Fluids and Barriers of the CNS最新文献

{"title":"The effects of dose, valency, and affinity on TfR-mediated brain delivery in vivo.","authors":"Gillian Bonvicini, Sunitha Singh, Lisa Sandersjöö, Dag Sehlin, Stina Syvänen, Ken G Andersson","doi":"10.1186/s12987-025-00643-y","DOIUrl":"https://doi.org/10.1186/s12987-025-00643-y","url":null,"abstract":"<p><strong>Background: </strong>Monovalent binding to the transferrin receptor (TfR) is considered the most efficient mode for high delivery of protein constructs across the blood-brain barrier via TfR-mediated transcytosis at therapeutic doses. However, growing evidence suggests this is not the case at lower, diagnostic doses. There is also a lack of data on how valency and affinity to TfR affect brain uptake independently since previous studies have not compared monovalent and bivalent antibodies with similar affinities regardless of valency (i.e. apparent affinity). Therefore, the aim was to evaluate the independent effects of valency and affinity on TfR-mediated brain delivery at different doses.</p><p><strong>Methods: </strong>Affinity variants of antibody 8D3 were produced by introducing alanine point mutations into the complementarity-determining regions. Eleven Fab fragments and 29 IgGs were affinity screened against mouse TfR (mTfR). Six of each were chosen for production with a knob-into-hole design to have monovalent and bivalent TfR binders in full-length antibody format. The apparent affinity of these 12 antibodies were tested in an Sp2/0-Ag14 cell assay. The 10 nM apparent affinity set and the bivalent wild-type antibody were radiolabelled and injected into wild-type mice at a low (0.22 ± 0.03 mg/kg) or high (7.5 ± 0.43 mg/kg) dose. The biodistribution was measured in brain, blood and peripheral organs 4 h post-injection.</p><p><strong>Results: </strong>Two sets of monovalent and bivalent 8D3 formats with similar mTfR apparent affinities were identified. Brain and tissue uptake was higher at the low dose than the high dose for all antibodies. At the low dose, the higher apparent affinity, bivalent antibody had higher brain uptake than either of the two lower apparent affinity antibodies. At the high dose, the monovalent antibody had higher brain uptake than the two bivalent antibodies. The peripheral distribution of the three antibodies were similar to the brain distribution at both doses.</p><p><strong>Conclusions: </strong>Valency and apparent affinity affect brain uptake in a dose-dependent manner such that: brain uptake was affected more by apparent affinity at the low dose and by valency at the high dose. Thus, when designing constructs for TfR-mediated brain delivery, the application, and consequently the dose, are critical to consider.</p>","PeriodicalId":12321,"journal":{"name":"Fluids and Barriers of the CNS","volume":"22 1","pages":"36"},"PeriodicalIF":5.9,"publicationDate":"2025-04-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143810790","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Hyphal penetration is the major pathway of translocation of Candida albicans across the blood-cerebrospinal fluid barrier.","authors":"S Schmidt, C Schwerk, H Schroten, H Ishikawa, R Schubert, T Lehrnbecher, H Rudolph","doi":"10.1186/s12987-025-00644-x","DOIUrl":"10.1186/s12987-025-00644-x","url":null,"abstract":"<p><strong>Background: </strong>Despite the availability of potent antifungal compounds, invasive fungal disease poses significant morbidity and mortality in immunocompromised patients. Candida albicans is one of the leading pathogens in this setting, and may affect the central nervous system (CNS), which is an extremely severe form of the infection. As the exact pathogenesis of Candida CNS infection is not clear, we investigated the mechanisms and effects of C. albicans transmigration into the CNS, which will be helpful for diagnosis, prevention and treatment.</p><p><strong>Methods: </strong>We used a human in vitro model of the Blood-Cerebrospinal Fluid Barrier (BCSFB), and we investigated the mechanisms of Candida albicans translocation into the CNS. Translocation was evaluated using immunofluorescence analysis focusing on tight and adherens junctions and the actin cytoskeleton. Barrier integrity was monitored via measurement of transepithelial resistance and the paracellular permeability of dextran. LIVE/DEAD assays were applied for viability controls and a cytometric bead array was performed to detect cytokine secretion of plexus epithelial cells.</p><p><strong>Results: </strong>Translocation at low doses occurs transcellularly in the absence of cytotoxicity or secretion of proinflammatory cytokines. This is accomplished by the formation of a tunnel-like structure exploiting the actin cytoskeleton. With higher infection doses of Candida albicans, a reduction in barrier integrity due to disruption of tight and adherens junctions was observed and cytotoxicity also increased.</p><p><strong>Conclusion: </strong>Our findings reveal that Candida albicans can use transcellular translocation to invade into the CNS and is able to circumvent major host immune response, which may impact on diagnostic and preventive strategies.</p>","PeriodicalId":12321,"journal":{"name":"Fluids and Barriers of the CNS","volume":"22 1","pages":"34"},"PeriodicalIF":5.9,"publicationDate":"2025-04-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11969880/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143779575","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Enlarged choroid plexus is linked with poorer physical function in rural older adults: a population-based study.","authors":"Qianqian Xie, Ziwei Chen, Jiafeng Wang, Huisi Zhang, Yan Wang, Xiaoyu Wang, Chunyan Li, Yongxiang Wang, Lin Cong, Daniel Ferreira, Anna-Karin Welmer, Lin Song, Yifeng Du, Chengxuan Qiu","doi":"10.1186/s12987-025-00642-z","DOIUrl":"10.1186/s12987-025-00642-z","url":null,"abstract":"<p><strong>Background: </strong>The choroid plexus (ChP) plays an important role in producing cerebrospinal fluid (CSF) and physical dysfunction has been associated with alterations in CSF circulation. However, no population-based studies have thus far examined the association of ChP with physical function in older people.</p><p><strong>Methods: </strong>This population-based cross-sectional study included 1217 participants (age ≥ 60 years; 57.35% women) in the MRI substudy of the Multimodal Interventions to delay Dementia and disability in rural China. ChP volume was automatically segmented using three-dimensional T1-weighted sequences. Physical function was assessed using the Short Physical Performance Battery (SPPB). Data were analyzed using general linear regression and mediation models.</p><p><strong>Results: </strong>Controlling for demographic characteristics, cardiovascular risk factors, stroke, disproportionately enlarged subarachnoid-space hydrocephalus (DESH), and total intracranial volume, per 1-ml increase in ChP volume was associated with β-coefficient of -0.24 (95% confidence interval: -0.37 to -0.11) for SPPB summary score, with the association being stronger in females (-0.40; -0.60 to -0.20) than in males (-0.17; -0.33 to -0.01) (p for ChP volume×sex interaction = 0.028). The associations were similar across three domains of balance, chair stand, and walking speed. In addition, enlarged ChP volume was associated with increased ventricular volume and white matter hyperintensity (WMH) volume. Mediation analysis suggested that lateral ventricular volume and periventricular WMH volume significantly mediated the association of ChP volume with the SPPB summary score, with the proportion of mediation being 54.22% and 14.48%, respectively.</p><p><strong>Conclusion: </strong>Larger ChP volume is associated with poorer physical function in older adults, especially in women. The association is largely mediated by lateral ventricular and periventricular WMH volumes.</p>","PeriodicalId":12321,"journal":{"name":"Fluids and Barriers of the CNS","volume":"22 1","pages":"33"},"PeriodicalIF":5.9,"publicationDate":"2025-04-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11966853/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143771841","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Rutin ameliorates stress-induced blood‒brain barrier dysfunction and cognitive decline via the endothelial HDAC1‒Claudin-5 axis.","authors":"Zhao-Wei Sun, Zhao-Xin Sun, Yun Zhao, Ling Zhang, Fang Xie, Xue Wang, Jin-Shan Li, Mao-Yang Zhou, Hong Feng, Ling-Jia Qian","doi":"10.1186/s12987-025-00639-8","DOIUrl":"10.1186/s12987-025-00639-8","url":null,"abstract":"<p><strong>Background: </strong>Emerging evidence suggests that chronic stress compromises blood‒brain barrier (BBB) integrity by disrupting brain microvascular endothelial cells (BMECs), contributing to the development of cognitive impairments. Thus, targeting the BBB is expected to be a promising treatment strategy. The biological function of rutin has been investigated in neurological disorders; however, its regulatory role in stress-induced BBB damage and cognitive decline and the underlying mechanisms remain elusive.</p><p><strong>Methods: </strong>In a chronic unpredictable mild stress (CUMS) mouse model, a fluorescent dye assay and behavioral tests, including a novel object recognition test and Morris water maze, were performed to evaluate the protective effects of rutin on BBB integrity and cognition. The effects of rutin on BMEC function were also investigated in hCMEC/D3 cells (a human brain microvascular endothelial cell line) in vitro. Furthermore, the molecular mechanisms by which rutin restores BBB endothelium dysfunction were explored via RNA-seq, quantitative real-time PCR, western blotting, immunofluorescence and chromatin immunoprecipitation. Finally, biotinylated tumor necrosis factor-α (TNF-α) was employed to test the influence of rutin on the ability of circulating TNF-α to cross the BBB.</p><p><strong>Results: </strong>We identified that rutin attenuated BBB hyperpermeability and cognitive impairment caused by the 8-week CUMS procedure. Moreover, rutin promoted the proliferation, migration and angiogenesis ability of BMECs, and the integrity of the cellular monolayer through positively regulating the expression of genes involved. Furthermore, rutin impeded histone deacetylase 1 (HDAC1) recruitment and stabilized H3K27ac to increase Claudin-5 protein levels. Ultimately, normalization of the hippocampal HDAC1‒Claudin-5 axis by rutin blocked the infiltration of circulating TNF-α into the brain parenchyma and alleviated neuroinflammation.</p><p><strong>Conclusions: </strong>This work establishes a protective role of rutin in regulating BMEC function and BBB integrity, and reveals that rutin is a potential drug candidate for curing chronic stress-induced cognitive deficits.</p>","PeriodicalId":12321,"journal":{"name":"Fluids and Barriers of the CNS","volume":"22 1","pages":"35"},"PeriodicalIF":5.9,"publicationDate":"2025-04-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11967129/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143771854","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"CSF outflow from the human spinal canal: preliminary results from an anatomical specimen-based model.","authors":"Radosław Rzepliński, Steven T Proulx, Sylwia Tarka, Tomasz Stępień, Bogdan Ciszek","doi":"10.1186/s12987-025-00645-w","DOIUrl":"10.1186/s12987-025-00645-w","url":null,"abstract":"<p><strong>Background: </strong>Recent discoveries focused on the role of cerebrospinal fluid (CSF) in metabolite clearance have initiated intense research on CSF circulation and outflow pathways. These studies have focused on the cranial subarachnoid space, whereas spinal outflow has been relatively less investigated. Moreover, most studies have been performed on rodent models, which allows thorough anatomical investigation, whereas evidence from humans has been generated primarily from in vivo neuroimaging techniques. In this paper, we introduce an anatomical specimen-based preparation for studying spinal CSF outflow in humans and present preliminary results from our initial studies.</p><p><strong>Methods: </strong>Unfixed anatomical specimens of the thoracolumbar spinal dural sac along with the spinal nerves were obtained from cadavers. Experiments involving low-pressure infusion of contrast medium (barium sulfate) into the spinal subarachnoid space with video recording of contrast spread were performed. After fixation, contrast agent distribution of the samples was assessed via histological and radiological analyses including 3D X-ray microscopy.</p><p><strong>Results: </strong>Five human anatomical specimens of the dural sac were assessed. Filling of spaces extending to the spinal dura (arachnoid granulations, cuffs around the proximal spinal nerves) and unrestricted outflow from postganglionic spinal nerve cross-sections were both observed. Histological and radiological results confirmed the presence of contrast around the spinal nerve fascicles under the perineurium, in the arachnoid granulations and within the lumens of vessels within the dura or in the surrounding epidural adipose tissue.</p><p><strong>Conclusions: </strong>The described model makes it possible to examine CSF outflow routes from the human spinal subarachnoid space. The methodology is reproducible, feasible, and does not require specialized equipment. Preliminary results have revealed two potential CSF outflow pathways that have been previously observed in animal models: along the spinal nerves and to the epidural tissue and vessels.</p>","PeriodicalId":12321,"journal":{"name":"Fluids and Barriers of the CNS","volume":"22 1","pages":"32"},"PeriodicalIF":5.9,"publicationDate":"2025-04-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11963703/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143771835","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"PepH3-modified nanocarriers for delivery of therapeutics across the blood-brain barrier.","authors":"Anikó Szecskó, Mária Mészáros, Beatriz Simões, Marco Cavaco, Catarina Chaparro, Gergő Porkoláb, Miguel A R B Castanho, Mária A Deli, Vera Neves, Szilvia Veszelka","doi":"10.1186/s12987-025-00641-0","DOIUrl":"10.1186/s12987-025-00641-0","url":null,"abstract":"<p><strong>Background: </strong>Nanocarriers targeting the blood-brain barrier (BBB) are promising drug delivery systems to enhance the penetration of therapeutic molecules into the brain. Immunotherapy, particularly monoclonal antibodies designed to bind amyloid-beta peptides have become a promising strategy for Alzheimer's disease, but ensuring efficacy and safety is challenging and crucial for these therapies. Our aim was to develop an innovative nanocarriers conjugated with PepH3, a cationic peptide derived from Dengue virus type-2 capsid protein that crosses the BBB and acts as a shuttle peptide for the encapsulated single domain antibody (sdAb) recognizing Aβ oligomers.</p><p><strong>Results: </strong>PepH3 peptide enhanced the uptake of the nanoparticles (NPs) into brain endothelial cells, and transcytosis of sdAb, as a potential therapeutic molecule, across both rat and human BBB culture models. The cargo uptake was a temperature dependent active process that was reduced by metabolic and endocytosis inhibitors. The cellular uptake of the cationic PepH3-tagged NPs decreased when the negative surface charge of brain endothelial cells became more positive after treatments with a cationic lipid or with neuraminidase by digesting the glycocalyx. The NPs colocalized mostly with endoplasmic reticulum and Golgi apparatus and not with lysosomes, indicating the cargo may avoid cellular degradation.</p><p><strong>Conclusions: </strong>Our results support that combination of NPs with a potential brain shuttle peptide such as PepH3 peptide can improve the delivery of antibody fragments across the BBB.</p>","PeriodicalId":12321,"journal":{"name":"Fluids and Barriers of the CNS","volume":"22 1","pages":"31"},"PeriodicalIF":5.9,"publicationDate":"2025-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11959756/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143763409","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Brain endothelial cells as phagocytes: mechanisms and implications.","authors":"Rudy T Chang, Mark J Fisher, Rachita K Sumbria","doi":"10.1186/s12987-025-00637-w","DOIUrl":"10.1186/s12987-025-00637-w","url":null,"abstract":"<p><p>Brain microvascular endothelial cells (BECs) lining the brain capillaries form the anatomical site of the blood-brain barrier (BBB), providing a highly selective barrier to support brain homeostasis and function. While the BBB acts as a barrier to immune cells and pathogens under normal conditions, BECs can facilitate their entry into the CNS via a phagocytosis-like mechanism. A similar process is now increasingly reported for a diverse set of cargos, resulting in the categorization of BECs as \"non-professional\" phagocytes and redefining the conventional view that these cells are functionally non-phagocytic. This review aims to summarize research demonstrating the capacity of BECs to phagocytose various cargos, including aged red blood cells (RBC), myelin debris, and embolic particles. Mechanistically, BEC phagocytosis can be triggered by the exposure of phosphatidylserine on RBC, expression of adhesion molecules such as ICAM-1 and VCAM-1 on BECs, cargo-opsonization, and/or involve BEC cytoskeleton remodeling. Phagocytic activity by BECs has significant clinical implications ranging from regulation of cerebral microvascular patency (particularly by contributing to and resolving capillary stalling), clearance of brain parenchymal debris, and brain parenchymal invasion by pathogens. Further, BEC phagocytosis of RBC, which represents a cell (RBC)-in-cell (BEC) phenomenon, is implicated in hemorrhagic lesions including cerebral microhemorrhages. This review aims to shed light on BEC phagocytosis as an important function within the brain microvascular system and will delve into the underlying mechanisms, discuss the clinical implications, and identify gaps in our understanding of this phenomenon.</p>","PeriodicalId":12321,"journal":{"name":"Fluids and Barriers of the CNS","volume":"22 1","pages":"30"},"PeriodicalIF":5.9,"publicationDate":"2025-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11959998/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143763257","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Is the ischemia found in normal pressure hydrocephalus secondary to venous compression or arterial constriction? A comment on Ohmura et al.","authors":"Grant Alexander Bateman, Alexander Robert Bateman","doi":"10.1186/s12987-025-00640-1","DOIUrl":"10.1186/s12987-025-00640-1","url":null,"abstract":"<p><strong>Background: </strong>In a recent study of normal pressure hydrocephalus published by Ohmura et al., there was a progressive reduction in the cerebral blood volume within the cortex, as measured by near-infrared spectroscopy, following an increase in the intracranial pressure from an infusion study. The authors contend that this reduction in blood volume occurred due to the collapse of the venous structures, starting from the smallest veins adjacent to the capillaries and involving the entire venous outflow tract. We wish to outline some problems with this interpretation.</p><p><strong>Main body: </strong>It has been previously shown that venous collapse secondary to an increase in intracranial pressure always starts at the most distal point in the veins. The critical buckling pressure for a tube depends on the cube of the ratio of the wall thickness and the internal diameter. The smallest veins have ratios which are larger than the distal cortical veins, so the latter are the ones to collapse first. The collapse of the distal venous outflow cuff always leads to an increase in the transmural pressure of the veins upstream from it, leading to venous dilatation and not a reduction in venous volume. Only a simultaneous arteriolar constriction of a greater volume than the venous volume increase can account for the progressive reduction in blood volume, which occurs once the ICP is greater than the sinus outflow pressure in normal pressure hydrocephalus.</p><p><strong>Conclusions: </strong>The reduction in cerebral blood volume which occurs in the cortex in normal pressure hydrocephalus cannot be due to widespread venous collapse. Therefore, there must be a large component of arteriolar constriction accompanying this disease.</p>","PeriodicalId":12321,"journal":{"name":"Fluids and Barriers of the CNS","volume":"22 1","pages":"29"},"PeriodicalIF":5.9,"publicationDate":"2025-03-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11924840/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143662734","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"VIEshunt: towards a ventricular intelligent and electromechanical shunt for hydrocephalus therapy.","authors":"Fabian Flürenbrock, Leonie Korn, Dominik Schulte, Anthony Podgoršak, Joris Chomarat, Janina Hug, Tiago Hungerland, Caroline Holzer, David Iselin, Luca Krebs, Rosina Weiss, Markus F Oertel, Lennart Stieglitz, Miriam Weisskopf, Mirko Meboldt, Melanie N Zeilinger, Marianne Schmid Daners","doi":"10.1186/s12987-025-00629-w","DOIUrl":"10.1186/s12987-025-00629-w","url":null,"abstract":"<p><strong>Background: </strong>Shunt systems for hydrocephalus therapy are commonly based on passive mechanical pressure valves that are driven by the intracranial, intra-abdominal, and hydrostatic pressure. The differential pressure acting on the valve determines the drainage rate of cerebrospinal fluid (CSF) but is not a gauge of the physiological condition of the patient. Internal and external influences can cause over- or underdrainage and lead to pathological levels of intracranial pressure (ICP).</p><p><strong>Methods: </strong>The first prototype of a ventricular intelligent and electromechanical shunt (VIEshunt) is developed, tested, and compared with previous efforts towards the development of a smart shunt. Its key components are a micro pump, a flow meter, a pressure sensor, an inertial measurement unit, a wireless communication interface, and a microcontroller. The VIEshunt prototype was tested in vitro using a hardware-in-the-loop (HiL) test bench that runs real-time patient simulations involving changes in intracranial and intra-abdominal pressure, as well as changes in posture ranging between supine and upright position. The prototype was subsequently tested in an in vivo pilot study based on an acute ovine animal model (n=1) with infusions of artificial CSF.</p><p><strong>Results: </strong>During 24 h in vitro testing, the prototype detected the simulated posture changes of the patient and automatically adapted the controller reference. The posture-specific ICP references of 12 mmHg for supine and -3 mmHg for upright position were tracked without offset, thus preventing adverse over- and underdrainage during the investigated HiL test scenario. During acute in vivo testing, the prototype first regulated the mean ICP of a sheep from 22 mmHg down to 20 mmHg. Each of the three subsequent intraventricular bolus infusions of 1 mL saline solution increased mean ICP by approximately 11 mmHg. While natural absorption alone decreased ICP by only 5 mmHg within 9 min, the prototype was able to regulate ICP back to the pre-bolus pressure value within 5 min.</p><p><strong>Conclusion: </strong>The developed VIEshunt prototype is capable of posture-dependent ICP regulation and CSF drainage control. Smart shunt systems based on VIEshunt could improve patient monitoring and enable optimal physiologic therapy by adapting to the individual patient. To derive statistically relevant conclusions for the performance of VIEshunt, future work will focus on the development of a next generation prototype for use in pre-clinical studies.</p>","PeriodicalId":12321,"journal":{"name":"Fluids and Barriers of the CNS","volume":"22 1","pages":"28"},"PeriodicalIF":5.9,"publicationDate":"2025-03-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11907855/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143633809","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Hypoxemia exerts detrimental effects on the choroid plexuses and cerebrospinal fluid system in rats.","authors":"Rawan Barakat, Hameed Al-Sarraf, Zoran Redzic","doi":"10.1186/s12987-024-00613-w","DOIUrl":"10.1186/s12987-024-00613-w","url":null,"abstract":"<p><strong>Background: </strong>Hypoxemia can cause secondary acute brain injury, but the mechanisms behind it are not entirely clear and could involve disturbances in the brain extracellular fluids. We aimed to explore the effects of hypoxemia on the choroid plexus (CPs) and cerebrospinal fluid (CSF) system in rats.</p><p><strong>Methods: </strong>Male Sprague Dawley rats were kept in O₂ control in vivo cabinet with either 21% (normoxia) or 8% O₂ (hypoxemia) for up to 48 h. In some cases, signaling of selected cytokines was inhibited prior to hypoxemia. CSF and blood samples were collected by Cisterna Magna puncture and through venous catheters, respectively. The percentages of dead cells in the CPs and ependymal layers (EL) after hypoxemia or normoxia was estimated using TUNEL staining. CP's ultrastructure was analyzed by transmission electron microscopy. Protein concentration in the CSF and plasma was measured and the CSF albumin-to-total protein ratios were estimated. Concentrations of hypoxia-related cytokines in the CSF and plasma samples were estimated using the multiplex immunoassay. Data was analyzed by one-way ANOVA followed by either Bonferroni or Tukey's multiple comparison tests, or Student's t-test. Results are presented as mean ± SD; p < 0.05 was considered statistically significant.</p><p><strong>Results: </strong>Duration of hypoxemia exerted significant effects on the cell viability in the CPs (p < 0.01) and EL (p < 0.01) and caused apoptosis-related changes in the CP. Hypoxemia had significant effects on the protein concentration in the CSF (p < 0.05), but not in plasma (p > 0.05), with a significant increase in the CSF albumin-to-total protein ratio after 6 h hypoxemia (p < 0.05). Thirty-two cytokines were detected in the CSF. Hypoxemia caused a statistically significant reduction in the concentrations of 12 cytokines, while concentrations of erythropoietin (EPO) and vascular endothelial growth factor (VEGF) increased significantly. Exposure to hypoxemia after inhibitions of EPO, VEGF, or tumor necrosis factor alpha (TNFα) signaling resulted in more dead cells (p < 0.01), less dead cells (p < 0.01) and more dead cells (p < 0.01) in the CPs, respectively, when compared to the number of dead cells when these cytokines were not inhibited. The density of macrophages in the CPs decreased significantly during hypoxemia; that effect was cancelled out by TNFα inhibition.</p><p><strong>Conclusion: </strong>Hypoxemia had detrimental effects on the CPs and CSF system, which was modulated by hypoxia- and inflammation-related cytokines.</p>","PeriodicalId":12321,"journal":{"name":"Fluids and Barriers of the CNS","volume":"22 1","pages":"27"},"PeriodicalIF":5.9,"publicationDate":"2025-03-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11905537/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143614108","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}