bims-blobar 2025-11-02 papers

bims-blobar

Biomed News

on Blood brain barrier repair

Issue of 2025–11–02
twenty-one papers selected by
Nicolas Rebergue

Sphingosine-1-Phosphate Protects Against Sepsis-Associated Encephalopathy by Suppressing Heparanase-Mediated Endothelial Glycocalyx Degradation.
FAD012, a Ferulic Acid Derivative, Preserves Cerebral Blood Flow and Blood-Brain Barrier Integrity in the Rat Photothrombotic Stroke Model.
Trapezoidal Wave Chest Compression Improves Blood-Brain Barrier After Cardiac Arrest via Downregulating Integrin β3 in Brain Microvascular Endothelial Cells.
Role of transforming growth factorβ in neurovascular unit during cerebral small vessel disease.
Histological and Functional Breakdown of the Blood-Brain Barrier in Alzheimer's Disease: A Multifactorial Intersection.
Exercise and the blood-brain barrier: Mechanistic insights and therapeutic implications.
Metabolic reprogramming of hippocampal endothelial cells contributes to blood-brain barrier dysfunction in perioperative neurocognitive disorder.
The role of ROCK1/MLC/NMMHC IIA-actin signaling in ischemic stroke-induced blood-brain barrier disruption: implications for therapeutic intervention.
Qin Gui Huo Luo Oral Liquid Attenuates Blood-Brain Barrier Dysfunction after Cerebral Ischemia-Reperfusion Injury in Mice via the Regulation of the PI3K/AKT/FOXO3A Signaling Pathway.
Modulation of the blood-brain barrier permeability by patient-derived glioblastoma stem cell secretome.
Osteopontin inhibitor alleviates neuroinflammation after subarachnoid hemorrhage in rats via TLR4/NF-κB pathway.
A Modified Repetitive Closed Head Injury Model Inducing Persistent Neuroinflammation and Functional Deficits Without Extensive Cortical Tissue Destruction.
Reduced endothelial TAK1 impairs vascular integrity in cerebral small vessel disease via the RIPK1-MLKL signalling pathway.
FGF21 confers neuroprotection in Parkinson's disease by activating the FGFR1-sirt1 pathway.
Environmental enrichment by targeting hippocampal claudins attenuates depressive-like behaviours in maternally separated male mice.
Perfluorocarbon nanotechnologies for blood-brain barrier modulation: Enhancing drug delivery and neuroprotection.
Lead acetate (PbAc) impairs blood-brain barrier in zebrafish via MMP-9/13-induced pericyte developmental defects.
Basic Fibroblast Growth Factor-Releasing Bioabsorbable Polyglycolic Acid Dura Mater Enhances Neural Progenitor Cell Proliferation and Neuroprotection After Brain Injury.
The link between gut microbiota and multiple sclerosis from the perspective of barrier function.
Concomitant Traumatic Brain Injury Exacerbates Endotheliopathy in Patients with Spinal Cord Injury.
Telomerase Depletion Accelerates Ageing of the Zebrafish Brain.

Eur J Pharmacol. 2025 Oct 28. pii: S0014-2999(25)01059-3. [Epub ahead of print] 178305

Sphingosine-1-Phosphate Protects Against Sepsis-Associated Encephalopathy by Suppressing Heparanase-Mediated Endothelial Glycocalyx Degradation.

Ling Tang, Baojun Liang, Yuchen Zhang, Junjie Li, Yi Feng, Jiarong Huang, Xing Li, Jiajia Zhu.

  Sepsis-associated encephalopathy (SAE) is a severe complication of sepsis, frequently accompanied by disruption of the blood-brain barrier (BBB), neuroinflammation, and cerebral edema. The endothelial glycocalyx, an essential component of the BBB, is vital for preserving vascular homeostasis and integrity. However, the specific contribution of glycocalyx degradation in cerebral endothelial cells to BBB permeability and subsequent brain injury in SAE remains inadequately defined. In this study, we hypothesized that glycocalyx degradation is a pivotal early event in SAE pathogenesis and investigated the protective effects of sphingosine-1-phosphate (S1P) in maintaining glycocalyx integrity. Using intraperitoneal lipopolysaccharide (LPS) to induce sepsis in C57BL/6 mice, we assessed neurological deficits, BBB integrity, cerebral edema, and neuroinflammation 24 hours after induction. Our results showed that S1P treatment effectively preserved glycocalyx structure, improved neurological reflex scores, reduced Evans blue extravasation, inhibited overactivation of microglia and astrocytes, and modulated cytokine expression. Mechanistically, S1P downregulated heparanase expression and promoted glycocalyx synthesis, thereby preventing glycocalyx-loss-driven BBB disruption and ultimately improving neurological outcomes. These findings suggest that S1P may protect against SAE by limiting heparanase-mediated glycocalyx degradation. This study supports the therapeutic potential of S1P and provides new insights into strategies for managing SAE.

Keywords:  Blood-brain barrier; Glycocalyx; Heparanase; Sepsis-associated encephalopathy; Sphingosine-1-phosphate

DOI:  https://doi.org/10.1016/j.ejphar.2025.178305
Biomedicines. 2025 Sep 30. pii: 2403. [Epub ahead of print]13(10):

FAD012, a Ferulic Acid Derivative, Preserves Cerebral Blood Flow and Blood-Brain Barrier Integrity in the Rat Photothrombotic Stroke Model.

Hiroshi Sugoh, Hirokazu Matsuzaki, Jun Takayama, Naohiro Iwata, Meiyan Xuan, Bo Yuan, Takeshi Sakamoto, Mari Okazaki.

  Background/Objectives: The rapid progression of stroke often results in irreversible brain damage and poor outcomes when treatment is delayed. Prophylactic administration of FAD012 (3,5-dimethyl-4-hydroxycinnamic acid), a synthetic derivative of ferulic acid (FA), has demonstrated cerebroprotective effects in ischemic models through antioxidant and endothelial protective mechanisms. This study investigated the effects of FAD012 on cerebral infarction and blood-brain barrier (BBB) integrity using a photothrombotic stroke model in rats. Methods: Male Sprague Dawley rats received a single intraperitoneal injection of FAD012 or FA (100 or 300 mg/kg) 60 min prior to stroke induction. Under isoflurane anesthesia, the middle cerebral artery was exposed, and stroke was induced by intravenous administration of Rose Bengal followed by green laser irradiation. Cerebral blood flow (CBF) was monitored by laser Doppler flowmetry. BBB disruption was evaluated by Evans Blue extravasation and immunohistochemistry for tight junction (TJ) proteins. Results: Control rats exhibited extensive infarction, BBB disruption, and reduced expression of claudin-5, occludin, and ZO-1, along with fragmented collagen IV. In contrast, FAD012 (300 mg/kg) significantly attenuated CBF reduction, reduced infarct size, preserved BBB integrity, and maintained TJ protein expression, with greater efficacy than an equivalent dose of FA. FAD012 also preserved the expression and phosphorylation of endothelial nitric oxide synthase (eNOS), a key marker of vascular integrity. The CBF-preserving effect of FAD012 was completely abolished by NG-nitro-L-arginine methyl ester (L-NAME), a nitric oxide synthase inhibitor. Conclusions: These findings suggest that FAD012 protects endothelial function, thereby contributing to the maintenance of CBF and BBB integrity, supporting its potential as a prophylactic therapeutic agent for ischemic stroke.

Keywords:  3,5-dimethyl-4-hydroxycinnamic acid (ferulic acid derivative 012; FAD012); blood–brain barrier (BBB); brain infarction; cerebral blood flow (CBF); cerebral vascular endothelial cells; endothelial nitric oxide synthase (eNOS); ferulic acid (FA); photothrombotic stroke; tight junction (TJ) protein

DOI:  https://doi.org/10.3390/biomedicines13102403
FASEB J. 2025 Oct 31. 39(20): e71181

Trapezoidal Wave Chest Compression Improves Blood-Brain Barrier After Cardiac Arrest via Downregulating Integrin β3 in Brain Microvascular Endothelial Cells.

Peng Yao, Songling Tang, Yarong He, Zhihao Liu, Zhiyuan Wang, Wen Ma, Yangchao Gan, Jiuyu Gao, Lu Gan, Yu Cao.

  Disruption of the blood-brain barrier (BBB) is a critical mechanism of global cerebral ischemic injury and neurological deficits under cardiac arrest (CA). Compared to traditional sinusoidal wave chest compression (SW-CPR), the trapezoidal wave chest compression (TW-CPR) technique has been shown to improve blood flow and increase microcirculation during CPR. However, the effect of TW-CPR on BBB and the underlying molecular mechanism remains to be illustrated. In this study, TW-CPR and SW-CPR were respectively used on rats following CA. After resuscitation, the cerebral cortical perfusion, BBB integrity, and neurological outcomes were assessed. RT-qPCR, immunofluorescence staining, and Western blot analyses were employed to measure the expression of mechanotransducer proteins. The integrin β3 inhibitor (cRGDfk) and adeno-associated virus-ITGB3 shRNA were administered, and protein expression was assessed by Western blot, including the expression of downstream signals of differentially expressed proteins. We found that rats receiving TW-CPR showed significantly higher survival rates (73.3% vs. 53.3%, p = 0.014) and improved neurological function scores compared to SW-CPR (p = 0.020). TW-CPR also reduced BBB disruption, as evidenced by decreased Evans blue dye extravasation and elevated levels of tight junction proteins occludin and claudin-5. Hemodynamic measurements indicated that TW-CPR enhanced peripheral circulation, as shown by increased arterial pressure and left common carotid artery blood flow velocity. Additionally, cerebral cortical microcirculation was better preserved in the TW-CPR group, with higher perfused vessel density (PVD) and microvascular flow index (MFI) compared to SW-CPR. TW-CPR was also associated with reduced integrin β3 expression in BMECs, which may contribute to its protective effects on the BBB. In conclusion, TW-CPR can improve cerebral microcirculation, thus attenuating BBB injury via inhibiting integrin β3 in BMECs after CA/CPR in rats.

Keywords:  blood–brain barrier; cardiac arrest; chest compression; integrin β3; mechanotransducer

DOI:  https://doi.org/10.1096/fj.202500168R
Fluids Barriers CNS. 2025 Oct 28. 22(1): 107

Role of transforming growth factorβ in neurovascular unit during cerebral small vessel disease.

Yangjie Li, Ying Cai, Kangling Xie, Fan Hu, Jiaohao Li, Cui Li, Runjie Zhang, Zhengwei Zhong.

Cerebral small vessel disease (CSVD) encompasses diffuse brain lesions arising from structural injury to small vessels, and is closely associated with chronic hypoperfusion and blood-brain barrier (BBB) dysfunction. Its insidious onset and heterogeneous clinical manifestations render elucidation of its pathogenesis and development of targeted interventions of paramount clinical importance. Transforming growth factorβ (TGFβ), a pivotal regulator of vascular homeostasis, exerts bidirectional effects within the neurovascular unit (NVU) during CSVD: under physiological conditions, TGFβ maintains barrier integrity by modulating endothelial tight junction proteins and pericyte adhesion; under pathological stress, dysregulated TGFβ signaling induces endothelial dysfunction, pericyte degeneration and neuroinflammation, thereby promoting white-matter injury. Precise, spatiotemporal modulation of TGFβ pathways therefore represents a promising avenue for stage-specific, molecularly targeted therapy in CSVD.

DOI: https://doi.org/10.1186/s12987-025-00713-1
Neurol Int. 2025 Oct 09. pii: 166. [Epub ahead of print]17(10):

Histological and Functional Breakdown of the Blood-Brain Barrier in Alzheimer's Disease: A Multifactorial Intersection.

Jordana Mariane Neyra Chauca, Graciela Gaddy Robles Martinez.

  Background: Alzheimer's disease (AD) is a multifactorial neurodegenerative disorder characterized by amyloid-β (Aβ) plaques, neurofibrillary tangles, and progressive cognitive decline. Recent evidence has highlighted the role of blood-brain barrier (BBB) dysfunction in the early stages of AD pathology. Objective: We sought to explore the histological structure and physiological function of the blood-brain barrier, and to identify the shared pathological mechanisms between BBB disruption and Alzheimer's disease progression. Methods: This narrative review was conducted through a comprehensive search of peer-reviewed literature from 1997 to 2024, using databases such as PubMed, Elsevier, Scopus, and Google Scholar. Results: Multiple histological and cellular components-including endothelial cells, pericytes, astrocytes, and tight junctions-contribute to BBB integrity. The breakdown of this barrier in AD is associated with chronic inflammation, oxidative stress, vascular injury, pericyte degeneration, astrocyte polarity loss, and dysfunction of nutrient transport systems like Glucose Transporter Type 1 (GLUT1). These alterations promote neuroinflammation, amyloid-β (Aβ) accumulation, and progressive neuronal damage. Conclusions: BBB dysfunction is not merely a consequence of AD but may act as an early and active driver of its pathogenesis. Understanding the mechanisms of BBB breakdown can lead to early diagnostic markers and novel therapeutic strategies aimed at preserving or restoring barrier integrity in Alzheimer's disease.

Keywords:  Alzheimer’s disease; blood–brain barrier; degeneration; histological; inflammation; microglia; oxidative stress; vascular damage

DOI:  https://doi.org/10.3390/neurolint17100166
Neurobiol Dis. 2025 Oct 29. pii: S0969-9961(25)00383-3. [Epub ahead of print] 107166

Exercise and the blood-brain barrier: Mechanistic insights and therapeutic implications.

Zhao-Xin Sun, Fang Xie, Yun Zhao, Xue Wang, Zhao-Wei Sun, Ling-Jia Qian, Hong Feng.

  The blood-brain barrier (BBB) is a critical structure for maintaining homeostasis in the central nervous system, and its dysfunction is widely implicated in the pathogenesis and progression of various neurological disorders. In recent years, exercise, as a low-cost and low-side-effect non-pharmacological intervention, has demonstrated significant potential in modulating the structure and function of the BBB. In this article, we comprehensively review the key mechanisms regulating BBB permeability under physiological and pathological conditions, with a focus on three core pathways: oxidative stress-inflammation-mediated disruption, vascular endothelial growth factor-mediated bidirectional repair, and Wnt/Sonic hedgehog/transcription factor-dependent homeostasis maintenance. Furthermore, we compare the effects of different exercise modalities, including aerobic exercise, high-intensity interval training, and resistance training, on the BBB and discuss their differential impacts across distinct brain regions, populations, and disease states. Additionally, this review integrates rodent and human evidence supporting the therapeutic potential of exercise interventions for patients with typical neurological disorders (e.g., Alzheimer's disease, multiple sclerosis, stroke, and depression) as well as non-disease risk conditions such as obesity and aging that profoundly affect BBB integrity, highlighting its multi-pathway and multi-target mechanisms in maintaining BBB dynamic homeostasis. Overall, the collected evidences support that moderate and regular exercise may protect BBB function through multidimensional mechanisms, offering novel insights and theoretical foundations for non-pharmacological therapies for neurological disorders.

Keywords:  BBB; Barrier permeability; Exercise intervention; Neurological disorders; Neurovascular regulation; Tight junctions

DOI:  https://doi.org/10.1016/j.nbd.2025.107166
Biochem Biophys Res Commun. 2025 Oct 24. pii: S0006-291X(25)01573-6. [Epub ahead of print]789 152857

Metabolic reprogramming of hippocampal endothelial cells contributes to blood-brain barrier dysfunction in perioperative neurocognitive disorder.

Yong Qiu, Chunheng Mo.

   BACKGROUND: The increasing demand for anesthesia and surgical interventions, driven by an aging population, has brought renewed attention to perioperative neurocognitive disorder (PND)-a condition characterized by cognitive decline occurring in the perioperative period. Up to 30 % of elderly surgical patients are reported to develop PND, often accompanied by blood-brain barrier (BBB) dysfunction. However, how endothelial metabolic reprogramming contributes to BBB dysfunction during PND remains poorly understood.
METHODS: We established a mouse model of PND using isoflurane anesthesia combined with unilateral nephrectomy. Cognitive performance was assessed via Y-maze and fear conditioning tests. Hippocampal endothelial cells were isolated post-surgery and analyzed using liquid chromatography-mass spectrometry (LC-MS). Metabolites involved in amino acid, lipid, nucleotide, and carbohydrate metabolism were quantified and analyzed.
RESULTS: Anesthesia and surgery led to significant cognitive decline. Transmission electron microscopy (TEM) revealed ultrastructural alterations in the hippocampus and BBB dysfunction, including perivascular edema and changes in the basement membrane and tight junctions. Metabolomic profiling revealed 12 significantly upregulated and 96 downregulated metabolites in hippocampal endothelial cells. KEGG pathway enrichment analysis identified prominent alterations in arginine and proline metabolism, glutathione metabolism, and aminoacyl-tRNA biosynthesis. Differential metabolites-such as succinate, tyrosine, guanethidine, chloramphenicol, indinavir, and olmesartan-were associated with multiple metabolic pathways. Consistent with these metabolite changes, the expression of key metabolic enzyme genes was markedly altered in hippocampal endothelial cells.
CONCLUSIONS: Anesthesia and surgery induce metabolic reprogramming in hippocampal endothelial cells, alterations pathways central to amino acid, lipid, nucleotide, and carbohydrate metabolism. These endothelial metabolic alterations may underlie BBB dysfunction and contribute to the pathogenesis of PND.

Keywords:  BBB dysfunction; Endothelial cells; Hippocampus; Metabolic reprogramming; PND

DOI:  https://doi.org/10.1016/j.bbrc.2025.152857
Cell Mol Life Sci. 2025 Oct 30. 82(1): 373

The role of ROCK1/MLC/NMMHC IIA-actin signaling in ischemic stroke-induced blood-brain barrier disruption: implications for therapeutic intervention.

Liangying Bao, Yuanhao Xu, Yuchuan Ren, Yujie Dai, Junhe Yu, Milin Zhang, Shuaishuai Gong, Junping Kou.

   BACKGROUND: Disruption of the blood-brain barrier (BBB) is a key event in the onset of ischemic stroke (IS), primarily driven by endothelial cytoskeletal rearrangement. The interaction between non-muscle myosin heavy chain IIA (NMMHC IIA) and actin, along with the ROCK/MLC pathway, is central to this cytoskeletal reorganization. While our previous studies have shown that the Caspase-3/ROCK1/MLC/NMMHC IIA-actin positive feedback loop mediates H2O2-induced neuronal apoptosis, its role in cerebral ischemia-reperfusion (I/R) injury and BBB disruption remains unclear.
METHODS: In vivo, we used endothelial-specific NMMHC IIA conditional knockdown mice, NMMHC IIA-inducible endothelial conditional knock-in mice and C57BL/6J to establish a middle cerebral artery occlusion/reperfusion model. In vitro, we employed brain microvascular endothelial cells in an oxygen-glucose deprivation/reoxygenation model. The effects of the NMMHC IIA inhibitor blebbistatin, the ROCK1 inhibitor Y-27632, and the actin depolymerizer cytochalasin D were assessed for their impact on I/R-induced activation of the ROCK/MLC/NMMHC IIA-actin pathway, tight junction proteins (TJs) degradation, and brain damage.
RESULTS: Inhibition of NMMHC IIA expression and stress fiber depolymerization significantly reduced NMMHC IIA-actin interactions, suppressed the ROCK/MLC pathway, decreased TJs degradation, and alleviated cerebral I/R injury. Conversely, overexpression of NMMHC IIA further exacerbated cerebral I/R injury and BBB disruption and amplified activation of the ROCK1/MLC pathway. Y-27632 inhibited the ROCK/MLC/NMMHC IIA-actin pathway, mitigating I/R-induced BBB disruption.
CONCLUSIONS: This study reveals that the ROCK1/MLC/NMMHC IIA-actin pathway is implicated in I/R-induced BBB disruption and operates as a positive feedback loop. These findings offer a promising therapeutic strategy for the treatment of IS and BBB damage.

Keywords:  Blood-brain barrier disruption; Ischemic stroke; ROCK1/MLC/NMMHC IIA-actin loop; Tight junction

DOI:  https://doi.org/10.1007/s00018-025-05808-4
Biol Pharm Bull. 2025 ;48(10): 1572-1583

Qin Gui Huo Luo Oral Liquid Attenuates Blood-Brain Barrier Dysfunction after Cerebral Ischemia-Reperfusion Injury in Mice via the Regulation of the PI3K/AKT/FOXO3A Signaling Pathway.

Xueyu Ling, Liangying Bao, Yuanhao Xu, Shuaishuai Gong, Junping Kou.

  Qin Gui Huo Luo oral liquid (QGHL) is a modern formulation derived from the Traditional Chinese Medicine (TCM) Daqinjiao Decoction. QGHL has been widely adopted in China's clinical settings as a therapeutic agent for microcirculatory dysfunction. However, the mechanistic interplay of QGHL in animal models for ischemic stroke (IS) treatment remains unexplored. This study aimed to investigate the impact of QGHL on blood-brain barrier (BBB) disruption induced by cerebral ischemia-reperfusion (I/R) injury. HPLC analysis was employed to identify the major chemical constituents of QGHL while maintaining stringent quality standards. Male C57BL/6J mice were subjected to 1-h right middle cerebral artery occlusion, followed by 24-h reperfusion to induce I/R injury. Subsequently, QGHL was administered intragastrically at 3 different doses (7.8, 15.6, and 31.2 g kg-1). QGHL treatment significantly attenuated cerebral I/R injury, as evidenced by reduced infarct volume, improved neurological scores, attenuated cerebral edema, and restored cerebral blood flow. Moreover, QGHL preserved BBB integrity by upregulating zonula occludens-1 (ZO-1) and occludin while suppressing matrix metalloproteinase (MMP)-2/9 expression. Network pharmacology revealed that phosphatidylinositol 3-kinase (PI3K)/AKT/FOXO3A axis served as a major signaling pathway mediating QGHL's therapeutic effects against IS, which was further confirmed by Western blot analysis. QGHL exerts neuroprotection against cerebral I/R injury in mice via modulation of the PI3K/AKT/FOXO3A signaling pathway, suggesting its potential as a novel therapeutic strategy for IS.

Keywords:  HPLC; Qin Gui Huo Luo oral liquid; blood–brain barrier; ischemic stroke; network pharmacology; phosphatidylinositol 3-kinase (PI3K)/AKT/FOXO3A signaling pathway

DOI:  https://doi.org/10.1248/bpb.b25-00455
Sci Rep. 2025 Oct 27. 15(1): 37437

Modulation of the blood-brain barrier permeability by patient-derived glioblastoma stem cell secretome.

Francesco Saverio Sica, Michela Patrucco, Martina Giambra, Martina Ghizzi, Silvia Sesana, Barbara Vergani, Biagio Eugenio Leone, Andrea Di Cristofori, Carlo Giorgio Giussani, Gabriella Nicolini, Angela Bentivegna, Francesca Re.

  The blood-brain barrier (BBB) is a highly selective barrier that strictly controls the passage of substances and cells into the brain, protecting it from potential harm while preserving homeostasis. It is composed of specialised endothelial cells (ECs), along with surrounding cells, such as pericytes and astrocytes. In glioblastoma (GBM), the most prevalent primary malignant brain tumour in adults, the BBB is heterogeneously dysfunctional. In the tumour microenvironment, regions enriched with glioblastoma stem cells (GSCs) are protected by an intact BBB. However, the influence of GSCs on BBB function remains largely unexplored. In this study, the impact of patient-derived GSC (PD GSC) secretomes on human brain capillary ECs has been investigated in vitro. Results showed that secretomes decrease the BBB permeability, leading to an increase of transendothelial electrical resistance and of tight junction protein claudin-5 (CLDN5) levels. Moreover, the receptor for advanced glycation endproducts (RAGE), which is involved in cancer and chemotherapy resistance, modulates CLDN5 expression by activating the pERK/ERK signaling pathway and influences junctional organization. These findings suggest a functional pathway through which PD GSC secretomes can modulate BBB permeability, potentially impacting therapeutic efficacy.

Keywords:  Blood–brain barrier; Chemoresistance; Endothelial permeability; Glioblastoma; Glioblastoma stem cells; Tight junctions

DOI:  https://doi.org/10.1038/s41598-025-21272-3
Brain Res Bull. 2025 Oct 27. pii: S0361-9230(25)00419-8. [Epub ahead of print]232 111607

Osteopontin inhibitor alleviates neuroinflammation after subarachnoid hemorrhage in rats via TLR4/NF-κB pathway.

Dexun Kong, Jing Guo, Sha Yang, Xiang Wang, Qihui Guo, Xiangqian Ren, Jiqin Zhang, Hao Yin, Xin Xiang, Ying Tan.

  Subarachnoid haemorrhage (SAH) has a high mortality and morbidity rate. In the early stages of subarachnoid haemorrhage, neuroinflammation is one of the important mechanisms leading to brain damage.The aim of this study was to investigate the protective effect of Osteobridging protein (OPN) inhibitors against subarachnoid haemorrhage in rats. The temporal lobe tissues of rats showed a significant increase in SPP1 (OPN) in the SAH group by single-cell RNA sequencing, differential gene expression. Brain stereotactic ventricular injection of 250 umol/L OPN inhibitor was used to observe cognition 24 h after SAH rat model. The permeability of the blood-brain barrier was detected and the activation degree of microglia was observed by immunofluorescence. The results showed that OPN inhibitor improved cognitive impairment and reduced the permeability of the blood-brain barrier in rats, as well as reduced microglia activation while inhibiting the expression of inflammatory factors, which may be related to the inhibition of the TLR4/NF-κB pathway. These findings suggest that OPN inhibitors may be promising agents for the treatment of SAH by modulating blood-brain barrier permeability and inhibiting neuroinflammation.

Keywords:  Blood-brain barrier; Early brain injury; Neuroinflammation; Subarachnoid hemorrhage

DOI:  https://doi.org/10.1016/j.brainresbull.2025.111607
J Neurotrauma. 2025 Oct 23.

A Modified Repetitive Closed Head Injury Model Inducing Persistent Neuroinflammation and Functional Deficits Without Extensive Cortical Tissue Destruction.

Lucia Fadon-Padilla, Chengyan Chu, Yajie Liang, Chinmoy Sarkar, Marta M Lipinski, Miroslaw Janowski, Piotr Walczak.

  Traumatic brain injury (TBI) remains a significant clinical challenge, with limited treatment options and long-term neurological impairments. Mild to moderate TBI represents the most common form, making it a critical therapeutic target. However, current animal models poorly reflect human TBI pathophysiology, necessitating improved preclinical paradigms. Here, we present a refined repetitive closed head injury (rCHI) model using consecutive controlled impacts within a single session, without craniotomy. We initially compared closed head injury (CCI) and rCHI models showing that the rCHI model enables precise impact application while preserving brain macrostructure. We evaluated the acute and chronic effects of increasing injury severity through 1, 3, or 5 consecutive impacts in adult C57BL6/J mice. MRI revealed severity-dependent blood-brain barrier (BBB) disruption, with significant gadolinium leakage in the 3- and 5-impact groups. Neuroinflammatory responses, assessed by immunofluorescence and qRT-PCR, demonstrated proliferation of microglia (IBA1) and astrocytes (GFAP), alongside increased inflammatory markers (NOS2, NOX2, Casp1, IL-1β, TNF-α). Functional assessments (beam walk, CatWalk gait analysis, novel object recognition) confirmed sustained motor and cognitive deficits in the 5-impact group over 28 days. Diffusion MRI indicated persistent white matter alterations supporting progressive neurodegeneration. This rCHI model successfully replicates key TBI features-BBB dysfunction, chronic neuroinflammation, and functional impairments-without direct cortical destruction. It serves as a valuable platform for evaluating acute-phase interventions and investigating neuroprotective strategies targeting inflammation and BBB integrity. Our findings highlight the importance of injury severity in shaping TBI outcomes and reinforce the need for tailored therapeutic approaches.

Keywords:  MRI; blood–brain barrier; inflammation; models of injury; traumatic brain injury

DOI:  https://doi.org/10.1177/08977151251387679
Stroke Vasc Neurol. 2025 Oct 28. pii: svn-2025-004469. [Epub ahead of print]

Reduced endothelial TAK1 impairs vascular integrity in cerebral small vessel disease via the RIPK1-MLKL signalling pathway.

Jing Yang, Chi Xiao, Ming Yi, Kun Zhou, Xiangming Xu, Yuhua Fan.

   BACKGROUND: Hypertension stands as a major modifiable risk factor for cerebral small vessel disease (CSVD), driving pathological cerebrovascular rarefaction and blood-brain barrier (BBB) compromise through endothelial dysfunction and death. However, the mechanisms regulating cerebral endothelial cell death and endogenous vascular repair pathways remain incompletely characterised. While transforming growth factor-β-activated kinase 1 (TAK1) is recognised as a central regulator of cell survival and homeostasis across multiple tissues, its cerebrovascular-specific functions in hypertension-related CSVD pathogenesis have not been fully delineated.Methods Stroke-prone renovascular hypertensive rats (RHRSP) were used as a CSVD model. Cerebrovascular integrity, endothelial death patterns and TAK1 expression were comparatively analysed between RHRSP and sham-operated controls. Dual-route administration (intracerebroventricular and intravenous) of adeno-associated virus (AAV) vectors (AAV-siTAK1 or AAV-TAK1) was employed to achieve brain endothelial-specific TAK1 knockdown or overexpression. The underlying mechanism was validated in vitro.
RESULTS: In RHRSP, chronic hypertension induces predominant necroptosis over apoptosis in cerebral cortical and hippocampal endothelial cells, accompanied by a marked reduction in TAK1 expression. Using genetic and pharmacological approaches, we found that TAK1 downregulation triggers a cascade of pathological events: endothelial necroptosis, tight junction protein degradation, irreversible microvascular rarefaction, BBB leakage and spatial memory deficits. Mechanistically, this cascade is centrally mediated by TAK1-dependent regulation of the receptor-interacting protein kinase 1 (RIPK1)-mixed lineage kinase domain-like (MLKL) axis.
CONCLUSIONS: Our results demonstrate that TAK1 downregulation in endothelial cells induces RIPK1-MLKL-mediated necroptosis and downregulation of tight junction protein expression. This coordinated mechanism orchestrates cerebrovascular integrity impairment and subsequent cognitive deterioration. This study positions TAK1 as a promising and potential therapeutic target for the prevention and treatment of hypertension-related CSVD.

Keywords:  Cerebrovascular Disorders; Cognitive Dysfunction; Genetics

DOI:  https://doi.org/10.1136/svn-2025-004469
Cell Mol Biol Lett. 2025 Oct 28. 30(1): 127

FGF21 confers neuroprotection in Parkinson's disease by activating the FGFR1-sirt1 pathway.

Tingting Liu, Jianshe Wei.

   BACKGROUND: Parkinson's disease (PD) lacks disease-modifying therapies. Fibroblast growth factor 21 (FGF21) is implicated in PD, but its neuroprotective mechanisms via fibroblast growth factor receptor 1 (FGFR1)-sirtuin 1 (Sirt1) remain unclear.
METHODS: Using 1-methyl-4-phenyl-1,2,3,6-te-trahydropyridine (MPTP)-induced PD mice and lipopolysaccharides (LPS)-stimulated BV2 microglia, this study employed recombinant adeno-associated virus (rAAV)-mediated FGF21 overexpression (OE). Multi-dimensional analyses (behavior, immunofluorescence, molecular docking, Western blot, PCR, transmission electron microscopy (TEM)) assessed FGF21's effects and mechanisms.
RESULTS: FGF21OE significantly improved motor deficits (gait, rotarod) and non-motor symptoms (depression/anxiety) in PD mice. It repaired the blood-brain barrier (BBB) by upregulating tight junction proteins (claudin, zonula occludens (ZO-1), occludin) and reducing astrocyte activation (glail fibrillary acidicprotein, GFAP). Mechanistically, FGF21 binding to FGFR1 activated Sirt1, enhancing mitochondrial fusion (optic atrophy 1 (OPA1), mitofusin 1 (Mfn1)) and inhibiting fission (dynamin-related protein 1 (Drp1), Fission 1 (Fis1)), improving membrane potential and ultrastructure. FGF21 also activated the AMP-activated protein kinase (AMPK)/mammalian target of rapamycin (mTOR) pathway, boosting PINK1/Parkin-mediated mitophagy and inhibiting Casp3/Bax-dependent apoptosis. Furthermore, FGF21 reduced neuroinflammation by suppressing nuclear factor kappa-B (NF-κB)/NOD-like receptor thermal protein domain associated protein 3 (NLRP3) and shifting microglia from pro-inflammatory M1 to anti-inflammatory M2. Molecular docking and co-IP confirmed FGF21 enhances direct FGFR1-Sirt1 interaction, synergistically regulating these pathways.
CONCLUSION: FGF21 exerts multi-faceted protection in PD via the FGFR1-Sirt1 axis, including BBB repair, mitochondrial homeostasis restoration, microglial polarization towards M2, balancing autophagy and apoptosis, and promoting neuronal survival.

Keywords:  Blood–brain barrier; FGF21; Microglia; Mitochondrial dysfunction; Parkinson’s disease; Sirt1

DOI:  https://doi.org/10.1186/s11658-025-00807-6
World J Biol Psychiatry. 2025 Oct 29. 1-12

Environmental enrichment by targeting hippocampal claudins attenuates depressive-like behaviours in maternally separated male mice.

Mehdi Ansari, Shima Balali-Dehkordi, Mohammad Rahimi-Madiseh, Elham Zarean, Hossein Amini-Khoei.

   OBJECTIVES: Maternal separation (MS) is a well-established risk factor for psychological disorders like depression. Alterations in the blood-brain barrier (BBB) and its tight junction proteins, such as claudins (CLDNs), may contribute to the pathophysiology of depression. Environmental enrichment (EE) has shown antidepressant-like effects, though its exact underlying mechanisms remain incompletely understood. This study aimed to assess the effect of EE on depressive-like behaviours induced by MS in male mice, centring on hippocampal CLDNs.
METHODS: Thirty-two male NMRI mice were randomly divided into control (C), MS, MS+EE, and C + EE groups. The MS paradigm was conducted from postnatal day (PND) 2 to 14. EE was implemented between PND 45 and 60. Behavioural tests, including the open field (OFT), forced swimming (FST), and splash tests, were performed. qRT-PCR was performed to evaluate the hippocampal expression of CLDN-1, CLDN-5, and CLDN-12.
RESULTS: MS induced depression-like behaviours, as an increase in immobility time in the FST and a decrease in grooming activity time in the splash test. MS increased the expression of CLDN-1, CLDN-5, and CLDN-12 in the hippocampus. EE significantly reduced depressive-like behaviours and downregulated CLDN-1 and CLDN-12 gene expression, while CLDN-5 overexpressed.
CONCLUSIONS: EE exerts antidepressant-like effects, potentially through modulation of BBB-associated CLDNs.

Keywords:  Maternal separation; blood-brain-barrier; claudins; depression; environmental enrichment

DOI:  https://doi.org/10.1080/15622975.2025.2577759
Biochem Biophys Res Commun. 2025 Oct 22. pii: S0006-291X(25)01559-1. [Epub ahead of print]789 152843

Perfluorocarbon nanotechnologies for blood-brain barrier modulation: Enhancing drug delivery and neuroprotection.

Evan Mahdi, Abbas Alalikhan, Hayder Ridha-Salman, Murtadha Azeez Ameen, Zainab Hannon Abbass, Abolfazl Bemidinezhad, Mohammad Soukhtanloo.

  The blood-brain barrier (BBB) presents a major obstacle to effective drug delivery for neurological disorders. Recent advances in perfluorocarbon (PFC) nanotechnologies have shown promise in modulating BBB permeability for improved therapeutic outcomes. This review explores the dual role of PFC-based systems in both enhancing drug delivery and stabilizing the BBB under pathological conditions. Unlike previous reviews that mainly emphasize microbubble-assisted focused ultrasound for BBB opening, this work specifically highlights the unique contributions of PFC nanotechnologies, including their laser- and ultrasound-responsiveness, smaller nanoscale formulations enabling deeper penetration, and their emerging neuroprotective properties. The use of PFC nanoemulsions combined with focused ultrasound (FUS) has demonstrated efficient cellular uptake and targeted drug delivery to brain tumors, while laser-activated PFC nanodroplets and low-boiling-point PFC nanodroplets offer transient BBB disruption via phase transitions and acoustic cavitation. Moreover, PFC derivatives like perfluorooctyl bromide (PFOB) have shown protective effects in models of subarachnoid hemorrhage by reducing BBB permeability and mitigating neuronal apoptosis. Despite these promising findings, challenges remain in optimizing PFC formulations, evaluating long-term safety, and understanding their mechanistic effects on the BBB. Future research should focus on refining these systems through combination strategies and exploring their potential in the treatment of neurodegenerative diseases and cerebrovascular disorders.

Keywords:  Blood-brain barrier (BBB); Drug delivery; Focused ultrasound (FUS); Neuroprotection; Perfluorocarbon (PFC) nanotechnology

DOI:  https://doi.org/10.1016/j.bbrc.2025.152843
Ecotoxicol Environ Saf. 2025 Oct 24. pii: S0147-6513(25)01595-7. [Epub ahead of print]305 119250

Lead acetate (PbAc) impairs blood-brain barrier in zebrafish via MMP-9/13-induced pericyte developmental defects.

Xiuru Zhang, Zhuangzhuang Liu, Yuna Li, Jingqin He, Lulu Yang, Yulin Yan, Shanshan Tong, Yeqi Wang, Tao Zhang.

  Lead (Pb), a persistent heavy metal, has caused widespread environmental contamination due to its extensive industrial use. Among its compounds, lead acetate (PbAc) is particularly hazardous in aqueous form, exhibiting neurotoxic potential. However, its toxic effects on the integrity of the blood-brain barrier (BBB) and the underlying mechanisms remain poorly understood. This study demonstrates that zebrafish embryos exposed to varying concentrations of PbAc exhibit dose-dependent morphological abnormalities, including growth retardation, delayed hatching, and cardiovascular dysfunction, along with pronounced neurobehavioral deficits in both embryonic and adult zebrafish. Live imaging analysis revealed that both acute and chronic exposure to different concentrations of PbAc can induce cerebral hemorrhage and BBB dysfunction. Additionally, PbAc selectively disrupted cerebral angiogenesis without affecting trunk intersegmental vessels and significantly reduced pericyte coverage within both cerebral and trunk vessels. Mechanistically, RNA sequencing and qPCR validation revealed significant upregulation of MMP-9 and MMP-13 in PbAc-exposed embryos. Pharmacological inhibition of MMP-9/13 using polygalacic acid significantly reduced cerebral hemorrhage and restored pericyte coverage, suggesting that these proteases mediate PbAc-induced cerebrovascular damage. Overall, our findings underscore the ecological and public health risks associated with lead contamination and provide a basis for future therapeutic strategies targeting MMPs to mitigate heavy metal toxicity.

Keywords:  Blood-brain barrier; Lead acetate; MMP-9/13; Neurotoxicity; Zebrafish

DOI:  https://doi.org/10.1016/j.ecoenv.2025.119250
Brain Behav. 2025 Nov;15(11): e71008

Basic Fibroblast Growth Factor-Releasing Bioabsorbable Polyglycolic Acid Dura Mater Enhances Neural Progenitor Cell Proliferation and Neuroprotection After Brain Injury.

Yoshiro Ito, Ayako Oyane, Yuji Matsumaru, Eiichi Ishikawa.

   BACKGROUND: Traumatic brain injury harms health, causes disability, and burdens health care systems and economies. Although new treatments for brain injury have been developed, their therapeutic efficacy remains insufficient. Herein, we demonstrate the therapeutic efficacy of artificial dura mater with varying basic fibroblast growth factor (bFGF)-releasing capabilities using a brain injury model.
METHODS: Artificial dura mater of lower (FGF-L) and higher (FGF-H) bFGF-releasing capabilities was prepared via oxygen plasma treatment for polyglycolic acid nonwoven fabric followed by bFGF adsorption. Mice received either bFGF-releasing dura mater (FGF-L, FGF-H) or bFGF-free dura mater (FGF-C) at the site of the induced brain injury.
RESULTS: Neurological functions significantly improved in the FGF-L and FGF-H groups compared with those in the FGF-C group on Day 14. No significant difference was observed in the brain injury area between the FGF-C group and either the FGF-L or FGF-H group. The number of SRY-box transcription factor 2-positive cells in the cortex was significantly larger in the FGF-L and FGF-H groups than in the FGF-C group on Day 7. The terminal transferase dUTP nick-end labeling-positive cell ratio was significantly lower in the FGF-H group than in the FGF-C group on Day 14. The occludin-positive and ZO-1-positive cell ratios were significantly greater in the FGF-H group than in the FGF-C group on Day 14, suggesting improved blood-brain barrier integrity.
CONCLUSION: The bFGF-releasing dura mater enhanced neural progenitor cell proliferation, inhibited apoptosis and blood-brain barrier breakdown, and contributed to neurological function recovery in brain-injured mice.

Keywords:  adsorption; artificial dura mater; delivery; neural regeneration; neurological function; oxygen plasma treatment

DOI:  https://doi.org/10.1002/brb3.71008
Front Immunol. 2025 ;16 1652796

The link between gut microbiota and multiple sclerosis from the perspective of barrier function.

Jingru Ren, Zhenyu Niu, Jianchun Wang, Jing Guo, Hongjun Hao, Feng Gao, Ran Liu, Zhaoxia Wang.

  Recently, more and more studies have begun to focus on the role of gut microbiota in neurological diseases, especially immune-mediated disorders including multiple sclerosis (MS). The bidirectional communication between the gut microbiome and the central nervous system (CNS) is known as the gut-brain axis, which includes two key barriers, namely blood-brain barrier (BBB) and the gut barrier, and has become a crucial framework for understanding the pathophysiological mechanisms of various neurological disorders. Gut microbes co-evolved with humans and play important roles in maintaining steady state via various pathways, including immune regulation. An altered gut microbiota, referred to as dysbiosis, not only induces increased intestinal permeability locally, but also promotes systemic immune responses in the CNS. Increased BBB permeability has been considered the core mechanism for MS, and a "leaky" gut has also been reported in MS as well as its animal models. Therefore, the gut-brain axis is increasingly being considered as playing a crucial role in the pathogenesis of MS, with a major focus on specific gut microbiota alterations associated with the disease. Here, we review how the possible dysfunction of the gut-brain axis might impact MS, with particular emphasis on the barrier function.

Keywords:  DMTs; MS; blood-brain barrier; brain-gut axis; gut microbiota; leaky gut

DOI:  https://doi.org/10.3389/fimmu.2025.1652796
Neurotrauma Rep. 2025 ;6(1): 915-927

Concomitant Traumatic Brain Injury Exacerbates Endotheliopathy in Patients with Spinal Cord Injury.

Shahab Hafezi, Miguel A Ruiz-Cardozo, Sarbani Ghosh, Sravanthi Bandla, Matthew N Montoya Rush, Anand Dharmarajan, Mark H Hoofnagle, Isaiah R Turnbull, Camilo A Molina, Grace M Niziolek.

  Neurotrauma can cause endothelial dysfunction, characterized by neurovascular barrier disruption, tissue edema, neuroinflammation, and coagulation abnormalities, all of which may contribute to secondary injuries and worsened clinical outcomes. Here, we assess the effect of different types of neurotrauma on the local levels of biomarkers of endothelial injury and inflammation. Cerebrospinal fluid (CSF) samples were collected at multiple time points from patients with isolated traumatic spinal cord injury (SCI) and patients with concomitant SCI and traumatic brain injury (TBI). CSF levels of analytes associated with endothelial damage, as well as inflammatory mediators, were measured. Compared with patients with isolated SCI, those with SCI + TBI demonstrated significantly elevated CSF levels of multiple biomarkers linked to endotheliopathy and inflammation. In the presence of TBI, the highest increases in CSF levels of endothelial markers were observed for matrix metalloproteinase 10 (MMP-10), vascular endothelial growth factor A (VEGF-A), and fibroblast growth factor 2 (FGF-2). Among inflammatory factors, thymic stromal lymphopoietin (TSLP) showed the most pronounced difference in CSF content in patients with SCI + TBI compared with those with SCI alone, followed by interferon α2 (IFNα2) and granulocyte-macrophage colony-stimulating factor (GM-CSF). Interestingly, CSF levels of MMP-1, MMP-10, VEGF-A, IFNα2, and TSLP significantly correlated with injury severity score. Our findings indicate that, in the presence of concomitant TBI, patients with SCI exhibit higher CSF levels of biomarkers associated with endotheliopathy, blood-brain barrier breakdown, protease-mediated degradation of endothelial glycocalyx, and neuroinflammation. These results identify potential theranostic biomarkers to stratify high-risk patients and mitigate neurovascular damage, thereby improving clinical outcomes.

Keywords:  biomarker; endotheliopathy; inflammation; neurotrauma; spinal cord injury; traumatic brain injury

DOI:  https://doi.org/10.1177/2689288X251377022
Aging Cell. 2025 Oct 28. e70280

Telomerase Depletion Accelerates Ageing of the Zebrafish Brain.

Raquel R Martins, Savandara Besse, Pam S Ellis, Rabia Sevil, Naomi Hartopp, Catherine Purse, Georgia Everett-Brown, Owain Evans, Nadiyah Mughal, Mina H F Wahib, Zerkif Yazigan, Samir Morsli, Ada Jimenez-Gonzalez, Andrew Grierson, Heather Mortiboys, Chrissy Hammond, Michael Rera, Catarina M Henriques.

  Decreased telomerase expression, telomere shortening, senescence-associated markers, and inflammation have all been independently observed in the ageing brain and associated with disease. However, causality between limited telomerase expression and brain senescence and neuro-inflammation in the natural ageing setting is yet to be established. Here, we address these questions using the zebrafish as an ageing model. Akin to humans, zebrafish display premature ageing and death in the absence of telomerase and telomere shortening is a driver of cellular senescence. Our work shows for the first time that telomerase deficiency (tert-/-) accelerates key hallmarks of ageing identified in the Wild Type (WT) zebrafish brain at transcriptional, cellular, tissue and functional levels. We show that telomerase depletion accelerates ageing-associated transcriptomic changes associated with dysregulation of stress response and immune genes. These are accompanied by accelerated in situ accumulation of senescence-associated markers and inflammation in the aged brain. Importantly, in vivo, these changes correlate with increased blood-brain barrier permeability and increased anxiety-like behaviour. Of note, the acceleration of senescence-associated markers in the absence of tert occurs not only in the expected proliferative areas but also in non-proliferative ones, where it is unlikely due to telomere-dependent replicative exhaustion. This suggests that non-canonical roles of telomerase may be involved. Together, our work shows that telomerase has a protective role in the zebrafish brain against the accumulation of senescence and neuro-inflammation and is required for blood-brain barrier integrity.

Keywords:  TERT; ageing; behaviour; blood–brain barrier (BBB); brain; inflammation; senescence; telomerase; transcriptomics; zebrafish

DOI:  https://doi.org/10.1111/acel.70280