castelein, Griet Van Imschoot, Elien Van Wonterghem, Hannah Lernout, Sjoerd T T Schetters, Charysse Vandendriessche, Lien Van Hoecke, Roosmarijn E Vandenbroucke.
      
    Keywords:  Blood-brain barrier; Blood-cerebrospinal fluid barrier; Blood-spinal cord barrier; Experimental autoimmune encephalomyelitis; Gut microbiota; Gut–brain axis; Multiple sclerosis; Short-chain fatty acids
    DOI:  https://doi.org/10.1186/s12987-025-00724-y
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