bims-blobar 2025-10-26 papers

bims-blobar

Biomed News

on Blood brain barrier repair

Issue of 2025–10–26
eighteen papers selected by
Nicolas Rebergue

Angiotensin III induces disruption of blood-brain barrier integrity in vitro in bEnd.3 brain endothelial cells.
Visualizing the Gatekeeper: Evan's Blue Dye-Based Assessment of Blood-Brain Barrier Permeability in Adult Zebrafish.
Claudin proteins and hemorrhage severity in aneurysmal subarachnoid hemorrhage: Correlation with modified Fisher score but not functional outcome.
Pharmacological inhibition of SPAK-NKCC1 complex attenuates astrogliosis and restores cerebral blood flow in a mouse model of VCID.
Reviewing the possible connection between cerebral amyloid angiopathy and blood-brain barrier integrity in Down syndrome.
Disruption of the Blood-Brain Barrier Predicts Progression of Cerebral Small Vessel Disease White Matter Hyperintensities.
The potential of taVNS in attenuating blood-brain barrier damage, promoting angiogenesis and improving impaired cognitive function in a rat model of vascular cognitive impairment and dementia by activating the Wnt7/β-catenin signaling pathway.
Real-time single-vessel analysis reveals vascular-type-dependent blood-brain barrier dysfunction in rodent models of status epilepticus and neuroinflammation.
Smoothened Agonist Treatment Mitigates Vasogenic Edema, Neuroinflammation, and Neurological Dysfunction Following Traumatic Brain Injury in Mice.
3D in vitro blood-brain barrier models: recent advances and their role in brain disease research and therapy.
Plasma biomarkers of neurogenesis are increased among people with HIV after COVID.
Letter to the editor "Preoperative blood-brain barrier disruption increased risk of postoperative cognitive decline after coronary artery bypass grafting: a prospective cohort study".
Angelicin alleviates sepsis-associated encephalopathy via inhibition of IKK2 and the NF-κB pathway.
Agmatine ameliorates morphine-induced behavioral sensitization through blood-brain barrier protection and anti-neuroinflammatory effects in the nucleus accumbens.
Rapamycin and Suramin Effects on TNF-⍺-Mediated Mast Cell and Brain Microvascular Endothelial Cell Dysfunction.
Post-mortem evidence of pathogenic angiogenesis and abnormal vascular function in early Alzheimer's disease.
The blood-brain barrier.
Plasma exchange as a neuroprotective strategy for post-spaceflight neuroinflammation in astronauts.

Hypertens Res. 2025 Oct 24.

Angiotensin III induces disruption of blood-brain barrier integrity in vitro in bEnd.3 brain endothelial cells.

Ecem Ayvaz, Ahmet Umur Topçu, Elif Sude Duran, Sena Birsen Güçlü, Mustafa Onur Yıldırım, Bülent Ahıshalı, Mehmet Kaya.

  Hypertension is well-known to cause disruption of the blood-brain barrier (BBB). Angiotensin (Ang) II is one of the major mechanistic factors leading to impairment of BBB integrity under hypertensive states. However, the impact of Ang III, produced by conversion from Ang II, on the BBB remains to be elucidated. Therefore, this study was aimed to evaluate the effect of Ang III on an in vitro model of BBB using mouse brain microvascular endothelial cell line (bEnd.3). Following exposure of bEnd.3 cells to Ang III at doses ranging between 10 and 1000 nM for 6, 12, and 24 h, cell viability, transendothelial electrical resistance (TEER), and permeability of sodium fluorescein (NaFl) tracer were determined. The expression of claudin-5, caveolin-1 (Cav-1) and major facilitator superfamily domain-containing protein 2a (Mfsd2a) were assessed using immunofluorescence and western blotting. Overall decreases in cell viability and TEER and increases in NaFl permeability were observed at all time points following Ang III administration at various doses (P < 0.05, P < 0.01). 12-h treatment of Ang III at 25, 50, and 500 nM doses decreased claudin-5 but increased Cav-1 expression, while Mfsd2a expression decreased significantly by 500 nm Ang III (P < 0.0001). Our data demonstrate for the first time that Ang III leads to alterations in transport of substances across the BBB through both paracellular and transcellular pathways when administered at specific concentrations and durations in in vitro setting which suggests that it may potentially play a role in the disruption of BBB integrity under hypertensive conditions.

Keywords:  Angiotensin III; Blood-brain barrier; Caveolin-1; Claudin-5; Implemental hypertension

DOI:  https://doi.org/10.1038/s41440-025-02426-2
J Vis Exp. 2025 Sep 30.

Visualizing the Gatekeeper: Evan's Blue Dye-Based Assessment of Blood-Brain Barrier Permeability in Adult Zebrafish.

Khairiah Razali, Mohd Hamzah Mohd Nasir, Jaya Kumar, Wael Mohamed.

The Blood-Brain Barrier (BBB) is a semi-permeable interface that maintains central nervous system (CNS) homeostasis by regulating the movement of substances into and out of the brain, thereby protecting neural tissue from potentially harmful agents. Disruption of the BBB is a well-established feature in many neurodegenerative diseases, including Parkinson's disease (PD) and Alzheimer's disease (AD), where increased permeability contributes to and exacerbates disease progression. Although the adult zebrafish (Danio rerio) is increasingly recognized as a valuable model for studying neurodegenerative diseases, standardized methods for evaluating BBB integrity in this species remain limited. This protocol describes a simple, reproducible, and cost-effective approach to assess BBB permeability in adult zebrafish by analysing Evan's Blue (EB) dye extravasation from the neurovasculature into brain tissue. The method combines qualitative visualization with quantitative image analysis of EB distribution to detect BBB disruption. Key steps include proper intraperitoneal injection of EB dye, confirmation of systemic dye circulation, careful brain dissection, and consistent imaging and greyscale intensity measurement. Positive and negative controls are incorporated to validate dye penetration and support accurate interpretation. Representative results demonstrate greater EB extravasation in Parkinsonian zebrafish brains compared to saline-injected controls, indicating increased BBB permeability. This technique requires minimal specialized equipment and is suitable for laboratories with limited resources. Overall, this protocol offers a practical tool for investigating BBB integrity in adult zebrafish models and can be adapted for diverse applications, including studies of disease mechanisms and the evaluation of therapeutic interventions targeting neurovascular function.

DOI: https://doi.org/10.3791/69010
Neurosurg Rev. 2025 Oct 20. 48(1): 725

Claudin proteins and hemorrhage severity in aneurysmal subarachnoid hemorrhage: Correlation with modified Fisher score but not functional outcome.

Gabor Lenzser, Gábor J Szebeni, Fanni Balogh, Nikolett Gémes, Attila Schwarcz, Peter Csecsei.

   BACKGROUND: Aneurysmal subarachnoid hemorrhage (aSAH) is a critical condition characterized by blood-brain barrier (BBB) disruption. Tight junction proteins, claudin-3 (CLDN3) and claudin-5 (CLDN5), are key regulators of BBB integrity and may serve as biomarkers of hemorrhage severity.
METHODS: In this prospective cohort study, 200 patients with aSAH were evaluated. Serum CLDN3 and CLDN5 levels were measured on days 1, 5, and 9 post-ictus and compared with healthy and aneurysm-bearing controls. Patients were stratified by modified Fisher Score (mFS), World Federation of Neurosurgical Societies (WFNS) score, and 3-month modified Rankin Scale (mRS). Associations with complications, including delayed cerebral ischemia (DCI) and infection, were also assessed.
RESULTS: CLDN3 and CLDN5 levels were significantly elevated in aSAH patients compared to controls (p <0.01 and p <0.0001, respectively), with CLDN5 levels consistently higher than CLDN3 at all time points (p <0.0001). CLDN5 levels were consistently higher than CLDN3 at all measured time points, and neither CLDN3 nor CLDN5 showed significant temporal variation between days 1, 5, and 9. Both markers showed significant positive correlation with mFS, with higher levels observed in mFS3 and mFS4 groups (p <0.05 to p <0.0001). No association was found between CLDN3 and 5 levels and WFNS score, 3-month mRS, age, sex, comorbidities, inflammatory markers, or DCI.
CONCLUSION: Elevated serum CLDN3 and especially CLDN5 levels reflect hemorrhage extent and potential BBB disruption in aSAH. Their strong correlation with mFS suggests utility in grading imageological hemorrhagic severity, though not in predicting long-term functional outcomes. CLDN5 emerges as a promising biomarker for early assessment of BBB integrity in neurovascular injury.

Keywords:  Aneurysmal subarachnoid hemorrhage; Claudin-3; Claudin-5; Modified Fisher score

DOI:  https://doi.org/10.1007/s10143-025-03829-y
Acta Neuropathol Commun. 2025 Oct 24. 13(1): 216

Pharmacological inhibition of SPAK-NKCC1 complex attenuates astrogliosis and restores cerebral blood flow in a mouse model of VCID.

Khadija Habib, Md Tipu Sultan, Israt Jahan, Md Shamim Rahman, Sujan Kumar Kundu, Barnali Sarker, Rabia Islam, Tanvir Ahmed, Ian A Mendez, Guodong Cao, Dandan Sun, Vesna Tesic, Mohammad Iqbal H Bhuiyan.

  Vascular contributions to cognitive impairment and dementia (VCID) are one of the leading causes of dementia, where reactive astrogliosis, blood-brain barrier (BBB) disruption, and white matter lesions (WML) are the key features. However, the molecular and cellular mechanisms underlying VCID are not well understood. Na-K-Cl cotransporter 1 (NKCC1) activation via its upstream regulatory kinase SPAK (STE20/SPS1-related proline/alanine-rich kinase) causes intracellular Na+ overload, hypertrophy, and astrogliosis, a cascade that has been implicated in VCID. In this study, we investigated whether treatment with the SPAK inhibitor ZT-1a at the symptomatic stage in a VCID mouse model is effective in reducing reactive astrogliosis and BBB breakdown, and in improving cerebral blood flow (CBF). VCID was induced in adult C57BL/6J mice using bilateral carotid artery stenosis (BCAS), and either Vehicle (Veh, DMSO) or ZT-1a was administered from weeks 4 to 8 post-BCAS. CBF was monitored by laser speckle imaging, and cognitive deficits were assessed using the Morris water maze test. BBB integrity, astrocytic endfeet coverage, and demyelination were assessed by immunofluorescence (IF) analysis. BCAS mice exhibited a biphasic reduction of CBF and cognitive impairments, parallel with a significant loss of myelin basic protein (MBP) in white matter tracts. Increased expression and phosphorylation of NKCC1 were detected in GFAP+ astrocytes and Iba1+ microglia/macrophage following BCAS. Reduced ZO-1, Claudin-5, and AQP4 expression in vessels and extravasation of serum albumin into the brain parenchyma in BCAS mice indicate the loss of BBB integrity. Importantly, ZT-1a treatment of the BCAS mice significantly improved CBF recovery and prevented the learning and memory deficit. These mice displayed reduced astrogliosis, microglial activation, MMP-2/9 expression, BBB damage, and axonal demyelination. Our results strongly suggest that hypoperfusion-induced SPAK-NKCC1 activation contributes to reactive astrogliosis, BBB disruption, CBF reduction, and cognitive impairment. The SPAK-NKCC1 complex represents a modifiable therapeutic target for counteracting VCID progression.

Keywords:  Astrogliosis; BBB integrity; BCAS; CBF; VCID; ZT-1a

DOI:  https://doi.org/10.1186/s40478-025-02137-2
Alzheimers Dement. 2025 Oct;21(10): e70814

Reviewing the possible connection between cerebral amyloid angiopathy and blood-brain barrier integrity in Down syndrome.

Louis Valay, Marie-Claude Potier.

  Individuals with Down syndrome (DS) have a higher risk of developing cerebral amyloid angiopathy (CAA), primarily because of the excessive production of amyloid beta (Aβ). However, the consequences of CAA on blood-brain barrier (BBB) integrity and the neurovascular unit (NVU) are still not well understood. Systematic search was conducted on PubMed using 12 targeted keywords related to CAA, BBB, and the NVU in combination with DS. Additional sources were identified and the research gap validated using Consensus and ChatGPT-assisted literature screening. Individuals with DS are vulnerable to cerebrovascular conditions across their lifespan. Despite pronounced Aβ pathology, CAA appears less frequent than in cases with microduplication of the APP locus, suggesting distinct vascular dynamics potentially influenced by chromosome 21 genes. Limited direct evidence on BBB integrity in DS highlights the need for mechanistic and longitudinal studies. DS offers a unique lens for exploring cerebrovascular resilience and CAA pathogenesis. HIGHLIGHTS: Down syndrome (DS) individuals overexpressing amyloid precursor protein (APP) are at risk for cerebral amyloid angiopathy (CAA) and lobar microbleeds. CAA is less severe in DS compared to APP microduplication (APPdup) cases. Intracerebral hemorrhage (ICH) is less common in DS than in APPdup cases. DS may have protective mechanisms against CAA and ICH involving BBB function. Few longitudinal studies examine BBB permeability in DS across the lifespan.

Keywords:  Alzheimer's disease; Down syndrome; amyloid beta; amyloid‐related imaging abnormalities; blood–brain barrier; cerebral amyloid angiopathy; chromosome 21; induced pluripotent stem cell models; intracerebral hemorrhage; microbleeds; neuroimaging; neurovascular unit; vascular pathology

DOI:  https://doi.org/10.1002/alz.70814
Ann Neurol. 2025 Oct 21.

Disruption of the Blood-Brain Barrier Predicts Progression of Cerebral Small Vessel Disease White Matter Hyperintensities.

Richard Leigh, Kyle C Kern, Nae-Yuh Wang, Rebecca F Gottesman, Clinton B Wright.

OBJECTIVE: The objective of this study was to test if blood-brain barrier (BBB) disruption, detected using dynamic susceptibility contrast (DSC) imaging, would predict progression of white matter hyperintensities (WMHs) over the subsequent year in patients with chronic cerebrovascular disease.
METHODS: The study included patients with a history of stroke and at least early confluence of WMH. Magnetic resonance imaging (MRI) scans performed at baseline (> 3 months from stroke) and again 1 year later were segmented to calculate the WMH volume expressed as a fraction of the total brain volume. Change in WMH volume between the 2 timepoints and progression of WMH were the outcome measures. BBB disruption was measured using DSC imaging on the baseline MRI. WMH masks were dilated by 3 mm to create a mask of the adjacent normal appearing white matter (penumbra). BBB disruption was averaged within the WMH and the penumbra.
RESULTS: Fifty patients were included; median age was 69 years, and 46% were women. The mean WMH fraction was 1.25% at baseline and 1.36% at 1 year. The mean baseline BBB disruption was 0.20% in the WMH and 0.22% in the penumbra. More severe BBB disruption was associated with greater WMH progression when measured in the WMH (ß = 0.95, confidence interval [CI] = 0.39-1.51, r2 = 0.19, p = 0.001) and in the penumbra (ß = 0.81, CI = 0.10-1.53, r2 = 0.10, p = 0.027). The best predictor of progression was BBB disruption in the penumbra with an odds ratio (OR) of 2 (OR = 2, CI = 1.01-3.96, p = 0.046) for each 0.1% increase in BBB disruption.
INTERPRETATION: More severe BBB disruption was predictive of greater WMH progression in patients with chronic cerebrovascular disease. ANN NEUROL 2025.

DOI: https://doi.org/10.1002/ana.78072
Auton Neurosci. 2025 Oct 13. pii: S1566-0702(25)00115-8. [Epub ahead of print]262 103353

The potential of taVNS in attenuating blood-brain barrier damage, promoting angiogenesis and improving impaired cognitive function in a rat model of vascular cognitive impairment and dementia by activating the Wnt7/β-catenin signaling pathway.

Rongshan Sun, Hong Li, Meng Wang, Long Yan, Jinglei Jiang, Qidi Liu, Shijun Li, Ying Liang, Yulin Qian, Tao Yu.

   BACKGROUND: Studies consistently demonstrate that vascular cognitive impairment and dementia (VCID) onset and progression are associated with diminished activity in the Wnt/β-catenin signaling pathway, crucial for maintaining blood-brain barrier (BBB) integrity and promoting angiogenesis in the central nervous system. Transcutaneous auricular vagal nerve stimulation (taVNS) has shown potential to enhance cognitive function by reducing BBB permeability and stimulating angiogenesis, yet its direct linkage to the Wnt7/β-catenin pathway activation remains uncertain and requires mechanistic validation.
METHODS: A rat model of VCID was established by inducing temporary bilateral common carotid artery occlusion (tBCCAO) in rats. Following surgery, rats received daily taVNS treatments for 14 consecutive days (Days 13-26). Cognitive function was assessed on postoperative day 26. Additionally, the hippocampal region was analyzed to detect changes in the Wnt7/β-catenin signaling pathway-related proteins, neuronal injury and apoptosis, angiogenesis, BBB tight junction integrity, and astrocyte activation.
RESULTS: TaVNS treatment resulted in significant cognitive improvements, alongside marked reductions in neuronal damage and apoptosis within the hippocampal CA1 region. It effectively decreased BBB permeability and enhanced angiogenesis. Mechanistically, taVNS suppressed astrocyte activation, promoted a shift from pro-inflammatory (A1) to anti-inflammatory (A2) phenotypes, and consequently upregulated the Wnt7/β-catenin signaling pathway, boosting expression of its downstream targets to foster neuroprotection and vascular repair.
CONCLUSIONS: This study confirms that taVNS effectively alleviates neurological damage in VCID by upregulating the Wnt7/β-catenin pathway, potentially through astrocyte phenotypic modulation. These findings underscore taVNS as a promising non-invasive intervention for cognitive deficits in vascular disorders, warranting further clinical investigation.

Keywords:  Angiogenesis; Astrocyte; Blood-brain barrier; The Wnt7/β-catenin signaling pathway; Transcutaneous auricular vagal nerve stimulation; Vascular cognitive impairment and dementia

DOI:  https://doi.org/10.1016/j.autneu.2025.103353
Neurophotonics. 2025 Oct;12(4): 045004

Real-time single-vessel analysis reveals vascular-type-dependent blood-brain barrier dysfunction in rodent models of status epilepticus and neuroinflammation.

Bok-Man Kang, Juheon Lee, Sungjun Bae, Taeyoung Park, Seong-Eun Ryu, Yoonyi Jeong, Seung Won Chung, Hyun-Kyoung Lim, Kayoung Han, Minah Suh.

   Significance: Recent evidence highlights significant heterogeneity of the blood-brain barrier (BBB) across vascular types, which becomes more pronounced under disease conditions. However, functional changes in vascular-type-dependent BBB leakage remain poorly characterized.
Aim: We aimed to establish an analysis framework for quantifying single-vessel BBB total leakage and identifying vascular-type-dependent patterns of total leakage change in disease states.
Approach: We introduce a method that combines in vivo real-time two-photon imaging with uniform manifold approximation and projection (UMAP)-based dimensionality reduction to assess BBB total leakage at the single-vessel level. Two rodent models were used, pilocarpine-induced status epilepticus (SE) and lipopolysaccharide-induced neuroinflammation (NI), which exhibit differential pathophysiological characteristics of BBB impairment.
Results: Real-time imaging clearly showed arterial BBB leakage in SE, whereas leakage in NI was likely venous. Conventional intensity-based metrics, including area under the curve (AUC), intensity fold change ( ΔF/F0 ), and averaged differential coefficient ( ΔF/Δt ), detected arteria-specific changes in SE but failed to capture vein-specific differences in NI. By contrast, UMAP-based analyses sensitively distinguished disease-specific total leakage patterns, allowing separation of SE from arterial data and NI from venous data.
Conclusions: This integrated approach enables quantitative evaluation of vascular-type-dependent BBB total leakage and provides a platform for future studies on vessel-specific BBB alterations in neurological disorders.

Keywords:  blood–brain barrier; lipopolysaccharide-induced neuroinflammation; pilocarpine-induced status epilepticus; two-photon imaging; uniform manifold approximation and projection; vascular types

DOI:  https://doi.org/10.1117/1.NPh.12.4.045004
FASEB J. 2025 Oct 31. 39(20): e71187

Smoothened Agonist Treatment Mitigates Vasogenic Edema, Neuroinflammation, and Neurological Dysfunction Following Traumatic Brain Injury in Mice.

Shotaro Michinaga, Kenta Takahashi, Yasuhiro Ogawa, Hiroyuki Mizuguchi, Shigeru Hishinuma.

  Traumatic brain injury (TBI)-a serious brain damage caused by accidents, falls, and sports-causes vasogenic edema, neuroinflammation, and neurological dysfunction resulting from blood-brain barrier disruption. Sonic hedgehog (Shh), a secretory protein belonging to the hedgehog family, protects cerebrovascular and neuronal function via the patched-1 (Ptch-1)-smoothened (Smo)-Gli pathway. In this study, we investigated the effects of Smo agonists (Shh and SAG) and antagonist (Jervine) on vasogenic edema, neuroinflammation, and neurological dysfunction in mice following TBI. Male ddy mice (8 weeks old) were used to minimize the influence of gonadal hormones on the results. A TBI model was established by inflicting a fluid percussion injury (FPI) on mouse cerebrum or cultured cells. Shh expression increased in mouse cerebrums and cultured astrocytes after FPI. Vasogenic edema was assessed by Evans blue extravasation into brain tissue and increased brain water content. Evans blue extravasation and brain water content increased after FPI. Repeated intracerebroventricular administration of recombinant Shh reduced Evans blue extravasation and brain water content in the cerebrum after FPI, whereas treatment with Jervine, an Smo antagonist, aggravated these conditions. Recombinant Shh administration also decreased the expression of inflammatory cytokines and chemokines in the cerebrum after FPI. Notably, repeated intravenous administration of SAG, a small-molecule Smo agonist, reduced FPI-induced vasogenic edema and neuroinflammation, and improved neurological dysfunction in mice. Furthermore, SAG treatment increased the expression of vascular protective factors and tight junction proteins. These results suggest that Smo agonists are promising therapeutic agents for TBI.

Keywords:  blood–brain barrier; brain edema; neuroinflammation; neurological dysfunction; smoothened; sonic hedgehog; traumatic brain injury

DOI:  https://doi.org/10.1096/fj.202502571R
Front Pharmacol. 2025 ;16 1637602

3D in vitro blood-brain barrier models: recent advances and their role in brain disease research and therapy.

Laura O'Halloran, Olutoyosi Akinsete, A Leah Kogan, Michelle Wrona, Amira F Mahdi.

  The blood-brain barrier (BBB) is a dynamic and highly selective interface crucial to central nervous system (CNS) homeostasis, presenting a major challenge for effective drug delivery in treating CNS pathologies such as brain tumours and neurodegenerative disease. Traditional two-dimensional (2D) in vitro models and animal models often fail to replicate the structural complexity and physiological functions of the human BBB. Recent advances in three-dimensional (3D) in vitro modelling offer enhanced physiological relevance by integrating cellular architecture, extracellular matrix (ECM) components, and dynamic fluid flow to simulate in vivo conditions more accurately. This review explores the structural and functional features of the BBB and highlights the evolution from 2D to 3D in vitro models, including hydrogel-based systems, microfluidics, organ-on-a-chip (OOAC) platforms, spheroids and organoids. The advantages of these models in recapitulating BBB dynamics and their application in cancer research and other CNS diseases are discussed. Finally critical comparison and discussion of current 3D models is presented, highlighting differences and best potential uses of each variation. Continued advancements are needed to develop accurate 3D in vitro models of the BBB in order to revolutionize drug screening, predict therapeutic efficacy, and support personalized medicine approaches. By providing robust, human-relevant platforms, 3D BBB models can accelerate drug development and treatment for patients affected by CNS pathologies.

Keywords:  3D; blood-brain barrier; brain tumour; central nervous system; in vitro; organ-on-a-chip

DOI:  https://doi.org/10.3389/fphar.2025.1637602
J Acquir Immune Defic Syndr. 2025 Oct 23.

Plasma biomarkers of neurogenesis are increased among people with HIV after COVID.

Daniel Adesse, Silvia Torices, Maria L Alcaide, Eleonore Beurel, Suresh Pallikkuth, Patricia Raccamarich, Alberto Cruz, Nicholas Fonseca Nogueira, Deborah L Jones, Michal Toborek.

   OBJECTIVES: While acute COVID does not appear to markedly differ by HIV status, the long-term impact of COVID in people with HIV (PWH) remains unclear.
METHODS: Samples from forty-four participants with or without HIV were obtained approximately 10 days after the initial COVID diagnosis (t=0) and then three (t=1) and six (t=2) months later. Biomarkers of blood brain barrier (BBB) and vascular dysfunction, neurogenesis, and inflammatory responses were assessed by multiplex profiling and ELISA.
RESULTS: The majority of inflammatory biomarkers either decreased or remained unchanged over the evaluated time frame. Notable exceptions were IL-9, TNF-α, and CCL-4, which increased at t=2 compared to earlier time points. The BBB disruption and vascular dysfunction biomarkers (S100β and soluble ICAM1, respectively) increased at t=1 and then returned to basal levels, suggesting transient loss of BBB integrity. No significant changes were observed between people without HIV (PWOH) and PWH across studied inflammatory and BBB markers. Among biomarkers of neurogenesis, eotaxin/CCL11 was not altered, FGF-2 was transiently decreased at t=1 in PHW, and G-CSF was elevated at t=2 in PWH when compared to the previous time-points.
CONCLUSIONS: BBB and vascular dysfunction occur after COVID and may be implicated in the development of post-COVID conditions. HIV-1 infection may potentiate post COVID-induced neuropathology by impairing neurogenesis.

Keywords:  HIV; Long COVID; blood-brain barrier; neurogenesis; neuroinflammation; post-COVID conditions

DOI:  https://doi.org/10.1097/QAI.0000000000003785
Int J Surg. 2025 Oct 21.

Letter to the editor "Preoperative blood-brain barrier disruption increased risk of postoperative cognitive decline after coronary artery bypass grafting: a prospective cohort study".

Yu Chang, Hany Atwan.

DOI: https://doi.org/10.1097/JS9.0000000000003719
Phytomedicine. 2025 Oct 16. pii: S0944-7113(25)01021-9. [Epub ahead of print]148 157383

Angelicin alleviates sepsis-associated encephalopathy via inhibition of IKK2 and the NF-κB pathway.

Enzhuang Pan, Mengxin Li, Panpan Zhao, Shasha Zhang, Jun Wang, Tianyue Guan, Qian Dong, Xiaomin Jin, Jingquan Dong.

   BACKGROUND: Sepsis-associated encephalopathy (SAE) is a critical neurological complication in patients with sepsis and is pathologically characterized by neuroinflammation, blood-brain barrier (BBB) damage and neurobehavioral dysfunction but remains therapeutically challenging because of the lack of targeted treatment options.
PURPOSE: The objective of this study was to explore the protective effects of angelicin (ANG) against cecal ligation and puncture (CLP)-induced SAE in mice, particularly its ability to mitigate neuroinflammation, BBB damage, and neurobehavioural dysfunction, and to investigate the underlying mechanisms involved.
STUDY DESIGN AND METHODS: A total of 168 mice were randomly divided into 7 groups: a sham-operated group (sham), a sham-treated group (sham + 10 mg/kg ANG), a CLP group, an angelicin low-dose group (CLP + 2.5 mg/kg ANG), an angelicin medium-dose group (CLP + 5 mg/kg ANG), an angelicin high-dose group (CLP + 10 mg/kg ANG) and a positive control group (CLP + DEX). A variety of experimental methods, including HE staining, Nissl staining, Evans blue staining, quantitative real-time PCR, western blotting, and behavioral trials, were used to evaluate the biological processes of neuroinflammation, the BBB, and neurobehavioral dysfunction in SAE.
RESULTS: ANG alleviated pathological changes in CLP-induced SAE (as indicated by preserved hippocampal structural integrity and elevated Nissl body density), neurobehavioral dysfunction (as indicated by significantly increased exploration time for new objects, recognition index, spontaneous alternation rate, and time spent exploring the target quadrant of the water maze), BBB damage (as indicated by reduced fluorescence intensity of Evans blue leakage, decreased levels of S100β and NSE secretion, increased levels of tight junction protein transcripts, and protein expression), and the inflammatory response (as indicated by reduced levels of the proinflammatory factors Il-1β, Il-6, and Tnf-α, and increased levels of the anti-inflammatory factor Il-10). Transcriptome analysis revealed that the NF-κB signaling pathway was significantly altered following ANG treatment. Further molecular docking, SPR, cell transfection, and inhibitor intervention experiments demonstrated that ANG ameliorated neuroinflammation in SAE by inhibiting IKK2.
CONCLUSION: ANG mitigated neuroinflammation, BBB damage, and neurobehavioral dysfunction in CLP-induced SAE mice by specifically inhibiting IKK2 activity and suppressing NF-κB signaling pathway activation, suggesting that ANG is a promising therapeutic candidate for SAE treatment.

Keywords:  Angelicin; IKK2; Neuroinflammation; Sepsis-associated encephalopathy

DOI:  https://doi.org/10.1016/j.phymed.2025.157383
Psychopharmacology (Berl). 2025 Oct 24.

Agmatine ameliorates morphine-induced behavioral sensitization through blood-brain barrier protection and anti-neuroinflammatory effects in the nucleus accumbens.

Haotian Ma, Wenrong Tian, Jing Xiao, Xilin Shao, Jincen Liu, Xinyue Yan, Jie Zhu, Jianghua Lai.

  The treatment of morphine addiction remains a significant clinical challenge, and the development of novel pharmacotherapies for opioid use disorder (OUD) is imperative. Agmatine, an endogenous neuromodulator, has promising antiaddictive potential, although its precise mechanisms remain incompletely characterized. In this study, a single morphine-induced behavioral sensitization model was established in mice, and immunofluorescence staining, transmission electron microscopy (TEM), RNA sequencing and network pharmacology were used to explore the mechanism of the anti-morphine addiction effects of agmatine. We found that agmatine improved morphine-induced behavioral sensitization without affecting spontaneous activity in mice and improved the changes in synapses in the NAc induced by morphine exposure. Network pharmacological analysis revealed that the key targets associated with agmatine-morphine dependence included TNF-α, IL-6 and IL-1β. Morphine exposure can lead to increased expression of these inflammatory factors, which are closely related with the M1 microglia. Agmatine administration significantly reduced morphine-induced neuroinflammation and activation of microglia. RNA sequencing revealed that the hub genes included TEK receptor tyrosine kinase (TEK), cadherin 5 (CDH5), platelet and endothelial cell adhesion molecule 1 (PECAM1) and so on, which are closely related to endothelial adhesion and angiogenesis. Morphine exposure can downregulate the expression of VE-cadherin, Pecam1, claudin-5, occludin and ZO-1, disrupt the integrity of the BBB and increase its permeability, whereas agmatine can protect the BBB. Agmatine reversed morphine induced BBB leakage and reduced NAc infiltration of peripheral cytokines. This study revealed that agmatine mitigates morphine-induced behavioral sensitization through anti-inflammatory and BBB protection in the NAc and thus provides mechanistic evidence for the development of therapeutic agents for OUD.

Keywords:  Agmatine; Behavioral sensitization; Blood-Brain barrier; Morphine; Neuroinflammation

DOI:  https://doi.org/10.1007/s00213-025-06944-2
Biotechnol Bioeng. 2025 Oct 22.

Rapamycin and Suramin Effects on TNF-⍺-Mediated Mast Cell and Brain Microvascular Endothelial Cell Dysfunction.

Katherine A Ebbert, Rui Chen, Robert A Culibrk, Daniel J Yeisley, Mariah S Hahn.

  Chronic blood-brain barrier (BBB) disruption due to impaired function of brain microvascular endothelial cells (BMECs) is commonly observed in neuroinflammatory and neurodegenerative conditions. Current treatment approaches are generally limited in their capacity to reduce this dysfunction, with the Akt/mTOR/GSK pathway modulator rapamycin showing recent promise in ameliorating neuroinflammatory BBB dysfunction. Understanding the role of early, cellular level BMEC dysfunction, particularly in the context of interplay with immune cells involved in neuroinflammation, such as mast cells (MCs), is important for identifying targets for therapeutic intervention related to BBB disruption. In the present work, we investigate primary human BMECs and human MC line HMC-1.2 dysfunction in response to inflammatory insult with TNF-α and paracrine interactions, with an emphasis on the Akt/mTOR/GSK pathway-an upstream regulator of angiogenesis and MC activation-and associated extracellular and intracellular cytokine production and oxidative stress. We further compare alterations in BMEC-MC paracrine inflammatory crosstalk in response to Akt/mTOR/GSK pathway modulator suramin (100 µM) relative to rapamycin (250 nM). In monoculture, TNF-α stimulation significantly increased oxidative stress-assessed through measuring PGE2-extracellularly in BMECs. Similarly, proangiogenic and pro-inflammatory cytokine and chemokine secretion was increased in both TNF-α stimulated BMEC and MC monocultures. Additionally, TNF-α stimulation increased BMEC levels of the Akt/mTOR/GSK pathway intermediates p-p70S6K and p-RPS6 and MC levels of p-GSK3α and p-GSK3β. Coculture of TNF-α stimulated BMECs and MCs resulted in a modest increase in extracellular PGE2, and effects on extracellular cytokine/chemokine levels were primarily limited to increases in pro-inflammatory CCL2, CCL3 and CCL5 relative to TNF-α-stimulated BMEC monoculture. In contrast, the levels of intracellular cytokines in MCs increased 2-100 fold with TNF-α-stimulated coculture, concomitant with a decrease in MC p-p70S6K levels. Rapamycin treatment of TNF-⍺-stimulated cocultures resulted a modest increase in extracellular PGE2 as well as decreases in extracellular chemokines CCL2 and CCL3. In contrast, suramin treatment significantly decreased extracellular PGE2, GM-CSF, CCL2, and CCL5 while markedly increasing the BBB-stabilizing PDGF-BB. However, suramin also increased intracellular BMEC levels of multiple pro-inflammatory cytokines. Neither rapamycin nor suramin improved the intracellular inflammatory profile of cocultured MCs, indicating that MC activation had not been resolved by either treatment.

Keywords:  Alzheimer's disease; brain microvascular endothelial cells; mast cells; neuroinflammation; rapamycin; suramin

DOI:  https://doi.org/10.1002/bit.70082
Brain. 2025 Oct 22. pii: awaf394. [Epub ahead of print]

Post-mortem evidence of pathogenic angiogenesis and abnormal vascular function in early Alzheimer's disease.

Daniel J Asby, Robert A Fisher, Johanna Jackson, Seth Love, Paul M Matthews, J Scott Miners.

  Cerebral hypoperfusion and blood-brain barrier (BBB) leakiness are pathological features of Alzheimer's disease (AD). To understand their relationship to the distribution and progression of Alzheimer's disease neuropathologic change (ADNC), we analysed associations between biochemical markers and mediators of cerebral hypoperfusion and BBB leakiness, and Aβ and hyperphosphorylated tau, in multiple brain regions at different Braak tangle stages (BS). We studied frontal, temporal, parietal, entorhinal, calcarine and cingulate cortex, putamen, and trigonal white matter from 8 controls with low pathology (BS0-II), 17 brains with early-stage/intermediate AD pathology (BSIII-IV) and 11 late-stage AD cases (BSV-VI), from the South West Dementia Brain Bank and the London Neurodegenerative Diseases Brain Bank. We excluded cases with widespread moderate-severe arteriolosclerosis, macroscopic infarcts or foci of haemorrhage, Lewy body pathology or other neurodegenerative pathology. ELISAs were used to measure the myelin-associated glycoprotein:proteolipid protein-1 ratio (MAG:PLP1), an index of ante-mortem cerebral perfusion, and fibrinogen levels, to assess BBB leakiness. Also by ELISA, we measured vascular endothelial growth factor-A (VEGF-A), upregulated in cerebral ischaemia; endothelin-1 (EDN1), a mediator of vasoconstriction; CD31, an endothelial marker; platelet-derived growth factor-β (PDGFRβ), a pericyte marker and Aβ1-40, Aβ1-42 and ptau-231 concentrations. In temporal cortex from a subset of cases, 55 angiogenesis-related proteins were assayed using a multiplex profiler assay. MAG:PLP1 was lower in BSIII-IV than BS0-II in all brain regions. VEGF-A, EDN1 and CD31 concentrations were highest in BSIII-IV in most regions and correlated inversely with MAG:PLP1. EDN1 level correlated strongly with Aβ1-42 concentration in low-pathology controls. Angiogenesis-related protein assays showed elevated levels of endoglin (CD105), a marker of neoangiogenesis, in BSIII-IV, coinciding with altered expression of several angiogenic mediators. The PDGFRβ:CD31 ratio, a marker of pericyte content adjusted for vessel density, was lower in BSIII-IV than BS0-II and correlated positively with MAG:PLP1 and inversely with Aβ1-42. BBB leakiness, evidenced by elevated fibrinogen in brain tissue homogenates, was highest in BSV-VI in most regions and correlated with VEGF-A, CD31, and ptau-231 concentrations. The present data provide evidence of widespread cerebral hypoperfusion associated with pathogenic angiogenesis and vascular remodelling in AD. The study highlights a complex and dynamic temporal relationship, beginning in early-stage AD, between mediators of cerebrovascular dysfunction and the regional spread of Aβ and tau pathology. The study also identifies several therapeutic targets, including EDN1 and VEGF-A signalling, with the potential to limit cerebrovascular damage in early AD.

Keywords:  angiogenesis; blood-brain barrier (BBB); cerebral hypoperfusion; endothelin-1; pericyte; vascular endothelial growth factor-A

DOI:  https://doi.org/10.1093/brain/awaf394
Curr Biol. 2025 Oct 20. pii: S0960-9822(25)00823-1. [Epub ahead of print]35(20): R1010-R1015

The blood-brain barrier.

Audrey Chagnot, Axel Montagne.

In animals, the central nervous system (CNS) plays a crucial role as the primary organ responsible for integrating environmental information and coordinating the responses of the organism. To protect its intricate and delicate structure, the CNS is enclosed within the rigid confines of the skull, an effective defence against physical trauma. However, threats to the brain also arise internally, in the form of toxins, pathogens, or activated immune cells. This has driven the evolution of specialised vascular adaptations that tightly control exchanges between the blood and the CNS. These 'blood barriers' are tailored to the specific structure they protect, whether it's the brain, spinal cord, retina, or cerebrospinal fluid (CSF). In this primer, we focus on the structural and functional features of the blood-brain barrier (BBB) (Figure 1A).

DOI: https://doi.org/10.1016/j.cub.2025.06.061
Life Sci Space Res (Amst). 2025 Nov;pii: S2214-5524(25)00073-2. [Epub ahead of print]47 95-97

Plasma exchange as a neuroprotective strategy for post-spaceflight neuroinflammation in astronauts.

Yamac Akgun.

  Extended space missions, such as upcoming crewed explorations to Mars, pose significant physiological challenges, including neuroinflammation due to microgravity, cosmic radiation, and prolonged confinement. This article explores therapeutic plasma exchange (TPE) as a potential countermeasure to mitigate post-spaceflight neuroinflammation by reducing circulating neurotoxic factors, stabilizing the blood-brain barrier, and replenishing protective plasma proteins. By examining parallels between spaceflight-induced neurological effects and terrestrial neurodegenerative conditions, we propose that TPE could serve as a viable intervention for astronaut health. The implementation of space-compatible apheresis technologies could play a crucial role in sustaining cognitive function and long-term brain health for deep-space travelers.

Keywords:  Astronaut health; Neuroinflammation; Plasma exchange; Spaceflight physiology

DOI:  https://doi.org/10.1016/j.lssr.2025.06.004