bims-blobar 2025-09-14 papers

bims-blobar

Biomed News

on Blood brain barrier repair

Issue of 2025–09–14
twelve papers selected by
Nicolas Rebergue

Neurokinin B Inhibition Preserves BBB Integrity in Ischemic Stroke via Suppression of Egr-1-Mediated Claudin-5 Downregulation.
Rutin alleviates lipopolysaccharide-induced neuroinflammation and blood brain barrier dysfunction.
Inhibition of cGAS Reduces Brain Injury and Facilitates Neurological Recovery via the STING-Mediated Signaling Pathway After Germinal Matrix Hemorrhage in Neonatal Mice.
Tight Junction Proteins at the Crossroads of Inflammation, Barrier Function, and Disease Modulation.
Repopulating Microglia Suppress Peripheral Immune Cell Infiltration to Promote Poststroke Recovery.
Mechanistic Insights and Translational Therapeutics of Neurovascular Unit Dysregulation in Vascular Cognitive Impairment.
Claudin 5 Across the Vascular Landscape: From Blood-Tissue Barrier Regulation to Disease Mechanisms.
Structural Defects Associated with Craniectomy Induce Neuroinflammation and Blood-Brain Barrier Permeability.
Salidroside Attenuates Cerebral Ischemia-Reperfusion Injury via ERβ/BNIP3-Mediated Mitochondrial Autophagy Activation in a Rat Model.
Navigation Between Alzheimer's Disease (AD) and Its Various Pathophysiological Trajectories: The Pathogenic Link to Neuroimmunology-Genetics and Neuroinflammation.
Heat stroke-induced central nervous system injury: Mechanisms and therapeutic perspectives.
Immunological Mechanisms and Therapeutic Strategies in Cerebral Ischemia-Reperfusion Injury: From Inflammatory Response to Neurorepair.

J Biochem Mol Toxicol. 2025 Sep;39(9): e70483

Neurokinin B Inhibition Preserves BBB Integrity in Ischemic Stroke via Suppression of Egr-1-Mediated Claudin-5 Downregulation.

Jijing Fu, Lihua Song, Fumin Ping, Ran Wang, Hui Li, Bo Yang, Suli Dong.

  Blood-Brain Barrier (BBB) dysfunction acts as a key mediator of ischemic brain injury, contributing to brain edema, inflammatory cell infiltration, and neuronal damage. The integrity of the BBB is largely maintained by tight junction proteins, such as Claudin-5, and its disruption exacerbates neurological deficits. Neurokinin B (NKB), a neuropeptide that belongs to the tachykinin family, has been implicated in various physiological processes, including neuroinflammation and vascular function. However, the precise effects of NKB on BBB integrity during ischemic stroke have not been thoroughly investigated. Herein, we explore the role of NKB and its receptor, NKB receptor 3 (NK3R), in the context of ischemic stroke. Our results show a significant increase in both NKB and NK3R levels in the infarcted hemisphere of middle cerebral artery occlusion (MCAO)-operated mice. When we experimentally reduced NKB levels, we observed a notable decrease in infarct volume, improved neurological function, and better BBB permeability. Additionally, we found that inhibiting NKB restored the expression of Claudin-5, which in turn reduced endothelial permeability in both in vivo and in vitro experiments. We additionally recognized early growth response protein 1 (Egr-1) as a critical downstream target of NKB, which plays a key role in compromising the endothelial barrier. Silencing Egr-1 effectively reversed the increase in endothelial permeability and the decrease in Claudin-5 caused by NKB, highlighting an important regulatory pathway. These findings emphasize the involvement of NKB in the disruption of the BBB during ischemic stroke, primarily through the upregulation of Egr-1, which leads to reduced Claudin-5 expression. Therefore, targeting NKB could be a promising therapeutic strategy for maintaining BBB integrity and reducing neuronal damage after ischemic stroke.

Keywords:  Claudin‐5; Egr‐1; NKB; blood‐brain barrier; stroke

DOI:  https://doi.org/10.1002/jbt.70483
Brain Res. 2025 Sep 08. pii: S0006-8993(25)00504-9. [Epub ahead of print] 149941

Rutin alleviates lipopolysaccharide-induced neuroinflammation and blood brain barrier dysfunction.

Yuanyuan Meng, Xingyu Liu, Ding Ding, Jingrong Wang, Jian Mao, Le Kang, Lili Cao.

  The blood-brain barrier (BBB) plays a pivotal role in safeguarding and sustaining the brain's microenvironment. Disruption of this barrier is commonly observed in various neurological disorders and is intricately linked with neuroinflammation. Rutin, a natural flavonoid known for its diverse biological activities, has showed protective effects against neuroinflammation. However, its anti-neuroinflammation role and potential to preserve the integrity of the BBB has yet to be fully elucidated. In the present study, we investigated the effects of rutin against lipopolysaccharide (LPS)-induced neuroinflammation and BBB dysfunction. The results showed that rutin pretreatment effectively mitigated LPS-induced BBB disruption and inflammatory changes in the mice brain. Mechanistically, rutin inhibited LPS-induced microglial activation and decreased the production of pro-inflammatory cytokines primarily via the caspase-mediated non-canonical inflammatory signaling pathway. These findings highlight rutin as a promising therapeutic candidate for alleviating neuroinflammation related neurological disorders.

Keywords:  Blood-brain barrier; LPS; Microglial; Neuroinflammation; Rutin

DOI:  https://doi.org/10.1016/j.brainres.2025.149941
J Integr Neurosci. 2025 Aug 22. 24(8): 39286

Inhibition of cGAS Reduces Brain Injury and Facilitates Neurological Recovery via the STING-Mediated Signaling Pathway After Germinal Matrix Hemorrhage in Neonatal Mice.

Yiheng Wang, Xuhui Yin, Xiaoli Zhang, Xixiao Zhu, Yiting Luo, Bing-Qiao Zhao.

   BACKGROUND: Germinal matrix hemorrhage (GMH) is a common complication of premature infants with lifelong neurological consequences. Inflammation-mediated blood-brain barrier (BBB) disruption has been implicated as a main mechanism of secondary brain injury after GMH. The cyclic guanosine monophosphate-adenosine monophosphate synthase (cGAS)-stimulator of interferon genes (STING) pathway plays a crucial role in inflammation, yet its involvement in GMH pathophysiology remains unclear.
METHODS: Collagenase was injected into the right germinal matrix of postnatal day 5 (P5) mouse pups to induce GMH. Either RU.521, or RU.521 combined with a STING agonist SR-717 was administered to the mice after GMH. The number of microglia, proinflammatory cytokines, microglial polarization, BBB permeability, demyelination, and axon degeneration were analyzed by immunofluorescence staining, western blotting, and quantitative real-time PCR. Neurobehavioral functions were evaluated using novel object recognition, Y-maze, and rotarod tests.
RESULTS: After induction of GMH, cGAS and STING were upregulated in the peri-hematomal area with a peak at 24 h, and they were mainly expressed in microglia. RU.521 treatment decreased the number of microglia, proinflammatory cytokines and microglial polarization, preserved BBB integrity, and decreased its permeability after GMH. Moreover, RU.521 decreased GMH-mediated upregulation of STING, phosphorylated TANK-binding kinase 1 (phospho-TBK1), phosphorylated interferon regulatory factor 3 (phospho-IRF3), and interferon-β (IFN-β), diminished demyelination, axon degeneration, and neurological deficits. The STING agonist SR-717 blunted RU.521-induced downregulation of phospho-TBK1, phospho-IRF3 and IFN-β and blocked RU.521-mediated inhibition of inflammation, protected against BBB breakdown, white matter lesions, and neurological dysfunction after GMH.
CONCLUSIONS: Inhibition of cGAS improved white matter lesions and neurological dysfunction by modulating the microglial polarization towards decreased neuroinflammation and maintaining BBB integrity through STING-mediated type I IFN-β production. Thus, cGAS may be a potential therapeutic target for the treatment of GMH.

Keywords:  STING/p-TBK1/p-IRF3/IFN-β signaling pathway; blood-brain barrier disruption; cGAS; germinal matrix hemorrhage; neuroinflammation; white matter lesions

DOI:  https://doi.org/10.31083/JIN39286
Int J Mol Sci. 2025 Aug 22. pii: 8115. [Epub ahead of print]26(17):

Tight Junction Proteins at the Crossroads of Inflammation, Barrier Function, and Disease Modulation.

Hee-Jae Cha.

Tight junctions (TJs), traditionally considered static structural elements sealing epithelial and endothelial monolayers, are now recognized as dynamic regulators of tissue homeostasis [...].

DOI: https://doi.org/10.3390/ijms26178115
CNS Neurosci Ther. 2025 Sep;31(9): e70565

Repopulating Microglia Suppress Peripheral Immune Cell Infiltration to Promote Poststroke Recovery.

Ligen Shi, Lingxiao Lu, Jun Hu, Jiarui Chen, Qia Zhang, Ziyang Jin, Zhen Wang, Zhe Zheng, Jianmin Zhang.

   AIMS: Sustained neuroinflammation following ischemic stroke impedes post-injury tissue repairment and neurological functional recovery. Developing innovative therapeutic strategies that simultaneously suppress detrimental inflammatory cascades and facilitate neurorestorative processes is critical for improving long-term rehabilitation outcomes.
METHODS: We employed a microglia depletion-repopulation paradigm by administering PLX5622 for 7 days post-ischemia; followed by a 7-day withdrawal period to allow microglia repopulation. Single-cell transcriptomics, behavioral testing, cytokine arrays, flow cytometry, and immunofluorescence were used to assess the effects of microglia repopulation and delineate the transition of reshaped immune microenvironment.
RESULTS: PLX5622 administration reshaped the poststroke immune microenvironment, promoting neurofunctional recovery. Repopulated microglia adopted a homeostatic phenotype, increasing homeostatic states by ~14.36% and reducing pro-inflammatory states by ~20.17%. This reshaped environment suppressed T cell exhaustion, limited neutrophil terminal differentiation, and promoted a phagocytic macrophage phenotype. Furthermore, we identified that these transitions in infiltrating immune cells may be driven by reduced chemokine production, enhanced blood-brain barrier (BBB) integrity, and transcriptional reprogramming.
CONCLUSION: Transient microglial depletion and repopulation via PLX5622 during the acute phase post stroke facilitate the recovery of neurological function. This immunomodulatory strategy offers a promising and clinically translationally relevant approach to enhance functional recovery following ischemic brain injury.

Keywords:  PLX5622; immunomodulation; neuroinflammation; replenished microglia

DOI:  https://doi.org/10.1111/cns.70565
J Integr Neurosci. 2025 Aug 28. 24(8): 40091

Mechanistic Insights and Translational Therapeutics of Neurovascular Unit Dysregulation in Vascular Cognitive Impairment.

Li-Shan Lin, Yu-Qi Huang, Jia-Yi Xu, Jun-Ming Han, Sheng Wu, Yin-Zhi Jin, Chao Han, Wei-Kang Hu, Zi-Xuan Xu, Takuya Sasaki, Chu Tong, Ying-Mei Lu.

  Cognitive impairment represents a progressive neurodegenerative condition with severity ranging from mild cognitive impairment (MCI) to dementia and exerts significant burdens on both individuals and healthcare systems. Vascular cognitive impairment (VCI) represents a heterogeneous clinical continuum, spanning a spectrum from subcortical ischemic VCI (featuring small vessel disease, white matter lesions, and lacunar infarcts) to mixed dementia, where vascular and Alzheimer's-type pathologies coexist. While traditionally linked to macro- and microvascular dysfunction, the mechanisms underlying VCI remain complex. However, contemporary research has gone beyond structural vascular damage, highlighting the neurovascular unit (NVU) as a critical mediator. Emerging evidence demonstrates that cerebral endothelial cells within the NVU not only regulate oxygen and nutrient transport but also orchestrate neuroinflammatory signaling and neurovascular coupling (NVC). Crucially, endothelial dysfunction initiates a self-perpetuating cycle of NVU dysregulation characterized by: (1) NVC impairment through diminished nitric oxide bioavailability and calcium signaling defects, (2) blood-brain barrier (BBB) breakdown via tight-junction protein degradation and pericyte detachment, and (3) neuroinflammation driven by endothelial-derived cytokine release and leukocyte infiltration. By integrating recent advances in NVU biology, we have established a framework to inform clinical strategies for early diagnosis and targeted therapies, which we outline in this review. Moreover, proactive management of vascular risk factors (e.g., hypertension, diabetes) in presymptomatic stages may mitigate the progression from vascular injury to irreversible dementia, underscoring its preventive potential. These insights reinforce the idea that preserving NVU integrity represents a pivotal approach to mitigating the global dementia burden.

Keywords:  brain vascular disorders; clinical progression; cognitive impairments; neurovascular coupling; pathology

DOI:  https://doi.org/10.31083/JIN40091
Cells. 2025 Aug 29. pii: 1346. [Epub ahead of print]14(17):

Claudin 5 Across the Vascular Landscape: From Blood-Tissue Barrier Regulation to Disease Mechanisms.

Mohamed S Selim, Bayan R Matani, Harry O Henry-Ojo, S Priya Narayanan, Payaningal R Somanath.

  Claudin 5 (Cldn5) is a critical tight junction protein essential for maintaining paracellular barrier integrity across endothelial and epithelial cells in barrier-forming tissues, including the blood-brain barrier and blood-retinal barrier. Cldn5 plays a central role in regulating vascular permeability, immune responses, and tissue homeostasis. The complex distribution and organ-specific regulation of Cldn5 underscore its potential as a promising therapeutic target. This review comprehensively analyzes the role of Cldn5 in endothelial and epithelial barrier function, its regulation of vascular permeability, and the discrepancies in the literature regarding its expression, regulation, and function in both physiological and pathological conditions across multiple organ systems, including the retina, brain, lung, heart, gut, kidney, liver, skin, and peripheral nerves, while emphasizing its tissue-specific expression patterns. We discuss how both reduced and excessive expressions of Cldn5 can disrupt barrier integrity and contribute to the pathogenesis of ischemic retinopathies, neuroinflammation, cardiovascular injury, and other forms of barrier dysfunction. Furthermore, we explore the dual role of Cldn5 as both a biomarker and a therapeutic target, highlighting emerging strategies such as RNA silencing, pharmacological stabilizers, and transcriptional modulators in controlling barrier leakage in disease conditions.

Keywords:  blood-tissue barrier; claudin 5; endothelial-barrier; organ injury; tight junction; vascular permeability

DOI:  https://doi.org/10.3390/cells14171346
Neurotrauma Rep. 2025 ;6(1): 586-599

Structural Defects Associated with Craniectomy Induce Neuroinflammation and Blood-Brain Barrier Permeability.

Aria W Tarudji, Brandon Z McDonald, Evan Curtis, Connor Gee, Forrest M Kievit.

  Heterogeneity associated with traumatic brain injury (TBI) outcomes necessitates validated controls to differentiate pathophysiological events from experimental methodology. While craniectomies are commonly used in TBI research, inadvertent dura disruption can result in structural deficits, impacting cellular function and neurobehavioral outcomes. Thus, there is a critical need to evaluate the effect of craniectomy on neurological outcomes to develop robust experimental controls and improve pre-clinical TBI research. In this study, craniectomy mice undergoing surgical and anesthetic intervention were assessed against naïve mice for neurological deficits and pathophysiological dysfunction. T2-weighted magnetic resonance imaging confirmed that no lesions or cavities were observed postcraniectomy. However, the cranial defect induced midline shifting over time, which might contribute to poorer behavioral outcomes in the novel object recognition assessment. Immunohistochemical analysis demonstrated an increase in GFAP and Iba1, indicating craniectomy elicited an inflammatory response. Indeed, neuroinflammation led to an increase in neuronal cell death, as measured by increases in α-II-spectrin breakdown products. However, craniectomy mice also presented with decreases in LC3BII and SQSTM1 expression, indicating an inhibition of autophagy. Last, craniectomy contributed to the altered expression of several tight junction proteins, including occludin and claudin-1/5, suggesting the blood-brain barrier was perturbed. Overall, the deficits associated with craniectomy preclude its use as an adequate sole control for TBI research, as craniectomy limits translational insights into the neurological changes observed in TBI. Additionally, these results support the need for the use of closed-head injury models where uninjured control mice do not show significant confounding minor injury patterns.

Keywords:  controlled cortical impact; craniotomy; naïve; sham

DOI:  https://doi.org/10.1177/08977151251362176
Neurochem Res. 2025 Sep 11. 50(5): 297

Salidroside Attenuates Cerebral Ischemia-Reperfusion Injury via ERβ/BNIP3-Mediated Mitochondrial Autophagy Activation in a Rat Model.

Xing Rong, Peipei Lu, Yu Li, Hongxiang Wang, Yuanjia Yue, Huimin Wang, Zhao Ji, Lin Jiang.

  This study aimed to assess the neuroprotective effects of salidroside (SAL) on cerebral ischemia-reperfusion injury (CIRI) in a rat model and to elucidate the underlying mechanisms, with a focus on the role of estrogen receptor beta (ERβ) and BCL2 interacting protein 3 (BNIP3)-mediated mitochondrial autophagy as potential therapeutic targets in ischemic stroke. A total of 165 female Sprague-Dawley rats were randomly assigned into 11 groups (n = 15 per group). One group served as the control. The remaining animals underwent bilateral ovariectomy and were subsequently allocated into the following groups: ovariectomy-only, middle cerebral artery occlusion/reperfusion (MCAO/R), estradiol control, ERβ inhibitor, two inhibitor arms (inhibitor-only and inhibitor-plus-SAL), three SAL treatment groups (low, mediummitochondrial division, high dose), and a positive control (edaravone). All groups, except the control and ovariectomy-only groups, were subjected to MCAO for one hour followed by 24 h of reperfusion. Neurological function, cerebral infarct volume, blood-brain barrier (BBB) permeability, and brain water content were evaluated. Histopathological alterations were assessed, and transmission electron microscopy was employed to detect autophagosomes. Western blot analysis was performed to quantify protein expression levels of ERβ, BNIP3, NIP3-like protein X, and microtubule-associated protein 1 A/1B-light chain 3. Administration of SAL and edaravone significantly reduced neurological impairment, infarct volume, BBB disruption, and cerebral edema in the MCAO/R model. SAL treatment upregulated ERβ and BNIP3 expression and enhanced mitochondrial autophagy-associated protein levels. These effects were attenuated by the use of ERβ and mitochondrial division inhibitors, indicating a mechanistic link between SAL-mediated neuroprotection and activation of the ERβ/BNIP3 signaling axis. SAL exerts a neuroprotective effect against CIRI in rats, primarily through activation of ERβ and enhancement of BNIP3-mediated mitochondrial autophagy. These findings suggest that modulation of the ERβ/BNIP3 pathway may represent a promising therapeutic approach for ischemic stroke.

Keywords:  BNIP3; Cerebral ischemia; ERβ; Mitochondrial autophagy; Salidroside

DOI:  https://doi.org/10.1007/s11064-025-04535-3
Int J Mol Sci. 2025 Aug 26. pii: 8253. [Epub ahead of print]26(17):

Navigation Between Alzheimer's Disease (AD) and Its Various Pathophysiological Trajectories: The Pathogenic Link to Neuroimmunology-Genetics and Neuroinflammation.

Abdalla Bowirrat, Albert Pinhasov, Aia Bowirrat, Rajendra Badgaiyan.

  One hundred and eighteen years have passed since Alzheimer's disease (AD) was first diagnosed by Alois Alzheimer as a multifactorial and complex neurodegenerative disorder with psychiatric components. It is inaugurated by a cascade of events initiating from amnesic-type memory impairment leading to the gradual loss of cognitive and executive capacities. Pathologically, there is overwhelming evidence that clumps of misfolded amyloid-β (Aβ) and hyperphosphorylated tau protein aggregate in the brain. These pathological processes lead to neuronal loss, brain atrophy, and gliosis culminating in neurodegeneration and fueling AD. Thus, at a basic level, abnormality in the brain's protein function is observed, causing disruption in the brain network and loss of neural connectivity. Nevertheless, AD is an aging disorder caused by a combination of age-related changes and genetic and environmental factors that affect the brain over time. Its mysterious pathology seems not to be limited to senile plaques (Aβ) and neurofibrillary tangles (tau), but to a plethora of substantial and biological processes, which have also emerged in its pathogenesis, such as a breakdown of the blood-brain barrier (BBB), patients carrying the gene variant APOE4, and the immuno-senescence of the immune system. Furthermore, type 2 diabetes (T2DM) and metabolic syndrome (MS) have also been observed to be early markers that may provoke pathogenic pathways that lead to or aggravate AD progression and pathology. There are numerous substantial AD features that require more understanding, such as chronic neuroinflammation, decreased glucose utilization and energy metabolism, as well as brain insulin resistance (IR). Herein, we aim to broaden our understanding and to connect the dots of the multiple comorbidities and their cumulative synergistic effects on BBB dysfunction and AD pathology. We shed light on the path-physiological modifications in the cerebral vasculature that may contribute to AD pathology and cognitive decline prior to clinically detectable changes in amyloid-beta (Aβ) and tau pathology, diagnostic biomarkers of AD, neuroimmune involvement, and the role of APOE4 allele and AD-IR pathogenic link-the shared genetics and metabolomic biomarkers between AD and IR disorders. Investment in future research brings us closer to knowing the pathogenesis of AD and paves the way to building prevention and treatment strategies.

Keywords:  APOE4; Alzheimer’s disease; blood–brain barrier; brain insulin resistance; metabolic syndrome; neuroinflammation

DOI:  https://doi.org/10.3390/ijms26178253
J Therm Biol. 2025 Sep 08. pii: S0306-4565(25)00220-7. [Epub ahead of print]132 104263

Heat stroke-induced central nervous system injury: Mechanisms and therapeutic perspectives.

Wenjun Yang, Zhen Gao, Chengjin Wang, Min Wang, Yuan Cao, Yun Li, Shaoqing Shi, Yiqi Wu, Lu Wang, Hongjun Kang.

  Heat stroke (HS), a life-threatening heat-related disorder, is characterized by a rapid elevation of core body temperature exceeding 40 °C, accompanied by central nervous system (CNS) dysfunction and multiple organ dysfunction syndrome (MODS). With the escalating impact of global warming, the incidence of HS has risen progressively, posing a significant threat to global health. The CNS is one of the primary target organs in HS, and its injury mechanisms involve intricate interactions among inflammatory cascades, oxidative stress, programmed cell death, and blood-brain barrier (BBB) disruption. These pathological processes synergistically contribute to neuronal damage, functional impairment, potential long-term cognitive and motor deficits. This review synthesizes current evidence on the molecular and cellular mechanisms underlying HS-induced CNS injury, explores the current progress in therapeutic strategies, and proposes future research directions to address critical knowledge gaps.

Keywords:  Central nervous system injury; Heat stroke; Mechanism; Therapeutic perspectives

DOI:  https://doi.org/10.1016/j.jtherbio.2025.104263
Int J Mol Sci. 2025 Aug 28. pii: 8336. [Epub ahead of print]26(17):

Immunological Mechanisms and Therapeutic Strategies in Cerebral Ischemia-Reperfusion Injury: From Inflammatory Response to Neurorepair.

Zhendong Li, Man Li, Zhi Fang, Haijun Wang.

  Cerebral ischemia-reperfusion injury (CIRI) is a complex pathological process that arises when blood flow is restored to the brain after ischemia, often resulting in significant neuronal damage and triggering secondary inflammatory responses. This review explores the immune mechanisms underlying CIRI, focusing on the activation and polarization of resident central nervous system (CNS) cells-particularly microglia and astrocytes-and the infiltration of peripheral immune cells such as neutrophils, monocytes/macrophages, and T lymphocytes. We discuss the central role of microglia in the neuroinflammatory cascade, their polarization between pro-inflammatory (M1) and anti-inflammatory (M2) phenotypes, and how this process influences neuronal damage and tissue repair. This review highlights the roles of the complement system, inflammasome activation, and blood-brain barrier disruption as key drivers of inflammation and neuronal injury. Additionally, we elaborate on the dynamic interactions between resident and infiltrating immune cells, which amplify inflammation and impede post-ischemic recovery. Finally, we discuss emerging therapeutic strategies targeting immune modulation, including cytokine regulation, microglial reprogramming, and targeted drug delivery systems, which offer promising avenues for improving outcomes in ischemic stroke.

Keywords:  blood–brain barrier; cerebral ischemia–reperfusion injury; immune cell; inflammasome; neuroinflammation

DOI:  https://doi.org/10.3390/ijms26178336