bims-blobar 2025-11-23 papers

bims-blobar

Biomed News

on Blood brain barrier repair

Issue of 2025–11–23
25 papers selected by
Nicolas Rebergue

Fatty Acid-binding Protein 4 Exacerbates Blood-brain Barrier Disruption Through the JNK/c-Jun/MMP12 Pathway After Traumatic Brain Injury.
Endothelial NLRP3-mediated pyroptosis induces blood-brain barrier and neuronal damage in Huntington's disease models.
Tetrahydrocurcumin Ameliorates Cerebral Ischemia-Reperfusion Injury and Restores Blood-Brain Barrier Dysfunction by Inhibiting Ferroptosis.
Protective effects of liver-derived apolipoprotein A1 against heat stress-induced hypothalamic lipid metabolism and blood-brain barrier integrity.
Brd4 BD1 Domain Antagonism of MS436 Preserves Blood-Brain Barrier Integrity via Rnf43/β-Catenin Signaling Pathway.
MYDGF attenuates blood-brain barrier breakdown and improves cognitive impairment in diabetic encephalopathy.
Across Barriers: Blood-Brain and Gut Barrier Signaling in Psychiatric Disorders.
A microfluidic chip recapitulating the human neurovascular unit with a functional blood-brain barrier for modeling gut-brain interactions.
Fluvoxamine Attenuates Blood-Brain Barrier Disruption in Drug-Resistance Epilepsy and inhibits Ferroptosis via the Sigma-1 Receptor-TAMM41 signaling in bEnd.3 cells.
Tumor exosomal miR-221-3p induces glycolysis through the LIFR/GLUT1 pathway to destroy the cerebral vascular endothelial cell barrier and promote breast cancer brain metastasis.
Increasing interleukin-17 induced by β-Amyloid deposition is involved in early cognitive decline after sevoflurane anesthesia.
APPswe mutation causes functional deficits in endothelial cells generated by transient ETV2 overexpression in human iPSCs.
The effects of doxorubicin on blood-brain barrier integrity in hCMEC/D3.
Escin displays neuroprotective effects in mice with intracerebral hemorrhage through ameliorating intestinal injury.
The neuroprotective effects of erythropoietin following traumatic brain injury in rats through the AMP-activated protein kinase pathway: A behavioral, biochemical, and histological study.
Decoding Blood-Brain Barrier Dysfunction in Alzheimer's Disease: Innovations and Challenges in Multimodal MRI and PET Imaging Biomarkers.
Acute liver failure-induced arginine deficiency impairs blood-brain barrier via inhibiting mTORC1-S6K1/4EBP1 pathway and inducing autophagy.
Investigating the impact of resveratrol and quercetin on glymphatic function, blood-brain barrier, and neuroglial health: A systematic review.
Imaging brain inflammation and blood brain barrier permeability in neurological and psychiatric diseases: a review.
Salidroside-Pretreated Small Extracellular Vesicles Derived from Human Umbilical Cord Mesenchymal Stem Cells Promote Blood-Spinal Cord Barrier Repair After Spinal Cord Injury in Mice.
The Protective Effects of the Triggering Receptor Expressed on Myeloid Cells-1 Inhibitor LP17 on Experimental Acute Brain Injury: A Systematic Review and Meta-Analysis Based on Animal Models.
Novel 3-n-butylphthalide derivatives as potent multi-functional anti-IS agents with BBB protective function.
Profiles of blood-brain barrier and neurodegeneration markers in cerebrospinal fluid of patients with cerebral amyloid angiopathy.
Protective effects of ginsenosides in cerebral small vessel disease: Cellular and molecular mechanisms.
Beyond the innate immune system: rethinking inflammasomes in multiple sclerosis.

Mol Neurobiol. 2025 Nov 21. 63(1): 130

Fatty Acid-binding Protein 4 Exacerbates Blood-brain Barrier Disruption Through the JNK/c-Jun/MMP12 Pathway After Traumatic Brain Injury.

Botao Ma, Dezhen Yang, Mengwu Tian, Shimei Dai, Zhuang Jing, Xuerui He, Xiaoqing Bao, Yinbo Long, Yu Gong, Yanling Dong, Jiaming Li, Gengshen Zhang, Hongbo Cheng, Jiegang Yu, Xiaoliang Wang, Yaqing An, Yang Wu.

  Elevated circulating levels of fatty acid-binding protein 4 (FABP4) correlate with poor prognosis in brain injury patients. However, the molecular mechanisms by which FABP4 regulates blood-brain barrier (BBB) disruption after traumatic brain injury (TBI) remain unclear. This study investigates the molecular mechanisms by which FABP4 regulates BBB disruption following TBI and evaluates the therapeutic potential of the selective FABP4 inhibitor BMS309403 in TBI pathology. Western blot and immunofluorescence were used to detect FABP4 expression in TBI mouse brain tissue and BV2 cells. Fabp4 knockout mice were generated, and MRI, TUNEL staining, brain water content measurement, and Evans blue staining were performed to assess BBB disruption and neuronal apoptosis. Behavioral experiments were conducted to evaluate neurological deficits. The effect of microglial cells on endothelial cell tight junctions was assessed using Transwell assays. Transcriptome sequencing identified potential downstream mechanisms, and ChIP-qPCR validated P-c-Jun binding to the MMP12 promoter region. The therapeutic potential of BMS309403 was also assessed. FABP4 expression was significantly increased in TBI mice and LPS-stimulated BV2 cells. Genetic deletion of FABP4 alleviated TBI pathology, as evidenced by reduced lesion volume, cerebral edema, neuronal apoptosis, and neurological deficits. BBB disruption was attenuated with reduced degradation of tight junction proteins. Mechanistically, FABP4 promotes the degradation of tight junction proteins and increases BBB permeability by regulating MMP12 expression. FABP4 activates JNK, facilitating the binding of P-c-Jun to the Mmp12 promoter. BMS309403 effectively preserved BBB integrity, reduced cerebral edema, and improved neurological outcomes in TBI mouse models. Finally, preclinical research revealed a correlation between the plasma FABP4 level and the neurological outcome in TBI patients. FABP4 exacerbates BBB disruption after TBI via the JNK/c-Jun/MMP12 pathway. Inhibition of FABP4 offers a potential therapeutic strategy for improving TBI outcomes.

Keywords:  Blood–brain barrier; Fatty acid-binding protein 4; JNK/c-Jun; MMP12; Microglia; Traumatic brain injury

DOI:  https://doi.org/10.1007/s12035-025-05539-4
J Pharmacol Sci. 2025 Dec;pii: S1347-8613(25)00089-1. [Epub ahead of print]159(4): 256-267

Endothelial NLRP3-mediated pyroptosis induces blood-brain barrier and neuronal damage in Huntington's disease models.

Jing Cai, Wenshuang Ji, Peng Liu, Libo Zou.

  The NLRP3 inflammasome is primarily expressed and activated in microglial and endothelial cells. Extensive research has been conducted on the activation of NLRP3 inflammasomes by microglial cells leading to pyroptosis. However, there have been no reports on the activation of NLRP3 inflammasomes in brain vascular endothelial cells in patients with Huntington's disease (HD) or HD animal models, leading to blood-brain barrier (BBB) disruption. We herein found that BBB leakage increased and the expression of tight junction proteins significantly decreased after transfecting the mutant Huntingtin protein (mHtt) Q74 plasmid into the mouse brain microvascular endothelial cell line bEnd.3. mHtt promoted the activation of NLRP3 by brain vascular endothelial cells, and increased the expression of the pyroptosis-related proteins. This resulted in a decrease in the expression of the NeuN in the brain of hHTT130 transgenic mice. Furthermore, by downregulating NLRP3 in Q74-transfected bEnd.3 cells or in hHTT130 mouse brain vascular endothelial cells, BBB disruption and endothelial cell pyroptosis were alleviated, the number of surviving neurons was significantly increased. In conclusion, mHtt can activate the NLRP3 inflammasome in brain microvascular endothelial cells to induce endothelial cell pyroptosis, thereby disrupting the function of the BBB, leading to neuronal damage.

Keywords:  Blood-brain barrier; Endothelial cells; Huntington's disease; NLRP3; Pyroptosis

DOI:  https://doi.org/10.1016/j.jphs.2025.09.003
CNS Neurosci Ther. 2025 Nov;31(11): e70662

Tetrahydrocurcumin Ameliorates Cerebral Ischemia-Reperfusion Injury and Restores Blood-Brain Barrier Dysfunction by Inhibiting Ferroptosis.

Shuang Zhang, Jizhong Han, Zhen Fan, Haoxiang Wang, Luotong Liu, Liang Liu, Liangxue Zhou, Huajiang Deng.

   BACKGROUND: Cerebral ischemia-reperfusion (I/R) injury is a major consequence of ischemic stroke, leading to blood-brain barrier (BBB) disruption, neuroinflammation, and neuronal death. Recent studies suggest that tetrahydrocurcumin (THC), a natural compound, may have neuroprotective effects in ischemic stroke. However, the underlying mechanisms remain unclear. This study aims to investigate THC's neuroprotective effects in cerebral I/R injury and explore its potential mechanisms.
METHODS: A middle cerebral artery occlusion (MCAO) model was used to induce ischemia-reperfusion injury in mice. Bioinformatics analysis identified key genes involved in ferroptosis. THC's effects were assessed by evaluating infarct volume, BBB permeability, and ferroptosis-related markers (GPX4, xCT, FTH1). Molecular mechanisms were explored using an Nrf2-specific inhibitor (ML385) and molecular docking analysis.
RESULTS: THC treatment significantly reduced infarct volume, alleviated BBB disruption, and improved neurological function. It inhibited ferroptosis by upregulating the expression of GPX4, xCT, and FTH1, and by decreasing lipid peroxidation and iron accumulation. THC promoted Nrf2 nuclear translocation, which in turn activated the downstream antioxidant pathway. Molecular docking analysis revealed that THC binds to Keap1, promoting Nrf2 dissociation and nuclear translocation. ML385 reversed THC's protective effects, confirming the involvement of the Keap1/Nrf2 signaling pathway.
CONCLUSION: THC inhibits ferroptosis through the activation of the Keap1/Nrf2 signaling pathway, significantly improving BBB dysfunction and alleviating neurological deficits following cerebral ischemia-reperfusion. These findings suggest that THC could serve as a potential therapeutic agent for ischemic stroke, providing a novel approach for the treatment of cerebral ischemia-reperfusion injury through ferroptosis modulation.

Keywords:  Nrf2; blood–brain barrier; cerebral ischemia–reperfusion injury; ferroptosis; neurological function; tetrahydrocurcumin

DOI:  https://doi.org/10.1111/cns.70662
Psychoneuroendocrinology. 2025 Nov 12. pii: S0306-4530(25)00414-7. [Epub ahead of print]184 107691

Protective effects of liver-derived apolipoprotein A1 against heat stress-induced hypothalamic lipid metabolism and blood-brain barrier integrity.

Bin Li, Ruixi Ming, Hongzhou Guo.

  Heat stress (HS), a prevalent occupational and environmental hazard, has increasingly been recognized as a major contributor to multiple physiological disorders. The hypothalamus, a key regulator of thermoregulation and endocrine signaling, is especially susceptible to metabolic and inflammatory disturbances induced by HS. This study investigates the interplay among lipid metabolism, blood-brain barrier (BBB) integrity, and neuroinflammation in the hypothalamus under HS conditions, with a specific focus on apolipoprotein A1 (APOA1) as a potential protective factor. To achieve this, we integrated proteomic and lipidomic analyses with experimental validation in porcine and murine models. Proteomic analysis identified 266 differentially expressed proteins (DEPs) in the hypothalamus following HS, with significant enrichment in lipid metabolism pathways-especially glycerophospholipid (GP) metabolism-in which APOA1 displayed a marked increase. Lipidomic profiling further revealed HS-induced disruptions in phosphatidylcholine (PC), phosphatidylethanolamine (PE), and cardiolipin (CL) metabolism. Additionally, blood-brain barrier integrity was compromised, as evidenced by increased perivascular IgG extravasation, reduced pericyte coverage, and decreased expression of tight junction proteins ZO-1 and Occludin. HS also triggered pronounced neuroinflammation, characterized by elevated levels of iNOS, GFAP, and pro-inflammatory cytokines (TNF-α, IL-1β, and IL-6). Notably, administration of D-4F, an APOA1 mimetic peptide, alleviated blood-brain barrier damage, reduced neuroinflammation, and preserved synaptic integrity, thereby suggesting a neuroprotective role for APOA1 in HS-induced hypothalamic dysfunction. These findings underscore the critical role of lipid metabolism in maintaining hypothalamic homeostasis under HS conditions and position APOA1 as a key regulator with potential therapeutic implications for mitigating HS-related neuroinflammatory and metabolic disturbances.

Keywords:  BBB integrity; HS; Lipid metabolism dysregulation; Liver-derived APOA1; Neuroinflammation

DOI:  https://doi.org/10.1016/j.psyneuen.2025.107691
Adv Sci (Weinh). 2025 Nov 20. e15584

Brd4 BD1 Domain Antagonism of MS436 Preserves Blood-Brain Barrier Integrity via Rnf43/β-Catenin Signaling Pathway.

Chenxiao Li, Xiaochen Zhang, Jiangwei Xia, Shuang Liu, Yushan Du, Sihan Li, Shukui Zhang, Yong Zhang, Fen Ji, Jianwei Jiao, Jingjing Zhang.

  Blood-brain barrier (BBB) disruption is central to neurodegenerative and cerebrovascular diseases, but its causal role and therapeutic targeting remain challenging. Bromodomain and extraterminal domain (BET) proteins, particularly Brd4, regulate transcription via dual bromodomains (BD1, BD2). While BD1 antagonists are explored for tumors and BD2 antagonists for inflammation, their impact on cerebrovascular integrity is unclear. Crucially, opposing BBB effects of domain-specific BET antagonism: the BD2 antagonist RVX208 disrupt the BBB, whereas the BD1 antagonist MS436 significantly reduces leakage and improves neurological outcomes, revealing therapeutic potential is demonstrated. Mechanistically, endothelial Brd4 critically suppresses BBB stability. Its ablation upregulates tight junction (TJ) proteins. Brd4, acting exclusively through its BD1 domain, destabilizes TJs via Rnf43 is identified, which promotes β-catenin and TJ protein degradation. This defines a novel Brd4 BD1/Rnf43/β-catenin axis essential for BBB integrity. The findings establish Brd4 BD1 inhibition as a novel BBB-protective strategy and position MS436 for repurposing in cerebrovascular diseases, necessitating reevaluation of domain-specific BET targeting for neurovascular pathologies.

Keywords:  Claudin 5; blood‐brain barrier; bromodomain; cerebrovascular diseases; tight junction

DOI:  https://doi.org/10.1002/advs.202515584
Endocrinology. 2025 Nov 19. pii: bqaf171. [Epub ahead of print]

MYDGF attenuates blood-brain barrier breakdown and improves cognitive impairment in diabetic encephalopathy.

Mingjuan He, Wen Mei, Jingjing Zhao.

  Blood-brain barrier (BBB) breakdown plays a key role in cognitive impairment in diabetic encephalopathy (DE). This study aimed to investigate whether myeloid-derived growth factor (MYDGF) can prevent BBB injury and cognitive impairment in DE. Circulating MYDGF levels were measured in patients with diabetes. In vivo experiments, both loss- and gain-of-function strategies were used to evaluate the effect of MYDGF on BBB injury and cognitive impairment in diabetic mice. We used multiple low-dose streptozotocin-treated Mydgf knockout and wild-type (WT) mice on high fat diets to induce diabetes. Then, cognitive function and BBB permeability were examined in diabetic mice that were subjected to adeno-associated virus-mediated Mydgf gene transfer. In vitro experiments, primary human brain microvascular endothelial cells (HBMECs) were treated with high glucose (HG) to mimic diabetic conditions. The effects of MYDGF on transendothelial permeability were investigated. The results indicated that circulating MYDGF levels were decreased in patients with DE and diabetic mice with cognitive impairment. Compared with WT mice, MYDGF deficiency presented more severe impaired cognitive performance, BBB leakage and cerebrovascular inflammation in diabetic mice. Inversely, MYDGF restoration alleviated cognitive decline, BBB breakdown and cerebrovascular inflammation in diabetic mice. In HG-treated HBMECs, MYDGF restoration attenuated the transendothelial permeability and junction protein downregulation and protected against endothelial inflammation and apoptosis. Mechanistically, the protective effect of MYDGF was attributed to MAP4K4/NF-κB signalling pathway inhibition. This study demonstrated that MYDGF protects against BBB injury and prevents the progression of cognitive decline in DE, suggesting that MYDGF may be an effective therapeutic strategy for DE.

Keywords:  Diabetic encephalopathy; blood–brain barrier; myeloid-derived growth factor

DOI:  https://doi.org/10.1210/endocr/bqaf171
J Neurochem. 2025 Nov;169(11): e70282

Across Barriers: Blood-Brain and Gut Barrier Signaling in Psychiatric Disorders.

Luisa Bandeira Binder, Laura Menegatti Bevilacqua, Flora Gro Lorentzen Thomassen, Manon Lebel, Benjamin A H Jensen, Caroline Menard.

  Psychiatric disorders affect millions of people worldwide. Despite widespread use of conventional treatments targeting monoaminergic systems, remission rates remain low, and many individuals experience treatment resistance or relapse. Consequently, there has been growing interest in the involvement of other systems, with exacerbated immune responses and barrier alterations reported in clinical settings and preclinical models. Indeed, emerging evidence supports disruption of the blood-brain barrier (BBB) and intestinal barrier in the etiology and progression of psychiatric conditions, notably major depression, bipolar disorder, and generalized anxiety. The BBB is a highly selective structure whose integrity is maintained by endothelial cells, astrocytes, pericytes, and cellular adhesion molecules. Loss of BBB integrity has been increasingly recognized not only as a marker of psychiatric disorders but also as a contributing factor in their development. The BBB and intestinal barrier share anatomical features and functions, especially with the gut-vascular barrier, which remains understudied. Intestinal barrier dysfunction is a hallmark of inflammatory bowel disease (IBD), a condition with a high rate of comorbidity with psychiatric disorders. Both barriers are characterized by similar cellular components and signaling pathways regulating permeability. Psychological stress, a major risk factor for psychiatric conditions and IBD, renders the BBB and intestinal barrier hyperpermeable, feeding a vicious cycle of exacerbated inflammation and ultimately, mood changes as discussed here. We highlight key signaling pathways linked to barrier development and function, including Wnt/β-catenin, VEGF, and FGF-2, and argue that they may contribute to the pathophysiology of mental disorders and IBD, and could be targeted to develop innovative diagnostic tools and treatments. Key limitations and knowledge gaps are reviewed. To sum up, barrier-related alterations have long been reported in clinical studies in psychiatry and are now receiving increasing attention at the mechanistic level, as they may be relevant to uncovering new therapeutic targets beyond traditional monoamine-focused treatments.

Keywords:  anxiety; blood–brain barrier; depression; gut–brain axis; gut–vascular barrier; stress

DOI:  https://doi.org/10.1111/jnc.70282
Lab Chip. 2025 Nov 18.

A microfluidic chip recapitulating the human neurovascular unit with a functional blood-brain barrier for modeling gut-brain interactions.

Wenxin Wang, Jingwei Cui, Yufei Guo, Xuesong Kang, Hong Liu, Zikai Hao.

The blood-brain barrier (BBB) is essential for central nervous system homeostasis, but most current in vitro models lack structural and functional fidelity. We developed a physiologically relevant human neurovascular unit microfluidic chip (hNVU-on-a-chip) incorporating brain microvascular endothelial cells, astrocytes, and microglia to reconstruct a biomimetic BBB microenvironment. Barrier function was confirmed by low apparent permeability (Papp) and active P-glycoprotein (P-gp) efflux, with performance superior to Transwell models. Transcriptomic profiling revealed endothelial maturation with upregulated barrier and transport genes and downregulated proliferative pathways. Introducing gut microbial metabolites altered brain-side neurotransmitter metabolism, elevating biogenic amines and reducing precursors, consistent with enhanced turnover. Together, the hNVU-on-a-chip recapitulates BBB architecture and function, and provides a robust platform to investigate gut-brain axis interactions.

DOI: https://doi.org/10.1039/d5lc00937e
Mol Neurobiol. 2025 Nov 21. 63(1): 120

Fluvoxamine Attenuates Blood-Brain Barrier Disruption in Drug-Resistance Epilepsy and inhibits Ferroptosis via the Sigma-1 Receptor-TAMM41 signaling in bEnd.3 cells.

Lin Guo, Siyu Liu, Na Lv, Jianlun Ji, Xinting Lin, Ying Ke, Zhidong Liu, Congcong Sun, Yun Wang.

  Drug resistance is common in epileptic patients, necessitating the exploration of novel therapeutic strategies to convert drug resistance into drug responsiveness. The repurposing of existing drugs has emerged as an attractive approach for finding novel drugs. In this study, we utilized a combination of network computation and text mining techniques to identify potential repurposable drugs for treating drug-resistant epilepsy (DRE) and elucidate the underlying mechanisms. Our analysis identified fluvoxamine as a promising candidate for repurposing in epilepsy treatment. Using the lamotrigine-pentylenetetrazol kindling drug-resistant epilepsy model, we found that fluvoxamine effectively converted drug-resistant epilepsy in mice to drug responsiveness, including against gabapentin, phenytoin sodium, and carbamazepine. Additionally, fluvoxamine mitigated the elevated blood-brain barrier permeability associated with drug-resistant epilepsy by activating the sigma-1 receptor (S1R). Furthermore, fluvoxamine inhibited ferroptosis in endothelial cells induced by kainic acid. Proteome test revealed that fluvoxamine increased the expression of TAM41 Mitochondrial Translocator Assembly And Maintenance Homolog (TAMM41), a protein located in the inner mitochondrial membrane of endothelial cells. Notably, the knockdown or conditional knockout of TAMM41 in brain microvascular endothelial cells (BMVECs) reversed the protective effects of fluvoxamine on the blood-brain barrier (BBB) integrity and its inhibitory action on ferroptosis. In contrast, fluoxetine, despite sharing similar pharmacokinetic features and receptor spectrum with fluvoxamine, didn't elevate TAMM41 levels or exhibit anti-drug-resistant epileptic activity. Collectively, our findings demonstrate that fluvoxamine restores the responsiveness of DRE mice to antiepileptic drugs, alleviates BBB impairment, and inhibits BMVECs ferroptosis by activating the S1R-TAMM41 axis in BMVECs. Given the critical role of BBB disruption in drug-resistant epilepsy pathogenesis, this study may offer novel therapeutic strategies for treating drug-resistant epilepsy.

Keywords:  Blood–brain barrier; Epilepsy; Fluvoxamine; Sigma-1 receptor; TAMM41

DOI:  https://doi.org/10.1007/s12035-025-05356-9
J Transl Med. 2025 Nov 21. 23(1): 1333

Tumor exosomal miR-221-3p induces glycolysis through the LIFR/GLUT1 pathway to destroy the cerebral vascular endothelial cell barrier and promote breast cancer brain metastasis.

Kaitao Zhu, Hongru Yao, Jilong Hei, Shiwei Li, Tongxin Ye, WenG Jiang, Shuwen Wang, Zhuojun Luo, Tracey Martin, Jie Zhou, Shanyi Zhang.

   BACKGROUND: Tumor-derived exosomal microRNAs mediate intercellular communication between malignant cells and distant organs and play a pivotal role in metastatic dissemination. Breast cancer brain metastasis (BCBM) poses a significant clinical challenge, with endothelial barrier dysfunction representing a critical yet poorly understood step in metastatic progression.
METHODS: A physiologically relevant in vitro blood‒brain barrier (BBB) model was established to evaluate exosomal functions. Mechanistic investigations included qPCR and western blotting for miR-221-3p, along with protein expression profiling, immunofluorescence-based tight junction protein visualization, apoptosis detection via annexin V/PI staining, EdU assays for proliferation quantification, and transendothelial migration assessments. To validate the underlying mechanism, ALIX/HRS were silenced to inhibit exosome secretion, and miR-221-3p antagonists were applied. Clinical relevance was assessed by analyzing plasma miR-221-3p levels in breast cancer (BC) patients.
RESULTS: Highly invasive breast cancer-derived exosomal miR-221-3p induced glycolysis and lactic acid accumulation in brain microvascular endothelial cells by targeting the leukemia inhibitory factor receptor (LIFR), leading to endothelial barrier destruction and reduced tight junction protein expression. This significantly enhanced endothelial barrier permeability and tumor cell transendothelial migration capacity. Silencing ALIX/HRS or antagonizing miR-221-3p markedly reversed these effects.
CONCLUSIONS: Our findings indicate that BC can target LIFR in hCMEC/D3 cells via exosomal miR-221-3p, thereby promoting glycolysis and inhibiting the expression of tight junction proteins, which facilitates tumor metastasis.

Keywords:  BCBM; Exosome; GLUT1; Glycolysis; LIFR; Occludin; ZO-1; miR-221-3p

DOI:  https://doi.org/10.1186/s12967-025-07372-8
Exp Brain Res. 2025 Nov 20. 244(1): 2

Increasing interleukin-17 induced by β-Amyloid deposition is involved in early cognitive decline after sevoflurane anesthesia.

Qi Zhao, Yue Ma, Xiaomei Zhang, Minyu Zhang, Zhuangzhuang Wang, Xiaodan Chen, Fangqi Duan, Dongyan Chen, Zhiqiang Yu.

  Postoperative delirium is a major concern in elderly patients and is associated with early cognitive decline after anesthesia exposure. Sevoflurane anesthesia increases amyloid-β (Aβ) production, leading to neuroinflammation, blood-brain barrier (BBB) disruption, and postoperative delirium. Interleukin-17 (IL-17) is implicated in BBB breakdown, and Aβ deposits induce elevated expression. Hence, we explored the relationships between early postoperative cognitive alterations and Aβ deposits, IL-17 expression in the hippocampus, and BBB damage in aged rats after fracture surgery under sevoflurane anesthesia. Aged rats underwent fracture surgery under 3.6% sevoflurane for 2 h. Cognitive changes were assessed using fear conditioning and Y-maze tests, and hippocampal occludin and Ly6g expression were measured using Western blotting. Aβ42, IL-17, and MMP-9 levels were measured using enzyme-linked immunosorbent assays, and BBB disruption was evaluated using Evans Blue at 6, 12, and 24 h post-anesthesia. We intrathecally administered the γ-secretase inhibitor (DAPT) and IL-17 antiserum to inhibit Aβ42 deposition and IL-17 expression, respectively. We observed cognitive changes, hippocampal Aβ42, Ly6g, IL-17, occludin, and MMP-9 levels, and BBB disruption 24 h post-anesthesia. Further, we noticed decreased freezing and residence time in the new Y-maze arm in aged rats, increased Aβ42, IL-17, MMP-9, and Evans blue contents, and decreased occludin expression at 6 h post-anesthesia. These phenotypes worsened at 12 and 24 h. However, DAPT and IL-17 antiserum administration improved cognitive performance and various hippocampal parameters 24 h post-anesthesia. Our study suggests that early postoperative cognitive decline is likely linked to Aβ42 deposition, triggering neuroinflammation and BBB disruption via increased IL-17 expression.

Keywords:  Aβ42; Blood–brain barrier; IL-17; Postoperative cognitive decline; Sevoflurane

DOI:  https://doi.org/10.1007/s00221-025-07194-6
Fluids Barriers CNS. 2025 Nov 21. 22(1): 118

APPswe mutation causes functional deficits in endothelial cells generated by transient ETV2 overexpression in human iPSCs.

Ying-Chieh Wu, Šárka Lehtonen, Riitta Kauppinen, Hiramani Dhungana, Jari Koistinaho, Taisia Rõlova.



Keywords:  Alzheimer’s disease (AD); Angiogenesis; Blood-brain barrier (BBB); Brain endothelial cells (ECs)

DOI:  https://doi.org/10.1186/s12987-025-00728-8
Neurotoxicology. 2025 Nov 18. pii: S0161-813X(25)00161-5. [Epub ahead of print] 103355

The effects of doxorubicin on blood-brain barrier integrity in hCMEC/D3.

Chadni Patel, Christina Glytsou, Mi-Hyeon Jang, Peter D Cole.

  Current chemotherapy regimens have significantly improved overall survival for children with cancer. However, these treatments are associated with detrimental side effects like chemotherapy-induced cognitive impairment (CICI), or "chemobrain." Measurable deficits in cognitive function persist years after treatment. Specifically, doxorubicin (DOXO), a commonly used chemotherapeutic agent in curative regimens for children with cancer, plays a pivotal role in the development of CICI, even though it doesn't cross the blood-brain barrier (BBB). Using a juvenile rat model, we found that DOXO compromises the BBB integrity. To further address the poorly understood mechanism of DOXO-related CICI, we utilized human cerebral microvascular endothelial cells (hCMEC/D3) to study the changes induced by DOXO in BBB integrity. RNA sequencing after DOXO exposure demonstrated changes in inflammatory pathways that may play a critical role in BBB integrity. Upon DOXO treatment, there was an increase in the secretion of proinflammatory cytokines including interleukin-6 (IL-6), regulated on activation, normal T cell expressed and secreted (RANTES) and granulocyte-macrophage colony stimulating factor (GM-CSF). DOXO induced the activation of p38 mitogen-activated protein kinase (MAPK), extracellular signal-regulated kinases (ERK1/2), and cAMP response element binding protein (CREB). Using xCELLigence Real Time Cell Analysis, we found that DOXO doesn't immediately compromise the barrier in hCMEC/D3. Additionally, we found that DOXO treatment significantly decreases maximal respiration and the spare respiratory capacity in hCMEC/D3 cells, indicating mitochondrial bioenergetic defects. Our findings provide critical insights on how DOXO impacts the BBB and builds a foundation for developing preventative measures that may improve the quality of life for patients.

Keywords:  blood-brain barrier (BBB); chemobrain; doxorubicin; doxorubicin-induced cognitive impairment

DOI:  https://doi.org/10.1016/j.neuro.2025.103355
Am J Transl Res. 2025 ;17(10): 8336-8346

Escin displays neuroprotective effects in mice with intracerebral hemorrhage through ameliorating intestinal injury.

Xue Jia, Xiaohan Zhang, Huiwen Li, Huijin Chen, Bing Han, Fenghua Fu, Tian Wang.

   OBJECTIVE: To investigate the relationship between secondary brain injury and intestinal injury in intracerebral hemorrhage (ICH) and whether escin can protect the function of the intestine and inhibit lipopolysaccharide (LPS) entry into the blood, thereby attenuating brain injury after ICH.
METHODS: Mice were injected stereotactically with collagenase to establish a model of ICH. The Garcia test, forelimb placement test, brain water content, blood-brain barrier (BBB) permeability, intestinal injury, intestinal permeability, and serum LPS levels were evaluated. The ICH mice were treated with escin to investigate the effect of escin on intestinal injury and neurological function.
RESULTS: The severity of secondary brain injury was highly correlated with the degree of intestinal injury. After administering escin, intestinal injury was significantly alleviated, intestinal permeability was markedly reduced, and LPS blood levels were significantly decreased. Additionally, results from the Garcia and forelimb placement tests showed significant improvement. However, intraperitoneal injection of LPS, simulating the entry of LPS into the bloodstream due to intestinal injury, weakened the neuroprotective effects of escin without affecting its intestinal protective effects.
CONCLUSIONS: The ICH-induced brain injury caused intestinal barrier damage, resulting in LPS in the gut to enter blood circulation, which subsequently disrupted the BBB. Therefore, LPS plays an important role in ICH-induced secondary brain injury. Escin exerts its neuroprotective effect by attenuating gut injury following ICH.

Keywords:  Intracerebral hemorrhage; escin; inflammation; intestinal barrier

DOI:  https://doi.org/10.62347/BQWN8476
Behav Brain Res. 2025 Nov 18. pii: S0166-4328(25)00530-3. [Epub ahead of print]499 115943

The neuroprotective effects of erythropoietin following traumatic brain injury in rats through the AMP-activated protein kinase pathway: A behavioral, biochemical, and histological study.

Erfan Ghadirzadeh, Seyed Pooria Salehi Mashhad Sari, Saeed Saed, Mobina Gheibi, Arya Asadi Rad, Samaneh Rahimi Bidrouni, Ghazal Mohseni, Ali Siahposht-Khachaki.

   BACKGROUND: While some animal studies have shown that erythropoietin (EPO) can reduce neuronal death and improve cognitive outcomes after traumatic brain injury (TBI), inconsistencies exist in research findings, possibly due to differences in dosage, timing, and injury models. Specifically, the role of EPO in modulating the AMP-activated protein kinase (AMPK) pathway remain unclear. Thus, this study aims to address these gaps by investigating the effects of EPO on neurobehavioral outcomes, brain edema, blood-brain barrier (BBB) permeability, and the AMPK pathway in a severe TBI rat model.
METHODS: 112 male Albino Wistar rats were traumatized by free-fall weight dropping Marmarou TBI induction method in eight groups (14 rats each): Intact, Sham, TBI, Saline (TBI + saline injection as placebo), intraperitoneal injection of EPO in 2500, 5000, and 10000 IU/kg doses, and Compound-C (TBI + Compound-C + EPO 5000) group. Cerebral edema, BBB permeability (via Evans blue method), veterinary coma scale (VCS), beam-walk (BW), beam-balance (BB), and p-AMPK/AMPK ratio (through enzyme-linked immunosorbent assay) were evaluated after trauma.
RESULTS: Administration of EPO at 2500 and 5000 IU/kg yielded lower brain water content, improved BBB integrity, better VCS, BW, and BB scores, and higher p-AMPK/AMPK ratio (all P < 0.01). Though the 5000 IU/kg dose was also effective, the 2500 IU/kg dose exhibited superior results. Notably, an escalation to 10000 IU/kg or addition of Compound-C worsened the results, suggesting a dose-dependent threshold for EPO's efficacy, and the potential role of AMPK pathway, respectively.
CONCLUSION: Our results suggest that EPO may exert neuroprotective effects in TBI-induced rats via modification of the AMPK pathway.

Keywords:  AMP-activated protein kinase; BBB disruption; Erythropoietin; Neuroprotective; Rat; Traumatic brain injury

DOI:  https://doi.org/10.1016/j.bbr.2025.115943
Ageing Res Rev. 2025 Nov 19. pii: S1568-1637(25)00298-3. [Epub ahead of print] 102952

Decoding Blood-Brain Barrier Dysfunction in Alzheimer's Disease: Innovations and Challenges in Multimodal MRI and PET Imaging Biomarkers.

Haolin Yin, Zihao Lu, YuePeng Deng, Xiaohe Tian, Qiyong Gong.

  Alzheimer's disease (AD), a leading neurodegenerative disorder, involves blood-brain barrier (BBB) dysfunction as a critical contributor to its pathogenesis. This review synthesizes current advancements in in vivo magnetic resonance imaging (MRI) and positron emission tomography (PET) techniques for imaging BBB breakdown in AD. The BBB, a dynamic neurovascular interface, regulates amyloid-beta (Aβ) and tau clearance through specialized transporters and cellular interactions. BBB dysfunction, driven by tight junction disruption, transporter deficits, and pericyte degeneration, exacerbates Aβaccumulation and neuroinflammation. Dynamic contrast-enhanced MRI quantifies subtle leakage via gadolinium kinetics, while water-exchange MRI probes trans-BBB water dynamics without contrast agents. Dynamic glucose-enhanced MRI maps glucose transport anomalies linked to glucose transporter- 1 dysfunction. PET imaging with tracers like [18F]-fluorodeoxyglucose and [11C]-verapamil evaluates glucose metabolism and efflux transporter activity, revealing early metabolic deficits and impaired Aβ clearance. Challenges include low sensitivity for subtle leakage, model-dependent quantification, and spatial-temporal resolution trade-offs. Emerging strategies emphasize multimodal integration, ultrahigh-field systems, and artificial intelligence-driven analytics to decode region-specific BBB pathology. Longitudinal studies correlating imaging biomarkers with clinical progression and novel PET tracer development are pivotal for early diagnosis and personalized therapies. These innovations promise to elucidate BBB's role and promote a paradigm shift in diagnostic and therapeutic strategies from solely targeting amyloid proteins to multi-target interventions in AD.

Keywords:  Alzheimer's disease; Biomarkers; Blood-brain barrier; Magnetic resonance imaging; Positron emission tomography

DOI:  https://doi.org/10.1016/j.arr.2025.102952
Cell Death Dis. 2025 Nov 17. 16(1): 842

Acute liver failure-induced arginine deficiency impairs blood-brain barrier via inhibiting mTORC1-S6K1/4EBP1 pathway and inducing autophagy.

Hanyu Yang, Weimin Kong, Ling Jiang, Liang Zhu, Xun Wang, Lu Yang, Liqiang Qian, Zijun Xu, Chenyang Zhang, Xiaodong Liu, Li Liu.

Blood-brain barrier (BBB) impairment plays a crucial role in the development of hepatic encephalopathy. Our previous work demonstrated that hepatic ischemia-reperfusion-induced acute liver failure (ALF) impairs the BBB by releasing arginase, but the underlying mechanism remains unclear. In this study, we discovered that ALF-induced arginase accumulation leads to arginine (Arg) deficiency, causing BBB cells to arrest in G1 phase. This arrest was associated with decreased expression of key cell cycle regulatory proteins, activation of autophagy, and inhibition of the mechanistic target of rapamycin complex 1 (mTORC1) pathway. Silencing mTORC1 downstream protein p70 ribosomal protein S6 kinase 1 (S6K1) or eukaryotic translation initiation factor 4E binding protein 1 (4EBP1) showed similar effects as Arg deficiency, while activating the mTORC1 pathway attenuated arginase-induced cell cycle delay. Furthermore, inhibition of autophagy with 3-methyladenine or silencing Beclin-1 partially reversed the arginase-induced effects. These in vitro findings were corroborated in rat models of ALF induced by thioacetamide or acetaminophen, as well as in rats treated with arginase, all of which exhibited elevated plasma arginase activity, reduced Arg levels, increased BBB permeability, and suppressed BBB cell proliferation. These changes were accompanied by alterations in markers related to cell cycles, mTORC1 signaling, and autophagy, which were reversible upon Arg supplementation. In summary, our research reveals that ALF-induced BBB damage is driven by Arg deprivation due to arginase release, leading to G1 phase arrest through mTORC1 pathway inhibition and autophagy induction, which provides new insights into the prevention and treatment of ALF-induced BBB damage and hepatic encephalopathy.

DOI: https://doi.org/10.1038/s41419-025-08152-4
Brain Res. 2025 Nov 13. pii: S0006-8993(25)00609-2. [Epub ahead of print]1870 150046

Investigating the impact of resveratrol and quercetin on glymphatic function, blood-brain barrier, and neuroglial health: A systematic review.

Renee Grandi, Vandana Gulati, Md Shahidul Islam, Okobi Ekpo, Nitin Chitranshi.

   OBJECTIVE: This systematic review evaluates the therapeutic potential of quercetin (QUE) and resveratrol (RSV) in Alzheimer's disease (AD), Parkinson's disease (PD), and multiple sclerosis (MS), focusing on their effects on glymphatic function, cerebrospinal fluid (CSF) dynamics, neuroglial health, and blood-brain barrier (BBB) permeability.
METHODS: A systematic search was conducted across PubMed, ScienceDirect, and ProQuest following PRISMA guidelines for studies published between 2019 and 2024. Thirty-six studies, including experimental models and clinical trials, were identified and assessed for outcomes relating to antioxidant, anti-inflammatory, and neuroprotective effects of QUE and RSV.
RESULTS: Across 36 studies, both QUE and RSV significantly enhanced antioxidant defences (upregulation of SOD, GSH, GPx, CAT) and downregulated pro-inflammatory cytokines (IL-1β, IL-6, TNF-α, NF-κB). BBB integrity improved via increased claudin‑5/occludin/ZO‑1 expression and reduced Evans blue/sodium fluorescein extravasation; cerebrovascular reactivity and cerebral blood flow (CBF) were frequently restored. Glymphatic outcomes demonstrated enhanced AQP4 polarisation at end feet and accelerated clearance of fluorescent tracers and β-amyloid in vivo, with preserved astrocyte-pericyte coupling. Neuroglial health improved (reduced microglial M1 markers, increased M2/Arg‑1 and astrocytic homeostatic markers), alongside neuronal survival, remyelination markers, and synaptic proteins. Nanoparticle/liposomal formulations of QUE/RSV increased BBB penetration and brain concentrations relative to free compounds.
CONCLUSION: QUE and RSV demonstrate significant potential as adjunctive therapies for mitigating neuroinflammation, oxidative stress, and neurodegenerative progression through glymphatic and BBB modulation. However, further high-quality, long-term clinical trials are needed to validate these findings, optimise delivery systems, and establish translational relevance to human neurodegenerative conditions.

Keywords:  Blood–brain barrier; Cerebrospinal fluid; Glymphatic; Neurodegeneration; Neuroinflammation; Quercetin; Resveratrol

DOI:  https://doi.org/10.1016/j.brainres.2025.150046
J Neuroinflammation. 2025 Nov 19. 22(1): 275

Imaging brain inflammation and blood brain barrier permeability in neurological and psychiatric diseases: a review.

Zanetta Kovbasyuk, Eden Tefera, Chenyang Li, Steven H Baete, Claude Steriade.

Neuroinflammation involving glial cell activation and BBB dysfunction has increasingly been recognized as a key feature of neuropsychiatric disorders. In vivo imaging methods, particularly translocator protein positron emission tomography (TSPO-PET) and dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI), have advanced our understanding of glial activation and BBB permeability in conditions such as Alzheimer's disease, Parkinson's disease, epilepsy, multiple sclerosis, Huntington's disease, schizophrenia, and depression. We present key findings from the clinical application of these imaging modalities and highlight critical methodological challenges-including variability in study protocols, tracer selection, input function derivation, and parameter estimation-that currently limit cross-study comparability and clinical translation. TSPO-PET and DCE-MRI provide valuable clinical insights on the inflammatory mechanisms contributing to CNS disease at various disease stages. Future methodological standardization, co-localization studies, and longitudinal multi-modal applications will be crucial for using these tools as markers of disease in the context of immune interventions in at-risk populations.

DOI: https://doi.org/10.1186/s12974-025-03598-x
Mol Neurobiol. 2025 Nov 19. 63(1): 89

Salidroside-Pretreated Small Extracellular Vesicles Derived from Human Umbilical Cord Mesenchymal Stem Cells Promote Blood-Spinal Cord Barrier Repair After Spinal Cord Injury in Mice.

Juan Wang, Qian Zhu, Peiran Chan, Ziyan Zhu, Mingming Zheng, Zhiyuan Mao, Mufeng Gu, Zijian Ren, Min Cui, Jie Liu, Yongjie Zhang.

  This study investigates the role of salidroside-pretreated small extracellular vesicles (SAL-sEVs) derived from human umbilical cord mesenchymal stem cells (Huc-MSCs) in spinal cord injury (SCI). Results demonstrate that these sEVs repair the damaged blood-spinal cord barrier (BSCB) and facilitate functional recovery. sEVs were collected from Huc-MSCs pretreated with salidroside via ultracentrifugation. sEVs were characterized using transmission electron microscopy (TEM), nanoparticle tracking analysis (NTA), and Western blot. The uptake of sEVs by endothelial cells was confirmed through immunofluorescence. The regulatory effects of SAL-sEVs on BSCB permeability and tight junction proteins were examined using immunofluorescence and Western blot. Microglial polarization was assessed via ELISA, qRT-PCR, and Western blot. Motor function was evaluated through behavioral tests. SAL-sEVs were endocytosed by endothelial cells, reduced BSCB permeability by regulating tight junction proteins, alleviated secondary inflammation, facilitated repair of spinal cord injury sites, and improved motor function in mice. Salidroside augments the therapeutic promise of Huc-MSC-derived small extracellular vesicles in repairing the BSCB, inflammation reduction, and functional recovery post-SCI, offering a novel therapeutic approach for the treatment of SCI.

Keywords:  Blood-spinal cord barrier; Salidroside; Small extracellular vesicles; Spinal cord injury

DOI:  https://doi.org/10.1007/s12035-025-05410-6
J Neurotrauma. 2025 Nov 12.

The Protective Effects of the Triggering Receptor Expressed on Myeloid Cells-1 Inhibitor LP17 on Experimental Acute Brain Injury: A Systematic Review and Meta-Analysis Based on Animal Models.

Lu Huang, Sisen Zhang, Cancan Wang, Fengying Wang.

  Acute brain injury (ABI) is a severe neurological disorder in which inflammation and immune responses play a key role, with the Triggering Receptor Expressed on Myeloid Cells-1 (TREM1) being involved. Inhibition of TREM1 can alleviate neuroinflammation and damage, but the evidence from these pre-clinical studies remains unclear. This study summarizes and evaluates the results of animal experiments on the treatment of ABI with the TREM1 inhibitor LP17, exploring the effects of using LP17 to treat ABI animal models on neurological function, inflammatory indicators, and brain barrier function. As of April 30, 2025, this review conducted a detailed search of eight databases for studies on LP17 in ABI animal models. It performed a systematic review and meta-analysis of the included studies. The literature was independently screened, and data were extracted and assessed. RevMan 5.4 software was used for the meta-analysis. Compared with controls, the TREM1 inhibitor LP17 significantly reduced brain water content (standardized mean difference [SMD]: -1.36; 95% confidence interval [CI]: -1.77, -0.94; p < 0.00001) and neurological deficit scores (SMD: -1.37; 95% CI: -1.76, -0.97; p < 0.00001). It also decreased the expression of pro-inflammatory cytokines, including IL-1β (SMD: -1.88; 95% CI: -2.63, -1.13; p < 0.00001) and TNF-α (SMD: -2.91; 95% CI: -3.89, -1.92; p < 0.00001). LP17 mitigated blood-brain barrier (BBB) disruption (SMD: -1.58; 95% CI: -2.47, -0.68; p = 0.0005) and enhanced ZO-1 expression (SMD: 2.77; 95% CI: 1.73, 3.80; p < 0.00001). It also inhibited the activation of nuclear factor-κB (SMD: -1.70; 95% CI: -2.58, -0.83; p = 0.0001), NLRP3 (SMD: -2.33; 95% CI: -3.27, -1.39; p < 0.00001), and Caspase-1 (SMD: -2.03; 95% CI: -2.92, -1.14; p < 0.00001). LP17 has neuroprotective effects in ABI animal models, likely through reducing neuroinflammation, preserving BBB integrity, and inhibiting apoptotic pathways. Further studies are needed to explore its mechanisms to better guide clinical use.

Keywords:  LP17; TREM1; acute brain injury; animal models; meta-analysis

DOI:  https://doi.org/10.1177/08977151251392582
Bioorg Chem. 2025 Nov 15. pii: S0045-2068(25)01117-4. [Epub ahead of print]167 109237

Novel 3-n-butylphthalide derivatives as potent multi-functional anti-IS agents with BBB protective function.

Li Shao, Gaofeng Lin, Zhaoxing Chu, Jiajia Mo, Qinlong Xu, Yan Zhao, Qihua Zhu, Shiqi Wu, Shaoyun Yue, Xiaodong Ma, Guangwei He, Jiaming Li.

  The discovery of multi-functional small-molecule compounds with potent blood-brain barrier (BBB) protective effect for treating ischemic stroke (IS) is a relatively unexplored area. Herein, a series of 33 novel hybrid molecules were rationally designed and synthesized via incorporating 4-methoxybenzyl alcohol-mimicking pharmacophore (With potential BBB protective activity) into 3-n-butylphthalide (NBP) scaffold. Among them, the representative compound 30 exhibited enhanced neuroprotective, anti-inflammatory, anti-oxidative, and BBB protective activities than those of NBP. After the chiral resolution, the neuroprotective potency of R-enantiomer (R-30) was identified to be more potent than the S-enantiomer. In vivo, R-30 significantly reduced infarct volume and markedly preserved BBB integrity. Furthermore, it displayed a good safety profile in acute toxicity study. These findings support the potential of R-30 as a multi-functional anti-IS candidate that deserves further development.

Keywords:  BBB protective; Chiral resolution; Ischemic stroke; Multi-functional; Neuroprotection

DOI:  https://doi.org/10.1016/j.bioorg.2025.109237
Alzheimers Dement (Amst). 2025 Oct-Dec;17(4):17(4): e70221

Profiles of blood-brain barrier and neurodegeneration markers in cerebrospinal fluid of patients with cerebral amyloid angiopathy.

João Pinho, Arno Reich, Omid Nikoubashman, Jörg B Schulz, Kathrin Reetz, Ana Sofia Costa.

   INTRODUCTION: There are few studies analyzing cerebrospinal fluid (CSF) in patients with cerebral amyloid angiopathy (CAA). Our goal was to compare blood-brain barrier and neurodegeneration markers in CSF in CAA patients with and without hemorrhagic markers.
METHODS: In a retrospective study of patients with CAA (Boston criteria version 2.0) identified from the Aachen Memory Database and from in-hospital admission records, we compared CSF neurodegeneration markers and albumin ratio (a blood-brain barrier permeability marker) in patients with and without hemorrhagic markers.
RESULTS: Among 371 patients with CAA, 113 patients had hemorrhagic markers (30.5%). Lower amyloid beta (Aβ) 42, lower Aβ40, and higher albumin ratio were independently associated with the presence of hemorrhagic markers and an increasing number of lobar microbleeds. Cortical superficial siderosis and a higher imaging burden of CAA were associated with total tau protein.
DISCUSSION: Presence of hemorrhagic markers in CAA patients is associated with lower CSF Aβ42 and Aβ40 and higher blood-brain barrier permeability.
HIGHLIGHTS: New diagnostic criteria allow for the diagnosis of CAA without hemorrhagic markers.CAA hemorrhagic markers are associated with lower Aβ42 and Aβ40 in CSF.CAA hemorrhagic markers are associated with higher blood-brain barrier permeability.Higher imaging burden of CAA is associated with higher total tau protein in CSF.

Keywords:  cerebral amyloid angiopathy; cerebrospinal fluid; cognitive impairment; intracerebral hemorrhage

DOI:  https://doi.org/10.1002/dad2.70221
J Ginseng Res. 2025 Nov;49(6): 640-651

Protective effects of ginsenosides in cerebral small vessel disease: Cellular and molecular mechanisms.

Zhiyong Zhai, Yan Gao.

  Cerebral small vessel disease (CSVD), an age-related vascular disorder linked to cognitive decline, lacks targeted therapies. Ginsenosides, bioactive compounds in ginseng, demonstrate multi-target potential against CSVD by modulating neurovascular dysfunction. Experimental studies highlight their anti-inflammatory, antioxidant, and neuroprotective properties. Ginsenosides suppress pro-inflammatory cytokines (tumor necrosis factor α [TNF-α], interleukin-1β [IL-1β], IL-6) via nuclear factor-kappa B/nod-like receptor protein (NF-κB/NLRP1) inflammasome inhibition, stabilize the blood-brain barrier by preserving tight junctions and reducing matrix metalloproteinase activity, and enhance endothelial survival through vascular endothelial growth factor/sonic hedgehog (VEGF/Shh)-mediated angiogenesis. They mitigate vascular remodeling by blocking vascular smooth muscle cell (VSMC) proliferation via phosphatidylinositol 3 kinase/protein kinase B (PI3K/Akt) and mitogen-activated protein kinase (MAPK) signaling, while attenuating microglial activation and astrocyte dysfunction to improve cerebral blood flow. These compounds also alleviate oxidative stress and promote neurovascular unit integrity. Future research should focus on optimizing ginsenoside combinations, elucidating protein interactions, and exploring synergies with complementary agents to enhance therapeutic efficacy. Ginsenosides represent a promising multi-mechanistic approach for CSVD treatment, addressing inflammation, vascular pathology, and neural damage.

Keywords:  Cerebral small vessel disease; Ginsenosides; Ischemic stroke; Neurovascular unit

DOI:  https://doi.org/10.1016/j.jgr.2025.08.007
Trends Immunol. 2025 Nov 20. pii: S1471-4906(25)00271-6. [Epub ahead of print]

Beyond the innate immune system: rethinking inflammasomes in multiple sclerosis.

Gayel Duran, Janne Verreycken, Yvonne Dombrowski, Mohamed Lamkanfi, Paulien Baeten, Bieke Broux.

  Inflammasomes have emerged as central regulators of (auto)immune pathology, including multiple sclerosis (MS). Once exclusively considered in the domain of myeloid cells, both canonical and noncanonical inflammasomes are now recognized in diverse immune and nonimmune populations relevant to MS, including T lymphocytes, blood-brain barrier (BBB) endothelial cells (EnC), and oligodendrocytes (ODCs). Elevated inflammasome activity is evident in patient-derived samples, particularly within active brain lesions. Experimental autoimmune encephalomyelitis (EAE) models confirm the pathogenic contribution of inflammasomes, as genetic deletion or pharmacological inhibition of inflammasomes mitigate disease. These advances position inflammasomes at the intersection of neuroinflammation and neurodegeneration, and highlight inflammasome inhibition as a promising therapeutic avenue currently under investigation in preclinical and early clinical studies.

Keywords:  AIM2; NLRP3; adaptive immunity; autoimmune disease

DOI:  https://doi.org/10.1016/j.it.2025.10.014