bims-blobar 2025-08-17 papers

bims-blobar

Biomed News

on Blood brain barrier repair

Issue of 2025–08–17
seventeen papers selected by
Nicolas Rebergue

From APOE to cellular changes: Unraveling the multidimensional mechanisms of blood-brain barrier damage in Alzheimer's disease.
L-3n-butylphthalide maintains BBB Permeability and attenuates cerebral ischemia-reperfusion injury in rats by increasing PGC-1α levels.
N,N-dimethyltryptamine mitigates experimental stroke by stabilizing the blood-brain barrier and reducing neuroinflammation.
Polystyrene nanoplastics-induced methuosis in brain microvascular endothelial cells: Rescue via ESCRT membrane repair system.
Long COVID-related blood-brain barrier breakdown and microstructure in older adults are modified by sex and Alzheimer's disease genetic risk.
BTVT ameliorates offspring blood-brain barrier damage induced by prenatal and lactational neodymium oxide exposure via the gut-brain axis.
Increased blood-brain barrier permeability is associated with dysfunctional α band connectivity in early-stage Parkinson's disease.
Sonic Hedgehog pathway: molecular mechanisms and therapeutic potentials in ischemic stroke recovery.
Diesel exhaust particles induced blood-brain barrier dysfunction through inflammation, oxidative stress, and activation of the RhoA/ROCK signaling pathway.
Sustained neuronal DNA damage and PARP activation lead to VEGFA-mediated blood-brain barrier disruption in radiation-induced brain injury.
NR2F6 as a Disease Driver and Candidate Therapeutic Target in Experimental Cerebral Malaria.
The DRP1 inhibitory peptide P110 provides neuroprotection after subarachnoid hemorrhage by suppressing neuronal apoptosis and stabilizing the blood-brain barrier.
Identification of Drug Repurposing Candidates for Coxsackievirus B3 Infection in iPSC-Derived Brain-like Endothelial Cells.
In vitro human brain barrier models for studying thyroid hormone transport.
Phyhip-Targeted Delivery of bFGF Platform with Dual Modulation for Enhancing Neurovascular Repair in Traumatic Brain Injury.
Monotropein alleviates sepsis-associated encephalopathy by targeting matrix metalloproteinase-9.
miR-221 activates Sox11 to reduce brain injury after intracerebral hemorrhage via inhibiting neuroinflammation.

J Alzheimers Dis. 2025 Aug 13. 13872877251360321

From APOE to cellular changes: Unraveling the multidimensional mechanisms of blood-brain barrier damage in Alzheimer's disease.

Fengwen Jiang, Niya Wang, Qiang Meng.

  The prevalence of Alzheimer's disease (AD) is on the rise due to the global aging population. AD is the most common cause of dementia, accounting for 60-80% of all cases, which makes it a significant health concern. In recent years, the failure to develop targeted pathological drugs has led researchers to shift their focus. The blood-brain barrier (BBB) is a specialized structure that separates the circulating blood from the brain tissue and tightly regulates the passage of molecules, ions, and cells between the blood and the brain. Through a comprehensive review of current literature, we highlight the multifaceted role of BBB dysfunction in the pathogenesis of AD and discuss the complex mechanisms involved. Changes in the structure and function of endothelial cells, pericytes, and astrocytes, along with elevated expression of the highest-risk gene APOE4, can all lead to BBB damage, thereby promoting the onset of AD. Furthermore, we explore potential therapeutic targets to preserve BBB integrity and function to mitigate AD progression. This review underscores the significance of ongoing research efforts in elucidating the intricate interplay between BBB integrity and AD pathology, offering valuable insights for future investigations and therapeutic strategies.

Keywords:  Alzheimer's disease; barrier dysfunction; blood-brain barrier; neurology; pathogenesis

DOI:  https://doi.org/10.1177/13872877251360321
Int J Neurosci. 2025 Aug 09. 1-14

L-3n-butylphthalide maintains BBB Permeability and attenuates cerebral ischemia-reperfusion injury in rats by increasing PGC-1α levels.

Yu Wang, Xiangsong Shi, Liling Wu, Hongfu Tian.

   AIM: The aim of the present study was to investigate the possible mechanisms of DL-3-n-butylphthalide (NBP) in maintaining the stability of the blood-brain barrier (BBB) and attenuating cerebral ischemia-reperfusion injury (CIRI) by increasing the levels of PGC-1α.
METHODS: A model of middle cerebral artery occlusion/reperfusion (MCAO/R) injury was established using Sprague-Dawley rats. The rats were divided into sham, MCAO/R, NBP, Vehicle and SR-18292 groups. 2,3,5-Triphenyltetrazolium chloride staining, hematoxylin and eosin (H&E) staining, and Evans Blue staining were performed to observe the volume of cerebral infarction, status of pathological injury, and BBB permeability of the brain tissue, respectively. Immunofluorescence staining and western blot analysis were performed to evaluate the expression of vascular endothelial cell markers (vWF and CD31), tight junction (TJ) protein markers (claudin5 and occludin), and PGC-1α.
RESULTS: H&E staining showed that the brain tissues of MCAO/R rats showed worsening vacuolar degeneration and necrosis. NBP reduced infarct volume, decreased the level of BBB extravasation, increased vascular density, and promoted the expression of TJs. Concurrently, NBP activated PGC-1α levels in rats subjected to MCAO/R. Downregulation of PGC-1α levels by PGC-1α inhibitors (SR-18292) could promote BBB permeability, infarct volume, and neurological deficits in the MCAO/R model.
CONCLUSIONS: The present study demonstrates that NBP plays a role in maintaining the stability of the BBB and attenuates CIRI by increasing PGC-1α levels as well as by increasing the levels of vascular endothelial cells and TJ markers.

Keywords:  BBB permeability; MCAO/R; NBP; PGC-1α; TJs

DOI:  https://doi.org/10.1080/00207454.2025.2545534
Sci Adv. 2025 Aug 15. 11(33): eadx5958

N,N-dimethyltryptamine mitigates experimental stroke by stabilizing the blood-brain barrier and reducing neuroinflammation.

Marcell J László, Judit P Vigh, Anna E Kocsis, Gergő Porkoláb, Zsófia Hoyk, Tamás Polgár, Fruzsina R Walter, Attila Szabó, Srdjan Djurovic, Béla Merkely, Alán Alpár, Ede Frecska, Zoltán Nagy, Mária A Deli, Sándor Nardai.

N,N-dimethyltryptamine (DMT) is a psychoactive molecule present in the human brain. DMT is under clinical evaluation as a neuroprotective agent in poststroke recovery. Yet, its mechanism of action remains poorly understood. In a rat transient middle cerebral artery occlusion stroke model, we previously showed that DMT reduces infarct volume. Here, we demonstrate that this effect is accompanied by reduction of cerebral edema, attenuated astrocyte dysfunction, and a shift in serum protein composition toward an anti-inflammatory, neuroprotective state. DMT restored tight junction integrity and blood-brain barrier (BBB) function in vitro and in vivo. DMT suppressed the release of proinflammatory cytokines and chemokines in brain endothelial cells and peripheral immune cells and reduced microglial activation via the sigma-1 receptor. Our findings prove that DMT mitigates a poststroke effect by stabilizing the BBB and reducing neuroinflammation. Such interactions of DMT with the vascular and immune systems can be leveraged to complement current, insufficient, stroke therapy.

DOI: https://doi.org/10.1126/sciadv.adx5958
Ecotoxicol Environ Saf. 2025 Aug 08. pii: S0147-6513(25)01145-5. [Epub ahead of print]303 118800

Polystyrene nanoplastics-induced methuosis in brain microvascular endothelial cells: Rescue via ESCRT membrane repair system.

Suhan Yin, Yiyuan Kang, Wei Du, Xiner Tan, Ziyang Wang, Longquan Shao, Jia Liu.

  Nanoplastic pollution has emerged as a significant environmental concern, with increasing evidence suggesting that these nanoparticles can disrupt the blood-brain barrier (BBB) and accumulate in the brain, ultimately leading to neurological impairment. However, the underlying mechanism for the toxic effects of nanoplastics on the BBB remain poorly understood. In this study, we explored the toxic effects of polystyrene nanoplastic (PSNP) on brain microvascular endothelial cells (BMECs), one of the most critical components for maintaining BBB integrity. Our results revealed that PSNP specifically accumulate in the endolysosomal system following their internalization by BMECs. This accumulation disrupts lysosomal function and blocks endolysosomal pathways, ultimately triggering methuosis-a unique form of cell death characterized by extensive cytoplasmic vacuolization. Although the endosomal sorting complexes required for transport (ESCRT) system is naturally activated as a cellular defense mechanism, it is insufficient to repair PSNP-induced lysosomal membrane damage. By enhancing ESCRT activity, we effectively restored lysosomal function, thereby preventing cellular methuosis and preserving BBB integrity. Therefore, our findings provide crucial insights into the mechanisms underlying PSNP-induced BBB disruption by focusing on methuosis in endothelial cells. These insights hold important implications for environmental toxicology and public health in the context of global plastic pollution.

Keywords:  Blood-brain barrier; ESCRT system; Endolysosomal system; Methuosis; Nanoplastics

DOI:  https://doi.org/10.1016/j.ecoenv.2025.118800
Imaging Neurosci (Camb). 2025 ;pii: IMAG.a.23. [Epub ahead of print]3

Long COVID-related blood-brain barrier breakdown and microstructure in older adults are modified by sex and Alzheimer's disease genetic risk.

Emilie T Reas, Austin Alderson-Myers, Seraphina K Solders, Qian Shen, Charlotte S Rivera, Xin Wang, Jordan Stiver, Sarah J Banks, Jennifer S Graves.

  Long COVID is characterized by lingering symptoms following SARS-CoV-2 infection, which may include neurological and cognitive complaints. Hypothesized mechanisms, including blood-brain barrier (BBB) dysfunction and neuroinflammation, are shared with Alzheimer's disease (AD) and related dementias. To address concern that long COVID may accelerate cognitive decline and neurodegeneration, this study examined neuroimaging-based markers of BBB breakdown and brain microstructure among older adults with long COVID, and modification by AD risk factors. Individuals with persistent cognitive complaints following SARS-CoV-2 infection (neurological long COVID, NLCV) and cognitively normal controls (50-90 years, 61% women) underwent neuropsychological evaluation, genotyping, dynamic contrast-enhanced MRI to measure BBB permeability, and multi-compartment diffusion MRI to measure brain microstructure. Cognitive and brain measures were compared between NLCV and controls using analysis of covariance, and associations among measures were assessed using linear regression. Interaction models probed modification by sex and AD genetic risk, quantified with a polygenic hazard score. Compared to controls, NLCV exhibited cognitive impairment, BBB breakdown, and subcortical microstructural abnormalities. NLCV-related BBB leakage was widespread across the brain and more pronounced among men, whereas white matter and subcortical microstructural differences were stronger among women. AD polygenic hazard score modified associations of BBB permeability with memory and microstructure, such that higher caudate BBB permeability correlated with worse immediate recall, and higher white matter permeability correlated with higher free water only for those with elevated genetic risk. BBB dysfunction and microstructural compromise may contribute to cognitive symptoms of long COVID in older adults. Sex-specific patterns, and more deleterious associations between brain and memory abnormalities among individuals with elevated AD genetic risk, highlight the need for precision medicine diagnostic and therapeutic approaches for long COVID.

Keywords:  Alzheimer’s disease; COVID-19; blood-brain barrier; diffusion MRI; sex differences

DOI:  https://doi.org/10.1162/IMAG.a.23
Zhong Nan Da Xue Xue Bao Yi Xue Ban. 2025 Apr 28. pii: 1672-7347(2025)04-0615-10. [Epub ahead of print]50(4): 615-624

BTVT ameliorates offspring blood-brain barrier damage induced by prenatal and lactational neodymium oxide exposure via the gut-brain axis.

Xiaoyan DU, Xiaocheng Gao, Jing Cao, Xin Zhao, Zhi Huo, Shaoqing Zhao, Qingqing Liang, Lei Gao, Yang Deng.

   OBJECTIVES: Exposure to rare earth elements (REEs) has been linked to various systemic diseases, but their impact on the offspring blood-brain barrier (BBB) via the gut-brain axis remains unclear. This study aims to investigate the effects of maternal exposure to neodymium oxide (Nd2O3) on the BBB integrity of offspring rats, and to evaluate the potential protective role of bifidobacterium tetrad viable tablets (BTVT) against Nd2O3-induced intestinal and BBB damage.
METHODS: Healthy adult SD rats were mated at a 1:1 male-to-female ratio, with the day of vaginal plug detection marked as gestational day 0. A total of 60 pregnant rats were randomly assigned to the following groups: Control, 50 mg/(kg·d) Nd2O3, 100 mg/(kg·d) Nd2O3, 200 mg/(kg·d) Nd2O3, and 200 mg/(kg·d) Nd2O3 + BTVT group. Treatments were administered by daily oral gavage throughout pregnancy and lactation. On postnatal day 21 (weaning), offspring feces, brain, and colon tissues were collected. Hematoxylin and eosin (HE) staining was used to assess structural changes in brain and intestinal tissues. Short-chain fatty acids (SCFAs) in feces were quantified by gas chromatography-mass spectrometry (GC-MS). Evans Blue (EB) dye extravasation assessed BBB permeability. Gene and protein expression levels of tight junction proteins occludin and zonula occludens-1 (ZO-1) were measured by reverse transcription PCR (RT-PCR) and Western blotting (WB), respectively. Neodymium levels in brain tissue were determined via inductively coupled plasma mass spectrometry (ICP-MS).
RESULTS: HE staining revealed that maternal Nd2O3 exposure caused mucosal edema, increased submucosal spacing, and lymphocyte infiltration in offspring colon, as well as neuronal degeneration and vacuolization in brain tissue. BTVT intervention alleviated these changes. GC-MS analysis showed that levels of acetic acid, propionic acid, butyric acid, and isobutyric acid significantly decreased, while valeric acid and isovaleric acid increased in offspring of Nd2O3-exposed mothers (P<0.05). BTVT significantly restored levels of acetic, propionic, and isobutyric acids and reduced valeric acid content (P<0.05). EB permeability was significantly elevated in Nd2O3-exposed offspring brains (P<0.05), but reduced with BTVT treatment (P<0.05). RT-PCR and WB showed downregulation of occludin and ZO-1 expression following Nd2O3 exposure (P<0.05), which was reversed by BTVT (P<0.05). ICP-MS results indicated significantly increased brain neodymium levels in offspring from all Nd2O3-exposed groups (P<0.05), while BTVT significantly reduced neodymium accumulation compared to the 200 mg/(kg·d) Nd2O3 group (P<0.05).
CONCLUSIONS: Maternal exposure to Nd2O3 during pregnancy and lactation disrupts intestinal health and BBB integrity in offspring, elevates brain neodymium accumulation, and induces neuronal degeneration. BTVT effectively mitigates Nd2O3-induced intestinal and BBB damage in offspring, potentially through modulation of the gut-brain axis.

Keywords:  bifidobacterium tetrad viable tablet; blood-brain barrier; gut microbiota; neodymium oxide; rare earth elements

DOI:  https://doi.org/10.11817/j.issn.1672-7347.2025.250173
J Neural Transm (Vienna). 2025 Aug 14.

Increased blood-brain barrier permeability is associated with dysfunctional α band connectivity in early-stage Parkinson's disease.

Matteo Conti, Valerio Ferrari, Mariangela Pierantozzi, Clara Simonetta, Federico Carparelli, Vincenza D'Angelo, Silvio Bagetta, Francesca Di Giuliano, Nicola B Mercuri, Tommaso Schirinzi, Alessandro Stefani.

  The blood-brain barrier (BBB) is disrupted in Parkinson's disease (PD); however, whether its alteration precedes neuroinflammation and central synucleinopathy or results from these conditions is still unclear. In this study, we aimed to explore how alterations in BBB permeability may relate to disruptions in functional connectivity (FC) across cortical networks using HD-EEG and combining a network-based approach with Machine Learning (ML). This study involved 68 early-stage PD patients and 62 sex- and age-matched healthy controls. Albumin Index (Qalb), obtained by albumin in the cerebrospinal fluid (CSF) divided by the amount in the plasma, was assessed in all PD patients. EEG data were recorded with a 64-channel EEG system. Source reconstruction based on personal MRI was used to identify brain activity. Cortico-cortical FC was analyzed based on the weighted phase-lag index (wPLI) in θ-α-β-low γ bands. Network-based statistic (NBS) was used to compare FC between HCs and PD and to study the relationship between FC and BBB permeability, as measured by Qalb. PD patients exhibited a hypoconnected network at α bands and a hyperconnected network at β band compared to HCs. We observed a negative relation between Qalb and α-FC (network t = 3.6, p = 0.008). Regions with higher degrees were part of the prefrontal, limbic, and temporal lobes. No significant correlations between Qalb and clinical features or neurodegenerative markers were found. Increased BBB permeability in early-stage PD is associated with frequency- and region-specific abnormal cortical FC, supporting the hypothesis that alteration of BBB may accelerate PD pathology, contributing to a more malignant disease phenotype.

Keywords:  Blood-brain barrier; Functional connectivity; High density EEG; Machine-learning; Parkinson’s disease

DOI:  https://doi.org/10.1007/s00702-025-03002-1
Biochem Pharmacol. 2025 Aug 12. pii: S0006-2952(25)00500-3. [Epub ahead of print] 117235

Sonic Hedgehog pathway: molecular mechanisms and therapeutic potentials in ischemic stroke recovery.

Mingbu Yan, Song Yang, Bo Zhao, Tongbo Ning.

  Ischemic stroke (IS) is a leading cause of global mortality and disability, characterized by restricted cerebral blood flow and subsequent neuronal damage. The Sonic Hedgehog (Shh) signaling pathway plays a pivotal role in the pathogenesis and recovery of IS by modulating neuroprotection, angiogenesis, blood-brain barrier (BBB) integrity, and neurogenesis. This review provides an updated analysis of the Shh pathway's molecular mechanisms, emphasizing its neuroprotective effects, including anti-apoptotic, anti-inflammatory, and antioxidant responses. At the cellular level, the Shh pathway supports neuronal survival, enhances synaptic health, promotes M2 microglial polarization, and facilitates astrocyte proliferation, all of which contribute to reducing ischemic damage and fostering tissue repair. Additionally, the pathway's role in regulating endothelial integrity and promoting neurogenesis underscores its therapeutic potential. Pharmacological agents, natural compounds, and advanced therapeutic strategies such as stem cell therapies and nanoparticles targeting the Shh pathway demonstrate significant potential for improving functional outcomes post-stroke. This review identifies critical gaps in understanding the Shh pathway's regulatory dynamics and highlights future directions for therapeutic interventions aimed at leveraging its neuroprotective potential in ischemic stroke recovery.

Keywords:  Cerebral ischemic reperfusion injury; Microglial polarization; Natural products; Neurogenesis; Neuroprotection; Sonic hedgehog pathway

DOI:  https://doi.org/10.1016/j.bcp.2025.117235
Neurotoxicology. 2025 Aug 08. pii: S0161-813X(25)00101-9. [Epub ahead of print]110 122-131

Diesel exhaust particles induced blood-brain barrier dysfunction through inflammation, oxidative stress, and activation of the RhoA/ROCK signaling pathway.

Yanming Lv, Yingying Chen, Zhijian Gao, Siqi Liu, Ya Zhang, Huimin Suo, Shuying Gao.

  Diesel Exhaust Particles (DEPs) emitted by diesel engines represent a substantial contributor to ambient particulate matter. Extensive research has demonstrated that DEPs pose significant risks to human health. This study seeks to elucidate the molecular mechanisms underlying DEPs-induced dysfunction of the blood-brain barrier (BBB). The research team exposed bEND.3 cells to various concentrations of DEPs for 24 h and evaluated parameters including cell morphology, viability, inflammatory markers, oxidative stress, tight junction protein expression, and modulation of the RhoA/ROCK signaling pathway. The findings revealed that DEPs exposure resulted in morphological and ultrastructural alterations, elevated apoptosis rates, and reduced cell viability. Additionally, DEPs stimulated the release of pro-inflammatory cytokines, induced oxidative stress, disrupted tight junction protein expression, increased BBB permeability, and activated the RhoA/ROCK signaling pathway, thereby amplifying these deleterious effects. Collectively, our results demonstrate that DEPs impair BBB functionality through a cascade of cellular injury mechanisms. These findings highlight the profound impact of air pollution on the central nervous system and underscore the urgent need for stringent regulations on diesel emissions to protect brain health, particularly among populations in urban areas with high exposure to traffic-related emissions.

Keywords:  Diesel exhaust particles (DEPs)，Blood-brain barrier (BBB)，Intercellular tight junction，Matrix metalloproteinase，RhoA/ROCK signaling pathway

DOI:  https://doi.org/10.1016/j.neuro.2025.08.002
Int J Radiat Oncol Biol Phys. 2025 Aug 07. pii: S0360-3016(25)04526-2. [Epub ahead of print]

Sustained neuronal DNA damage and PARP activation lead to VEGFA-mediated blood-brain barrier disruption in radiation-induced brain injury.

Minyi Wu, Jinping Cheng, Yu Hu, Jiatian Xie, Jialin Huang, Jingru Jiang, Siqi Chen, Zhan Zhang, Sitai Chen, Honghong Li, Ho Ko, Yi Li, Yamei Tang, Yongteng Xu, Wei-Jye Lin.

Cranial radiotherapy is commonly used for treatment of patients with head and neck tumors, yet a considerable number of patients encounter long-lasting medical complications, including compromised blood-brain barrier (BBB) function and cognitive impairment. The mechanisms underlying BBB leakage after radiation exposure and potential preventive strategies remain elusive. In this study, we reported persistent accumulation of unrepaired DNA damage and PARP hyperactivation in neurons of both patients with radiation-induced brain injury and a mouse model. Importantly, PARP inhibition prevented radiation-induced NAD+ depletion, DNA damage, and neuronal degeneration. Furthermore, PARP inhibition ameliorated radiation-induced BBB leakage, perivascular astrogliosis, and cognitive impairment, accompanied by a significant decrease in VEGFA expression in the cortex. These findings demonstrate PARP's role in vascular degeneration and suggest a potential therapeutic approach to address radiation-induced BBB leakage with neuroprotective benefits.

DOI: https://doi.org/10.1016/j.ijrobp.2025.06.3885
Cells. 2025 Jul 28. pii: 1162. [Epub ahead of print]14(15):

NR2F6 as a Disease Driver and Candidate Therapeutic Target in Experimental Cerebral Malaria.

Victoria E Stefan, Victoria Klepsch, Nikolaus Thuille, Martina Steinlechner, Sebastian Peer, Kerstin Siegmund, Peter Lackner, Erich Schmutzhard, Karin Albrecht-Schgör, Gottfried Baier.

  Cerebral malaria (CM) is the severe progression of an infection with Plasmodium falciparum, causing detrimental damage to brain tissue and is the most frequent cause of Plasmodium falciparum mortality. The critical role of brain-infiltrating CD8+ T cells in the pathophysiology of CM having been revealed, our investigation focuses on the role of NR2F6, an established immune checkpoint, as a candidate driver of CM pathology. We employed an experimental mouse model of CM based on Plasmodium berghei ANKA (PbA) infection to compare the relative susceptibility of Nr2f6-knock-out and wild-type C57BL6/N mice. As a remarkable result, Nr2f6 deficiency confers a significant survival benefit. In terms of mechanism, we detected less severe endotheliopathy and, hence, less damage to the blood-brain barrier (BBB), accompanied by decreased sequestered parasites and less cytotoxic T-lymphocytes within the brain, manifesting in a better disease outcome. We present evidence that NR2F6 deficiency renders mice more resistant to experimental cerebral malaria (ECM), confirming a causal and non-redundant role for NR2F6 in the progression of ECM disease. Consequently, pharmacological inhibitors of the NR2F6 pathway could be of use to bolster BBB integrity and protect against CM.

Keywords:  CD8+ T cell brain infiltration; compromised blood–brain barrier (BBB) integrity; experimental cerebral malaria (ECM); group F; innovative pharmacological therapy solution for CM; member 6 (NR2F6); nuclear receptor subfamily 2

DOI:  https://doi.org/10.3390/cells14151162
Free Radic Biol Med. 2025 Aug 08. pii: S0891-5849(25)00880-9. [Epub ahead of print]240 1-14

The DRP1 inhibitory peptide P110 provides neuroprotection after subarachnoid hemorrhage by suppressing neuronal apoptosis and stabilizing the blood-brain barrier.

Shuangying Hao, Junrui Luo, Shuai Yuan, Wenbo Chen, Xinhong Zhang, Cheng Zhao, Hao Xu, Zhiqiang Liu, Dingding Zhang.

  Endoplasmic reticulum (ER) stress and mitochondrial dysfunction are key pathological features of early brain injury (EBI) following subarachnoid hemorrhage (SAH). Increasing evidence highlights mitochondria-associated ER membranes (MAMs) as central regulators of ER proteostasis and mitochondrial quality control. Given the dual role of dynamin-related protein 1 (DRP1) in modulating MAMs integrity and mitochondrial dynamics, we hypothesized that pharmacological inhibition of DRP1 would exert neuroprotective effects in SAH by preserving inter-organelle communication and restoring mitochondrial bioenergetics. To test this hypothesis, we employed an endovascular perforation model to induce SAH in mice and used oxyhemoglobin-treated HT22 hippocampal neurons to mimic SAH in vitro. Both models demonstrated a significant increase in DRP1 and phosphorylated DRP1 (p-DRP1) expression at 24 h and 72 h post-injury. Treatment with the selective DRP1 inhibitor P110 effectively reduced DRP1 and p-DRP1 levels, attenuated neuronal apoptosis and blood-brain barrier disruption, and improved neurological outcomes. Mechanistically, P110 treatment significantly mitigated SAH-induced inflammation, MAMs formation, mitochondrial calcium overload, reactive oxygen species production, ATP depletion and cytochrome c release. Collectively, these findings suggest that DRP1 inhibition via P110 confers neuroprotection after SAH by modulating inflammation, MAMs Formation, and mitochondrial dysfunction.

Keywords:  DRP1; Inflammation; Mitochondria-associated ER membranes; Neuroprotection; P110; Subarachnoid hemorrhage

DOI:  https://doi.org/10.1016/j.freeradbiomed.2025.08.011
Int J Mol Sci. 2025 Jul 22. pii: 7041. [Epub ahead of print]26(15):

Identification of Drug Repurposing Candidates for Coxsackievirus B3 Infection in iPSC-Derived Brain-like Endothelial Cells.

Jacob F Wood, John M Vergis, Ali S Imami, William G Ryan, Jon J Sin, Brandon J Kim, Isaac T Schiefer, Robert E McCullumsmith.

  The enterovirus Coxsackievirus B3 causes a range of serious health problems, including aseptic meningitis, myocarditis, and pancreatitis. Currently, Coxsackievirus B3 has no targeted antiviral treatments or vaccines, leaving supportive care as the primary management option. Understanding how Coxsackievirus B3 interacts with and alters the blood-brain barrier may help identify new therapies to combat this often-devastating infection. We reanalyzed a previously published RNA sequencing dataset for Coxsackievirus B3-infected human-induced pluripotent stem-cell-derived brain endothelial cells (iBECs) to examine how Coxsackievirus B3 altered mRNA expression. By integrating GSEA, EnrichR, and iLINCs-based perturbagen analysis, we present a novel, systems-level approach to uncover potential drug repurposing candidates for CVB3 infection. We found dynamic changes in host transcriptomic response to Coxsackievirus B3 infection at 2- and 5-day infection time points. Downregulated pathways included ribosomal biogenesis and protein synthesis, while upregulated pathways included a defense response to viruses, and interferon production. Using iLINCs transcriptomic analysis, MEK, PDGFR, and VEGF inhibitors were identified as possible novel antiviral therapeutics. Our findings further elucidate Coxsackievirus B3-associated pathways in (iBECs) and highlight potential drug repurposing candidates, including pelitinib and neratinib, which may disrupt Coxsackievirus B3 pathology at the blood-brain barrier (BBB).

Keywords:  Coxsackievirus B3; blood–brain barrier; differential gene expression; drug repurposing; transcriptomics

DOI:  https://doi.org/10.3390/ijms26157041
Crit Rev Toxicol. 2025 Aug 14. 1-17

In vitro human brain barrier models for studying thyroid hormone transport.

Kim Heikamp, Timo Hamers, Ellen V S Hessel.

  Early brain development is dependent on the supply of thyroid hormone (TH) to the fetal brain. Disruption of TH concentrations in early brain development is associated with lower IQ and delayed motor development in children. How TH system disruption may affect brain development has mainly been studied in animal models that are not always relevant to humans and do not reflect the TH system in the developing brain. Furthermore, using animal models for safety assessments also raises ethical concerns, is still low-throughput and associated with high costs. All these reasons stress the need to develop new approach methodologies (NAMs), including in vitro methods that help to improve human relevant risk assessment. Initiatives are taken to develop in vitro assays for important key events in the fetal brain, but before TH can enter the fetal brain, it has to pass the developing blood-brain barrier (BBB) and the blood-cerebrospinal fluid barrier (BCSFB). During brain development, the composition of the barriers change over time, as well as the interplay between the two different barriers. Therefore, barrier models need to be included in testing strategies for TH system disruption in the developing brain and these models should take the timepoint of development into account. Barriers are crucial for the supply of TH in the brain. TH is actively transported through these barriers via TH transmembrane transporters (THTMTs) such as MCT8 and OATP1C1, but alternatively, other THTMTs may be involved too. Furthermore, transport of TH across the brain barriers can be disrupted by chemicals. Currently, the extent of THTMT inhibition and its subsequent adverse effects on brain development is largely undiscovered. To further investigate TH transport across the BBB and BCSFB, human cell-based NAMs are being developed that more closely resemble the human brain barriers. These models take the complex cellular composition of the brain barriers into account and in case of organ-on-chip models, the blood/cerebrospinal fluid flow as well. In this review, aspects of accurate in vitro models ranging from simple mono-cultures to extended 3D cultures of the brain barriers are discussed as well as how (a combination of) these in vitro models can be utilized to study TH transport and its disruption in the brain.

Keywords:  Blood–brain barrier; blood–cerebrospinal fluid barrier; in vitro brain-barrier models; microfluidics; organoids; pluripotent stem cells; thyroid hormone transport

DOI:  https://doi.org/10.1080/10408444.2025.2540446
Adv Healthc Mater. 2025 Aug 11. e02075

Phyhip-Targeted Delivery of bFGF Platform with Dual Modulation for Enhancing Neurovascular Repair in Traumatic Brain Injury.

Weihong Nie, Xianglin Hou, Shuwei Sun, Mingxue Zhang, Xiao Zou, Kaiyan Su, Zhuoran Li, Jingyi Li, Qing Yu, Xiaohong Huang, Chunying Shi.

  Traumatic brain injury (TBI) remains a critical neurosurgical challenge with limited therapeutic options. While basic fibroblast growth factor (bFGF) demonstrates neuroprotective and angiogenic potential, its clinical translation is hindered by nonspecific biodistribution and poor blood-brain barrier (BBB) penetration. In the present study, a brain-targeted recombinant protein (AcuP-bFGF) is developed by fusing bFGF with an acute peptide (SLYGSSRHTAPISF, named as AcuP), which enables Phyhip-mediated active transport across the compromised BBB while preserving the bioactivity of bFGF and prolonging its half-life in vivo. Employing Immunoprecipitation-mass spectrometry (IP-MS), phantom-CoA 2-hydroxylase-interacting protein (Phyhip) is identified as the molecular target of AcuP in TBI. This discovery defines a new targeting axis for TBI intervention that overcomes the traditional BBB penetration challenges. A comprehensive study demonstrates that Phyhip-targeted delivery of engineered bFGF exerts significant effects, including enhanced neuronal survival, increased neovascularization, restored BBB integrity, and suppressed neuroinflammation. These effects ultimately promote the recovery of motor function in rats with TBI. Transcriptomic profiling reveals dual-pathway modulation: pro-regenerative activation of NRG1-ErbB4-AKT signaling coupled with anti-inflammatory suppression of cGAS-STING-NFκB cascade. Therefore, the targeted delivery of AcuP-bFGF can represent a potential therapeutic approach for TBI, addressing both neuronal survival and neuroinflammation via Phyhip-mediated bFGF delivery and crosstalk in neuroimmune pathways.

Keywords:  AcuP peptide; basic fibroblast growth factor; neuroinflammation; neuroprotection; phyhip‐targeted delivery; traumatic brain injury

DOI:  https://doi.org/10.1002/adhm.202502075
Neuropharmacology. 2025 Aug 12. pii: S0028-3908(25)00344-2. [Epub ahead of print] 110636

Monotropein alleviates sepsis-associated encephalopathy by targeting matrix metalloproteinase-9.

Yue Xin, Tianyue Guan, Guanglu Wang, Yannan Xiang, Mengxin Li, Yikun Zhao, Panpan Zhao.

  Sepsis is a severe systemic infection that leads to multiple organ dysfunction and high mortality, making it one of the primary causes of death in ICU patients. Sepsis also induces septic encephalopathy (SAE), resulting in acute and long-term cognitive impairments. Research indicates that inhibiting BBB damage, anti-inflammatory, and antioxidant responses are critical therapeutic directions for SAE. Monotropein (Mon), the main active component of the traditional Chinese medicine Epimedium, possesses various pharmacological effects, including antioxidant properties. This study aims to explore the protective effects and potential targets of Mon in SAE. Firstly, the GEO database was utilized to screen for highly expressed genes, identifying matrix metalloproteinase-9 (MMP9) as a target. Drug target reverse screening using Schrodinger software confirmed MMP9 as a potential therapeutic target for Mon. Subsequently, in vitro experiments using an LPS-stimulated BV-2 and HUVECs co-culture model examined the interaction between Mon and MMP9. A CLP-induced mouse model was employed to investigate Mon's role in SAE. Results indicate that MMP9 is highly expressed in SAE and promotes its progression. Mon targets MMP9, enhancing its protein stability and exerting anti-inflammatory, improved vascular permeability, and barrier protective effects. Mon alleviates brain tissue damage, BBB disruption, and synaptic loss induced by CLP, increases antioxidant enzyme activity to eliminate ROS, and suppresses sepsis-induced oxidative stress, thereby mitigating CLP-induced cognitive impairment in mice. In conclusion, Mon targets MMP9, exerting anti-inflammatory, antioxidant, and barrier protective effects, alleviating SAE. Mon may serve as a potential natural therapeutic agent for treating sepsis-induced brain dysfunction.

Keywords:  CLP; MMP9; Monotropein; Oxidative stress; Sepsis-associated encephalopathy; brain tissue damage

DOI:  https://doi.org/10.1016/j.neuropharm.2025.110636
Sci Rep. 2025 Aug 13. 15(1): 29643

miR-221 activates Sox11 to reduce brain injury after intracerebral hemorrhage via inhibiting neuroinflammation.

Tianyu Liang, Yongchun Liu, Renyang Liu, Xianmei Shen, Mingxia Xu.

  As a global public health issue, intracerebral hemorrhage (ICH) is characterized by high morbidity and mortality. Brain injury following ICH is composed of primary and secondary injury, with the latter being more severe and resulting in increased apoptosis. Sox11 (sex-determining region Y-related high-mobility-group 11), a vital member of the Sox gene family, is broadly discovered in the developing nervous system and may have a vital impact on neurogenesis, neuronal survival, and neurite outgrowth. The level and impacts of Sox11 in brain with ICH remain indistinct. The major objective of the current work was to explore the spatiotemporal expression of Sox11 and its roles in secondary brain injury under the ICH impairment. The ICH rat model was established by injecting autologous blood into the right basal ganglia of male Sprague-Dawley rats. It was observed that Sox11 expression was notably elevated in brain tissue after ICH. The enhancement of Sox11 expression through miR-221 reduced neuronal apoptosis and inflammation in the affected rats. Furthermore, overexpression of Sox11 mitigated ICH-induced brain edema, blood-brain barrier disruption, and cognitive impairments. In contrast, Sox11 knockdown resulted in opposing effects. These findings highlight the crucial role of Sox11 in alleviating secondary brain injury following ICH. Thus, upregulating Sox11 presents a promising therapeutic strategy to reduce secondary brain injury in clinical ICH cases.

Keywords:  Intracerebral hemorrhage; MiR-221; Neuroinflammation; Secondary brain injury; Sox11

DOI:  https://doi.org/10.1038/s41598-025-15239-7