bims-blobar 2025-06-29 papers

bims-blobar

Biomed News

on Blood brain barrier repair

Issue of 2025–06–29
sixteen papers selected by
Nicolas Rebergue

Brain Endothelial Cells in Blood-Brain Barrier Regulation and Neurological Therapy.
Protective Effects of Extracts from Green Leaves and Rhizomes of Posidonia oceanica (L.) Delile on an In Vitro Model of the Human Blood-Brain Barrier.
[Effect of electroacupuncture on expression in blood-brain barrier in rats with cerebral ischemia-reperfusion injury by regulating HIF-1α/VEGF/MMP-9 signaling pathway].
Caveolin-1-Mediated Blood-Brain Barrier Disruption via MMP2/9 Contributes to Postoperative Cognitive Dysfunction.
Targeting CD38 to alleviate brain endothelial cell dysfunction and cognitive impairment in vascular dementia.
Endothelial HOXB9/SDC4 signaling exacerbates post-ischemic blood-brain and blood-spinal cord barrier disruption by promoting PKCα activation.
CCL2 Inhibitor Bindarit Improve Postoperative Cognitive Function by Attenuating Pericyte Loss-Related Blood-Brain Barrier Disruption and Neuroinflammation.
VEGFA induces anxiety and depression-like behaviors in post-stroke mice by regulating the permeability of the blood-brain barrier.
Photobiomodulation mitigates blood-brain barrier disruption in APP/PS1 mouse model of Alzheimer's disease by activating the AMPK pathway.
Vascular homeostasis in suicidal behavior: from molecular mechanisms to clinical implications.
[Cerebrolysin with reperfusion therapy in ischemic stroke: a prospective analysis of multimodal brain imaging data from the CEREHETIS trial].
Astrocytic abnormalities in brain-specific Cacna1c-deficient mice: Implications for BBB impairment in neuropsychiatric diseases associated with CACNA1C mutations.
Periplaneta americana (L.) Extract PAS840 Promotes Ischemic Stroke Recovery by Inhibiting Inflammasome Activation.
Hydroxysafflor yellow A attenuates the blood-brain barrier dysfunction and neuroinflammation through anti-inflammatory microglial polarization after intracerebral hemorrhage.
Multiple sclerosis: etiology in the context of neurovascular unit and immune system involvement and advancements with in vitro blood-brain barrier models.
Microfluidic Systems to Mimic the Blood-Brain Barrier: from Market to Engineering Challenges and Perspectives.

Int J Mol Sci. 2025 Jun 18. pii: 5843. [Epub ahead of print]26(12):

Brain Endothelial Cells in Blood-Brain Barrier Regulation and Neurological Therapy.

Yuqing Xiang, Qiuxiang Gu, Dong Liu.

  Brain endothelial cells (BECs) constitute the core component of the blood-brain barrier (BBB), regulating substance exchange between blood and the brain parenchyma to maintain central nervous system homeostasis. In pathological states, the BBB exhibits the disruption of tight junctions, endothelial cell (EC) damage, and increased permeability, accompanied by neuroinflammation, oxidative stress, and abnormal molecular signaling pathways, leading to neurotoxic effects in the brain parenchyma and exacerbating neurodegeneration and disease progression. This review systematically summarizes the developmental origin, structural characteristics, and pathological mechanisms of BECs in diseases such as Alzheimer's disease, multiple sclerosis, stroke, and glioblastoma with a particular focus on the regulatory mechanisms of the Wnt/β-catenin and VEGF signaling pathways. By integrating the latest research advances, this review aims to provide a comprehensive perspective for understanding the role of BECs in physiological and pathological states and to provide a theoretical basis for the development of BBB-based therapeutic approaches for neurological diseases.

Keywords:  blood–brain barrier; brain endothelial cells; neurological disorders; signaling pathways; therapeutic strategies

DOI:  https://doi.org/10.3390/ijms26125843
Biology (Basel). 2025 Jun 14. pii: 699. [Epub ahead of print]14(6):

Protective Effects of Extracts from Green Leaves and Rhizomes of Posidonia oceanica (L.) Delile on an In Vitro Model of the Human Blood-Brain Barrier.

Giulia Abruscato, Manuela Mauro, Marie-Christine Boucau, Vincenzo Arizza, Mirella Vazzana, Lucie Dehouck, Fabien Gosselet, Claudio Luparello, Pietra Candela.

  Posidonia oceanica (L.) Delile, a Mediterranean seagrass, is rich in bioactive compounds with anti-inflammatory potential. While marine-derived molecules are increasingly studied, their direct effects on blood-brain barrier (BBB) integrity under inflammatory conditions remain largely unexplored. This study evaluated the ability of aqueous extracts from its green leaves (GLEs) and rhizomes (REs) to protect the BBB using a human in vitro model consisting of brain-like endothelial cells co-cultured with brain pericytes. The model was exposed to TNFα, with or without GLEs or REs. We assessed NO production, endothelial permeability, expression of IL-6, NLRP3, ICAM-1, VCAM-1, CLAUDIN-5, and VE-CADHERIN, and the localization of junctional proteins. TNFα increased NO and IL-6 release, upregulated ICAM-1, VCAM-1, and NLRP3, and impaired BBB integrity by altering junctional protein levels and distribution. Co-treatment with GLEs or REs reduced the production of NO, the expression of NLRP3 and adhesion molecules and restored tight and adherens junction integrity. IL-6 levels remained unaffected. These findings suggest that P. oceanica's extracts may help preserve BBB function and mitigate inflammation-induced damage. While further studies are needed to assess their bioavailability and in vivo efficacy, these natural compounds represent promising candidates for developing preventive strategies against neuroinflammatory disorders.

Keywords:  ICAM-1; NLRP3; VCAM-1; blood–brain barrier; seagrass; tight junctions

DOI:  https://doi.org/10.3390/biology14060699
Zhen Ci Yan Jiu. 2025 Jun 25. pii: 1000-0607(2025)06-0613-11. [Epub ahead of print]50(6): 613-623

[Effect of electroacupuncture on expression in blood-brain barrier in rats with cerebral ischemia-reperfusion injury by regulating HIF-1α/VEGF/MMP-9 signaling pathway].

Teng-Wei Liao, Ying-Yan Wang, Shao-Wen Li, Xiao-Wen Xu, Yan-Zhen Zhu, Yu-Ting Tang, Lin Liu, Rui-Huan Pan, Hong-Xia Chen, Le-Chang Zhan.

   OBJECTIVES: To observe the effect of electroacupuncture (EA) on the expression of hypoxia-inducible factor 1α (HIF-1α), vascular endothelial growth factor (VEGF), matrix metalloproteinases 9 (MMP-9) and tight junction proteins in rats with cerebral ischemia-reperfusion injury (CI/RI) , so as to explore its potential mechanism in alleviating injury of neurological function and blood-brain barrier (BBB).
METHODS: A total of 84 male SD rats were used in the present study. The CIRI model was established by occlusion of the middle cerebral artery and reperfusion (MCAO/R), followed by dividing the CIRI rats into model group, EA group, and edaravone group (n=21 in each group). And another 21 normal rats were used as the sham operation group. For rats of the EA group, EA (2 Hz/15 Hz, 1 mA) was applied to "Baihui" (GV20) and "Zusanli" (ST36) on the affected limb for 20 min, once a day for 3 days. Rats of the edaravone group were intraperitoneally injected with edaravone injection (3 mg/kg), once a day for 3 days. The modified neurological severity score (mNSS) was used to evaluate the neurological behavior of rats. TTC staining was used to detect the percentage of cerebral infarction volume. HE staining was used to observe the pathological changes of cerebral cortex in ischemic area. Transmission electron microscopy was used to observe the changes of BBB ultrastructure in ischemic cortex. Evans blue (EB) staining was used to evaluate BBB permeability. Immunofluorescence was used to detect the expression of HIF-1α and VEGF protein in ischemic cortex. The protein and mRNA expressions of HIF-1α, VEGF, MMP-9, Zonula Occludens 1 (ZO-1), Occludin and Claudin-5 in the ischemic cortex were detected by Western blot or real-time PCR, respectively.
RESULTS: Compared with the sham operation group, the neurological deficit score, the percentage of cerebral infarction volume, EB leakage, the positive expressions of HIF-1α and VEGF, the protein and mRNA expressions of HIF-1α, VEGF and MMP-9 of ischemic cortex were increased (P<0.01) in the model group , while the protein and mRNA expressions of ZO-1, Occludin and Claudin-5 were decreased (P<0.01). After the intervention and compared with the model group, the neurological deficit score, the percentage of cerebral infarction volume, EB leakage, the positive expressions of HIF-1α and VEGF, the protein and mRNA expressions of HIF-1α, VEGF and MMP-9 of ischemic cortex were decreased (P<0.01, P<0.05) in the EA and edaravone groups;the protein and mRNA expression of ZO-1, Occludin and Claudin-5 were increased (P<0.05, P<0.01) in the EA group;the protein and mRNA expression of Occludin were increased (P<0.01, P<0.05) and the mRNA expression of ZO-1 and Claudin-5 were increased (P<0.05, P<0.01) in the edaravone group. The ultrastructure of BBB was damaged in the model group, which were relatively milder in the EA and edaravone groups.
CONCLUSIONS: EA intervention can reduce BBB injury and improve neurological dysfunction in rats with cerebral ischemia-reperfusion, and the underlying mechanism may be related to the regulation of HIF-1α/VEGF/MMP-9 signaling pathway.

Keywords:  Blood-brain barrier; Cerebral ischemia reperfusion; Electroacupuncture; HIF-1α/VEGF/MMP-9 signaling pathway

DOI:  https://doi.org/10.13702/j.1000-0607.20241047
Neurochem Res. 2025 Jun 26. 50(4): 210

Caveolin-1-Mediated Blood-Brain Barrier Disruption via MMP2/9 Contributes to Postoperative Cognitive Dysfunction.

Xinrui Li, Weihua Ding, Xia Zhang, Xiaodong Tang, Yueying Zheng, Yi Ma, Xiuxia Bao, Xianhui Kang, Shengmei Zhu.

  Postoperative cognitive dysfunction (POCD) is a prevalent complication following major surgery, particularly in older adults, and is associated with increased morbidity, prolonged hospitalization, and reduced quality of life. Although blood-brain barrier (BBB) disruption has been implicated in POCD pathogenesis, the molecular mechanisms remain poorly defined. In this study, we identify Caveolin-1 (Cav-1), a membrane scaffolding protein highly expressed in endothelial cells (ECs), as a key regulator of BBB integrity and cognitive function following surgical trauma. Using a tibial fracture internal fixation model in mice, we observed a significant upregulation of Cav-1 in the hippocampus, accompanied by reduced expression of tight junctions (TJs) proteins (Claudin-5 and ZO-1), increased BBB permeability, and impaired performance in behavioral assays indicative of cognitive decline. Pharmacological inhibition of Cav-1 via methyl-β-cyclodextrin (MβCD) attenuated these effects, restoring TJs expression, reducing BBB leakage, and improving cognitive outcomes. To elucidate the underlying mechanism, we employed an in vitro inflammation model using LPS-stimulated brain microvascular ECs. Cav-1 upregulation was found to increase the expression of matrix metalloproteinases MMP2 and MMP9, which in turn degraded TJs. Inhibition of Cav-1 suppressed MMP2/9 expression and preserved barrier integrity, confirming a Cav-1/MMP2/9 signaling axis. These findings demonstrate that Cav-1 plays a central role in mediating BBB breakdown and postoperative cognitive impairment via MMP-dependent degradation of TJs. Targeting Cav-1 may offer a novel therapeutic strategy to preserve BBB function and reduce the incidence of POCD in surgical patients.

Keywords:  Blood-brain barrier; Caveolin-1; Matrix metalloproteinase 2/9; Postoperative cognitive dysfunction; Tight junctions

DOI:  https://doi.org/10.1007/s11064-025-04458-z
J Pharmacol Sci. 2025 Aug;pii: S1347-8613(25)00058-1. [Epub ahead of print]158(4): 310-321

Targeting CD38 to alleviate brain endothelial cell dysfunction and cognitive impairment in vascular dementia.

Mingjing Yu, Zhi Qi, Jiaxin Zhang, Ziyi Zhang, Jieli Chen, Tao Yan, Zhili Chen.

  Vascular dementia (VaD) is a leading cause of cognitive decline, closely associated with cerebrovascular endothelial cell (CEC) dysfunction, blood-brain barrier (BBB) disruption, and neuroinflammation. CD38, an enzyme implicated in neuroinflammation and cellular senescence, has emerged as a potential regulator of these pathological processes, yet its role in CEC dysfunction within the context of VaD remains unclear. In this study, we investigated the impact of CD38 on CEC dysfunction using a mouse model of VaD induced by bilateral common carotid artery stenosis (BCAS). Our results demonstrate that BCAS significantly reduces cerebral blood flow (CBF), increases BBB permeability, and induces cognitive deficits, all accompanied by elevated CD38 expression in CECs and heightened levels of pro-inflammatory cytokines (IL-1β, IL-6, TNF-α). Notably, treatment with the selective CD38 inhibitor 78c (10 mg/kg, twice daily for 1 month) effectively mitigated these effects, reducing white matter damage, improving CBF, enhancing the expression of CEC tight junction proteins, and decreasing neuroinflammation and BBB disruption. In vitro experiments further revealed that 78c attenuates TNF-α-induced CD38 expression and inflammatory responses in CECs, likely through the NOX4/eNOS aixs. These findings identify CD38 as a crucial mediator of CEC dysfunction in VaD, linking chronic cerebral hypoperfusion to neurovascular damage.

Keywords:  Blood-brain barrier; CD38; Chronic cerebral hypoperfusion; Endothelial dysfunction; Vascular dementia

DOI:  https://doi.org/10.1016/j.jphs.2025.05.013
Brain Res Bull. 2025 Jun 24. pii: S0361-9230(25)00253-9. [Epub ahead of print]229 111441

Endothelial HOXB9/SDC4 signaling exacerbates post-ischemic blood-brain and blood-spinal cord barrier disruption by promoting PKCα activation.

Li-Qing Wang, Xiao-Yi Wang, Zuo-Xu Fan, Jie-Sheng Zheng, Yue-Hui Ma, Heng-Jun Zhou.

   BACKGROUND: Ischemic stroke is one of the most deadly chronic diseases, it damages blood-brain barrier (BBB) and blood-spinal cord barrier (BSCB). Syndecan-4 (SDC4) affects BBB integrity and function, but the specific mechanism is unclear.
METHODS: The middle cerebral artery occlusion (MCAO) rat model and the oxygen-glucose deprivation/reoxygenation (OGD/R) cell model were conducted. The influences of SDC4 on the integrity and function of BBB were detected by the transmembrane resistance (TEER) assay, immunofluorescence staining and Evans Blue assay. Luxol Fast Blue staining was used to observe the changes of motoneurons structure. Additionally, the effect of SDC4 on protein kinase Cα (PKCα) activation was measured. Finally, the effect and mechanism of Homeobox B9 (HOXB9) on SDC4 was measured with chromatin immunoprecipitation assays and dual-luciferase reporter assay.
RESULTS: SDC4 was upregulated in brain of MCAO rat, hCMEC/D3 cells and rBMVEC cells treated with OGD/R. SDC4 overexpression reduced cell viability, TEER and the expression of tight junction proteins. Importantly, SDC4 overexpression promoted PKCα activation. SDC4 interference had the opposite effects. In vivo experiments, SDC4 interference hindered Evans Blue entering brain, protected neurons structure and reduced IL-6 and TNF-α levels. As the transcription factor of SDC4, HOXB9 was upregulated in hCMEC/D3 cells induced by OGD/R. HOXB9 overexpression promoted the expression of SDC4, reduced cell viability, TEER, and tight junction protein expressions. Importantly, HOXB9 interacts with SDC4 promoter region site 2 to affect SDC4 transcription.
CONCLUSION: HOXB9 interference inhibited SDC4 transcription to attenuate PKCα activation, finally alleviate BBB disruption, spinal cord injury and BSCB damage.

Keywords:  BBB disruption; HOXB9/SDC4; Ischemic stroke; PKCα activation; Spinal cord injury and BSCB damage

DOI:  https://doi.org/10.1016/j.brainresbull.2025.111441
Mediators Inflamm. 2025 ;2025 7248780

CCL2 Inhibitor Bindarit Improve Postoperative Cognitive Function by Attenuating Pericyte Loss-Related Blood-Brain Barrier Disruption and Neuroinflammation.

Hui Yuan, Bo Lu, Daofan Sun, Junping Chen, Xiangming Fang.

  Perioperative neurocognitive disorder (PND) is a common complication in elderly patients undergoing surgery and anesthesia and associated with the impaired recovery. Previous studies have demonstrated that PND was correlated with the pericyte (PC) loss in brain, but the underlying mechanisms remain unclear. This study investigates whether C-C motif chemokine ligand 2 (CCL2) in hippocampal tissues contributes to postoperative PC injury, blood-brain barrier (BBB) disruption, neuroinflammation, and cognitive dysfunction. Sixteen-month-old C57BL/6 mice underwent tibial fracture surgery to induce PND. CCL2 expression in hippocampal tissues was downregulated using intraperitoneal injections of 200 mg/kg daily Bindarit for 4 days prior to surgery. Behavioral tests were conducted on the third day postsurgery and brain tissues were collected. Western blotting assessed CCL2 expression in the hippocampus, immunofluorescence evaluated PC coverage, BBB integrity, and neuroinflammation, and transmission electron microscopy (TEM) examined BBB microstructure. Bindarit effectively inhibited the surgery-induced increase in hippocampal CCL2 expression and improved postoperative cognitive function. Behavioral tests, including the open field (OF) test and novel object recognition (NOR) test, indicated enhanced locomotor activity and short-term memory in Bindarit-treated mice compared to controls. Immunofluorescence analysis revealed that Bindarit treatment mitigated the reduction in capillary length and tight junction (TJ) protein expression, specifically claudin-5 and occludin, which was seen with decreased PC coverage. Additionally, Bindarit suppressed the activation of hippocampal microglia and astrocytes, as evidenced by reduced Iba-1 and GFAP staining. TEM analysis confirmed that Bindarit preserved BBB microstructure integrity postsurgery. This study demonstrates that the CCL2 inhibitor Bindarit significantly reduces the incidence of PND by preventing PC loss, thereby protecting the BBB and alleviating neuroinflammation. These findings suggest that targeting CCL2 could be a potential therapeutic strategy for preventing and treating PND.

Keywords:  CCL2; blood–brain barrier; neuroinflammation; pericyte; perioperative neurocognitive disorder

DOI:  https://doi.org/10.1155/mi/7248780
Neuroscience. 2025 Jun 25. pii: S0306-4522(25)00744-4. [Epub ahead of print]

VEGFA induces anxiety and depression-like behaviors in post-stroke mice by regulating the permeability of the blood-brain barrier.

Yushuang Gou, Jiayao Zhang, Huanhuan Liu, Chuanzhou Zhu, Xiaojia Song, Shouxuan Geng, Qi Peng, Shengxi Jin, Xiaoli Wang, Yang Xiao, Fuping Zhang, Zhaohui Zhang, Jinggui Song.

  Post-stroke depression (PSD) is the most common neuropsychiatric sequela of stroke, and its pathogenesis remains unclear. The blood-brain barrier (BBB) is an important barrier for maintaining the normal operation of neurons. The impairment of its function leads to the occurrence of various neurological diseases. Vascular endothelial growth factor A (VEGFA) is an important factor in regulating the permeability of the BBB. Its expression increases after stroke and aggravates brain injury. However, the role of VEGFA in PSD remains unclear. We used middle cerebral artery occlusion combined with shock to establish a PSD mouse model and evaluated the anxiety and depression-like behaviors of the mice through behavioral tests. The permeability of the BBB, the inflammatory response, and the expression levels of VEGFA and tight junction proteins in the hippocampus of PSD mice were detected. The results showed that middle cerebral artery occlusion combined with shock could lead to severe anxiety and depression-like behaviors in mice, and the increased expression of VEGFA led to BBB damage in PSD mice. Bevacizumab improved the permeability of the BBB, alleviated the inflammatory response in the hippocampus, and promoted neuronal repair in PSD mice by inhibiting VEGFA/VEGFR, thereby improving the depression-like behaviors of PSD mice. In conclusion, the above results indicate that VEGFA participates in the depression-like behaviors of PSD mice by regulating the permeability of the BBB.

Keywords:  Blood-brain barrier; Post-stroke depression; Tight junction; Vascular endothelial growth factor A

DOI:  https://doi.org/10.1016/j.neuroscience.2025.06.056
Alzheimers Res Ther. 2025 Jun 23. 17(1): 141

Photobiomodulation mitigates blood-brain barrier disruption in APP/PS1 mouse model of Alzheimer's disease by activating the AMPK pathway.

Chunyan Ma, Yutong Ye, Xinyu Shi, Na Li, Zhiming Mu, Tao Tan, Huijuan Yin, Jianwu Dai, Yi Liu, Hongli Chen.

   BACKGROUND: Photobiomodulation (PBM), which utilizes specific light wavelengths to regulate cellular metabolism, signal transduction, and gene expression, has emerged as a promising intervention for enhancing cognitive function in Alzheimer's disease (AD). The blood-brain barrier (BBB) plays a critical role in protecting the central nervous system, and its dysfunction is a major contributor to AD pathogenesis. Although PBM has shown therapeutic potential, its effects on BBB integrity and the underlying mechanisms remain unclear.
METHODS: Six-month-old female APP/PS1 transgenic mice were subjected to PBM intervention (808 nm, 20 mW/cm2) for six weeks. Cognitive function was assessed using behavioral tests, while biochemical and histological analyses were conducted to evaluate BBB integrity, β-amyloid (Aβ) deposition, and protein expression related to tight junction proteins (TJs). In vitro, an inflammatory model was established by treating brain microvascular endothelial cells (bEnd.3) with lipopolysaccharide (LPS) to induce an inflammatory response, and the mechanisms of PBM were further explored by analyzing mitochondrial function.
RESULTS: PBM significantly improved cognitive deficits and anxiety-like behaviors in AD mice. It enhanced BBB integrity by upregulating the TJs Occludin, Claudin-5, and ZO-1, while also facilitating Aβ clearance via the low-density lipoprotein receptor-related protein 1 (LRP1) pathway and microglial phagocytosis, thereby reducing Aβ accumulation in the brain. Mechanistically, PBM attenuated apoptosis and mitochondrial oxidative stress while promoting mitochondrial energy metabolism. Notably, PBM markedly increased phosphorylated AMPK (p-AMPK) levels in the brains of AD mice. In vitro, the protective effects of PBM on BBB integrity were substantially diminished upon AMPK inhibition, confirming that PBM exerts its neuroprotective effects through the activation of the AMPK pathway.
CONCLUSION: This study demonstrates that PBM enhances BBB integrity and mitigates Aβ pathology in AD mice by activating the AMPK signaling pathway, underscoring its potential as a novel, non-invasive therapeutic strategy for AD.

Keywords:  AMPK; Alzheimer's disease; Blood–Brain Barrier; Low-density lipoprotein receptor-related protein 1; Mitochondrial function; Photobiomodulation; β-amyloid

DOI:  https://doi.org/10.1186/s13195-025-01787-7
Biol Psychiatry. 2025 Jun 23. pii: S0006-3223(25)01271-5. [Epub ahead of print]

Vascular homeostasis in suicidal behavior: from molecular mechanisms to clinical implications.

Aiste Lengvenyte, Philippe Courtet.

  Suicidal behaviors (SB) remain a major global health challenge, reflecting persistent gaps in understanding their neurobiological underpinnings. The scarcity of validated biological markers for diagnosis, prediction, or treatment response impedes clinical progress. Emerging evidence implicates vascular dysregulation as a contributing factor in the pathophysiology of SB. This review critically synthesizes findings from clinical and preclinical studies to explore how disruptions in vascular homeostasis - including endothelial integrity, blood-brain barrier (BBB) permeability, platelet function, and microvascular flow - are associated with SB and related phenotypes. Epidemiological and genetic data further highlight shared vulnerability between SB and cardiovascular or neurovascular conditions. Additionally, individuals with SB exhibit signs of increased BBB permeability, platelet activation, nitric oxide dysregulation, altered kynurenine metabolism, elevated matrix metalloproteinase-9 activity, and white matter hyperintensities. These vascular disturbances may promote a pro-inflammatory and oxidative environment that impairs neuroplasticity, thereby heightening vulnerability to SB through cognitive and emotional dysregulation. Emerging molecular indicators of vascular dysfunction - such as claudin-5, thrombospondins, platelet-derived growth factors, and components of the nitric oxide system - show potential for improving diagnosis and guiding therapeutic development, though further replication is needed. While the current evidence remains preliminary and subject to limitations discussed herein, vascular dysfunction may serve as a dynamic indicator of both acute suicide risk and longer-term susceptibility. This review integrates vascular homeostasis into the broader biological framework of SB, alongside stress-response pathways, inflammation, and neural dysfunction, offering novel insights into SB pathophysiology and paving the way for developing targeted diagnostic tools and interventions.

Keywords:  blood-brain barrier; endothelial function; stress; suicide; vascular homeostasis

DOI:  https://doi.org/10.1016/j.biopsych.2025.06.012
Zh Nevrol Psikhiatr Im S S Korsakova. 2025 ;125(6): 84-98

[Cerebrolysin with reperfusion therapy in ischemic stroke: a prospective analysis of multimodal brain imaging data from the CEREHETIS trial].

M N Kalinin, D R Khasanova.

   OBJECTIVE: To evaluate the effects of Cerebrolysin on brain microstructural integrity and blood-brain barrier (BBB) permeability, as well as their longitudinal changes, using diffusion tensor imaging (DTI) and perfusion computed tomography (PCT) in patients with acute ischemic stroke (AIS).
MATERIAL AND METHODS: This analysis included patients from the multimodal brain imaging subgroup of the prospective CEREHETIS trial (ISRCTN87656744) with AIS in the middle cerebral artery territory. The intervention group (IG, n=16) received Cerebrolysin in combination with intravenous thrombolysis (IVT) and standard care, while the control group (CG, n=17) received IVT and standard care alone. Brain imaging was performed at 24 hours and on day 14 post-IVT. DTI metrics included axial diffusivity (AD), radial diffusivity (RD), mean diffusivity (MD; 10-6 mm²/s), and fractional anisotropy (FA; ·10-4) assessed within the infarct core and contralateral region. BBB permeability (PS; mL/100 g/min) was measured on day 14 using PCT. Infarct volume (mL) was determined by diffusion-weighted imaging at 24 hours and by non-contrast CT on day 14. Mixed-effects linear regression models accounting for repeated measures were used to evaluate treatment effects over time, incorporating clinical and imaging predictors, timepoints, and interaction terms.
RESULTS: At 24 hours, no significant differences in imaging parameters were observed between groups. By day 14, the IG exhibited significantly higher values of AD (predicted marginal contrast: 259.05; 95% CI 142.19-375.91; p<0.001), RD (209.89; 95% CI 106.91-312.87; p<0.001), and FA (185.13; 95% CI 22.88-347.37; p=0.021), alongside lower PS values (-1.41; 95% CI -1.69 to -1.13; p<0.001) and smaller infarct volume (-6.98; 95% CI -10.13 to -3.82; p<0.001). The severity of ischemic injury and functional outcomes were largely influenced by the baseline condition of brain tissue and BBB integrity.
CONCLUSION: Cerebrolysin treatment was associated with favorable changes in quantitative imaging biomarkers, indicating better preservation of brain microstructure, stabilization of BBB permeability, and a reduction in infarct volume in patients with AIS. These findings support the potential cytoprotective effects of Cerebrolysin and highlight the utility of DTI and PCT for evaluating therapeutic efficacy and guiding individualized neuroprotective strategies.

Keywords:  Cerebrolysin; blood–brain barrier permeability; diffusion tensor MRI; intravenous thrombolysis; ischemic stroke

DOI:  https://doi.org/10.17116/jnevro202512506184
Channels (Austin). 2025 Dec;19(1): 2523788

Astrocytic abnormalities in brain-specific Cacna1c-deficient mice: Implications for BBB impairment in neuropsychiatric diseases associated with CACNA1C mutations.

Yeojung Koh, Maria Noterman-Soulinthavong, Anusha Bangalore, Uapingena P Kandjoze, Zea Bud, Kamryn L Noel, Hami Lee, Kathryn Franke, Coral J Cintrón-Pérez, Anjali M Rajadhyaksha, Eric B Taylor, Andrew A Pieper.

  Intronic genetic variants within the CACNA1C gene, which encodes the pore-forming alpha 1c subunit of the Cav1.2 L-type calcium channel, are significant risk factors for a multitude of neuropsychiatric disorders. In most cases, these intronic SNPs have been associated with reduced CACNA1C expression. Here, we demonstrate that targeted genetic deletion of Cacna1c in mouse brain leads to increased astrocyte reactivity, increased expression of aquaporin 4 (AQP4) in astrocytes adjacent to the blood-brain barrier (BBB), and neuroinflammation, including changes in the levels of brain chemokines and inflammatory cytokines. Astrocytes are vital for maintaining BBB integrity, with AQP4 predominantly expressed in astrocytic endfeet where it regulates water balance in the brain. This function is critical to brain health, and deterioration of the BBB is a major feature of virtually all forms of neuropsychiatric disease. Our results highlight a previously unrecognized role for CACNA1C in astrocytes at the BBB, which could be a major factor in how intronic CACNA1C SNPs broadly increase the risk of multiple forms of major neuropsychiatric disease.

Keywords:  AQP4; CACNA1C; Calcium; Cav1.2; aquaporin 4; neuropsychiatric disease

DOI:  https://doi.org/10.1080/19336950.2025.2523788
Biology (Basel). 2025 May 22. pii: 589. [Epub ahead of print]14(6):

Periplaneta americana (L.) Extract PAS840 Promotes Ischemic Stroke Recovery by Inhibiting Inflammasome Activation.

Xin Yang, Canhui Hong, Tangfei Guan, Chenggui Zhang, Yongshou Yang, Peiyun Xiao, Huai Xiao, Zhengchun He.

  Ischemic stroke (IS) is a high-mortality, multi-complication cardiovascular disease. Reducing brain injury and promoting neuronal repair after IS onset remain important challenges for current treatments. Our team previously found that PAS840, an extract from Periplaneta americana (L.), protects nerve function; this study further uses LC-MS/MS and peptidomics to analyze PAS840's components and network pharmacology to predict its ischemic stroke (IS) therapeutic targets. We then employed Transwell, a biochemical kit, real-time quantitative polymerase chain reaction (RT-qPCR), and transcriptomics to investigate PAS840's effects on migration ability, oxidative stress levels, and cellular pathways in mouse microglial cells (BV-2) following oxygen-glucose deprivation/reoxygenation (OGD/R) injury. Finally, using Evans blue staining, immunohistochemical analysis, and RT-qPCR, we investigated PAS840's effects on the blood-brain barrier, inflammation pathways, and neural function in a transient middle cerebral artery occlusion (tMCAO) rat model. PAS840 components target multiple IS pathways, effectively inhibit NF-κB/NLRP3/Caspase-1/IL-1β inflammasome pathway activation in BV-2 cells following OGD/R, reduce cellular oxidative stress, inflammation, and pyroptosis, and improve cell viability and migration ability. PAS840 decreases NF-κB/NLRP3/Caspase-1/IL-1β inflammasome pathway expression in tMCAO rat brains, reduces inflammation, activates BDNF/VGF/NGR1/Erbb4 neurotrophic factor and vascular endothelial growth factor pathways, enhances neuronal cell viability, and effectively protects and repairs the blood-brain barrier.

Keywords:  Periplaneta americana (L.); blood–brain barrier; inflammatory body; ischemic stroke; network pharmacology; transcriptomics

DOI:  https://doi.org/10.3390/biology14060589
Neuropharmacology. 2025 Jun 24. pii: S0028-3908(25)00282-5. [Epub ahead of print] 110576

Hydroxysafflor yellow A attenuates the blood-brain barrier dysfunction and neuroinflammation through anti-inflammatory microglial polarization after intracerebral hemorrhage.

Fei Zheng, Guo Xiaohang, Qiuju Yan, Yaya Zhou, En Hu, Haonan Zhu, Menghan Cheng, Zhe Yu, Mingrui Hu, Ruoqi Ding, Haigang Li, Wei Zhang, Tao Tang, Yang Wang, Teng Li, Changqing Deng.

  The destruction of the blood-brain barrier (BBB) is the most common life-threatening event of intracerebral hemorrhage (ICH). Balancing microglia polarization is a prospective therapeutic strategy for BBB injury. This study aims to explore the neuroprotective effects and the underlying mechanisms of Hydroxysafflor yellow A (HSYA) from the perspective of BBB disruption and neuroinflammation. ICH was induced by intracerebral injection of collagenase Ⅶ in C57BL/6J male mice, and HSYA was injected through the tail vein for three days. We established three oral concentrations for HSYA and found that the administration of HSYA (20 mg/kg/d) significantly improved the neurological deficits of ICH mice and reversed the histopathological damage of the brain. Using IgG and Evans Blue staining, we demonstrated that HSYA prominently facilitated the BBB repair after ICH with no bleeding risk. HSYA greatly enhanced the expression of tight junction proteins (ZO-1, occludin, and claudin-5) but decreased MMP9. HSYA also significantly reduced the CD68+ microglia with pro-inflammation mediators (IL-1β, IL-6, TNF-α, iNOS, HO-1, and COX2) and increased the Arg-1+ microglia with anti-inflammation mediators (IL-10, and TGF-β). We identified the PI3K/Akt signaling pathway through database mining and bioinformatics analysis and verified the activation of PI3K/Akt by HSYA intervention. Further, employing the PI3K-specific antagonist LY294002 confirmed that the pre-administration of LY294002 mostly negated the neuroprotective effects of HSYA. HSYA activates the PI3K/Akt/mTOR signaling pathway, balancing microglial polarization and improving BBB integrity, highlighting its potential to be an effective drug option for ICH treatment.

Keywords:  Blood-brain barrier; Hydroxysafflor yellow A; Intracerebral hemorrhage; Microglial polarization; Neuroinflammation; PI3K/Akt signaling pathway

DOI:  https://doi.org/10.1016/j.neuropharm.2025.110576
Front Immunol. 2025 ;16 1595276

Multiple sclerosis: etiology in the context of neurovascular unit and immune system involvement and advancements with in vitro blood-brain barrier models.

Aya A El-Taibany, Parichehr Heydarian, Daniel A Porada, Michael C Seeds, Anthony Atala.

  Multiple sclerosis affects a significant portion of the world's adult population and is the most common nontraumatic neuroimmunology disorder. Although the specific etiology of multiple sclerosis remains unknown, it has been associated with autoimmune components. While current treatment options relieve some symptoms in MS patients, most are immunosuppressive and only delay the progression of the disease without conferring definitive curative measures. Hence, a thorough understanding of disease pathobiology, the contribution of the neurovascular unit (NVU), and biological body-on-a-chip systems that replicate the blood-brain barrier may open new horizons for the discovery of potential therapeutics for MS.

Keywords:  autoimme disease; blood brain barrier; in-vitro model; multiple sclerosis; neuroinf lammation; neurovascular unit

DOI:  https://doi.org/10.3389/fimmu.2025.1595276
ACS Biomater Sci Eng. 2025 Jun 25.

Microfluidic Systems to Mimic the Blood-Brain Barrier: from Market to Engineering Challenges and Perspectives.

Gabriela Gomes da Silva, Daniel Pereira Sacomani, Bruna Gregatti de Carvalho, Marimélia Aparecida Porcionatto, Angelo Gobbi, Renato Sousa Lima, Lucimara Gaziola de la Torre.

  Studying and understanding complex biological systems is a challenge that requires technologies that go beyond traditional cell culture methods. Among the new technologies that have been developed in recent times, blood-brain barrier-on-a-chip (BBB-on-a-chip) models are becoming popular. Due to their ability to integrate fluid flow, which is absent in traditional static models, it has been possible to create a cellular microenvironment that mimics blood vessels and blood flow. In addition, the possibility of coculturing different cell types in multicellular models allows the observation of their interactions and increases interest in these systems. With different possibilities in terms of prototyping techniques (e.g., laminate manufacturing, molding, and 3D impression), chip designs (e.g., planar and cylindrical configurations), and materials (e.g., thermoplastics, elastomers, and hydrogels), the number of publications in the BBB research field has significantly increased in the last five years. In parallel, the emergence and consolidation of several companies have made the commercialization and application of these chips possible, mainly in the pharmaceutical area, which is not yet integrated into the drug development pipeline. In this context, the present review describes the intersection between technique, market, and applications that mimic the BBB. We showed organ-on-a-chip (OoC) market growth and the collaborative research between the main OoC supplier companies and industrial collaborators. Also, we present an overview of the primary fabrication methods used in constructing the OoC systems and their application in developing the BBB models. In addition, we discussed the BBB-on-a-chip designs developed in the last five years, including their engineering aspects (such as materials, dimensions, and configuration), characterization, and challenges in mimicking the BBB.

Keywords:  BBB-on-a-chip; blood–brain barrier; microfluidics; organ-on-a-chip

DOI:  https://doi.org/10.1021/acsbiomaterials.4c02221