CNS Neuroscience & Therapeutics最新文献

{"title":"The Roles of Macrophage Lineage Cells (MLCs) in Brain Aging.","authors":"Qin Qin, Liubin Zhang, Manning Guo, Danli Lu, Yuxin Liu, Zihong Wang, Mengyan Hu, Shisi Wang, Xinmei Kang, Haotong Yi, Wei Qiu, Zhengqi Lu, Wei Cai","doi":"10.1002/cns.70873","DOIUrl":"10.1002/cns.70873","url":null,"abstract":"<p><strong>Background: </strong>Brain aging poses a major public health challenge and is the primary risk factor for neurodegenerative diseases. Macrophage lineage cells (MLCs) have emerged as pivotal mediators of brain aging. While fundamental to central nervous system (CNS) homeostasis through their scavenging, detoxification, and neurotrophic functions, their transition to a senescent state is a primary driver of pathology. This shift is marked by a loss of clearance capacity and the adoption of a pro-inflammatory senescence-associated secretory phenotype (SASP).</p><p><strong>Objectives: </strong>Here, we summarize the distinct and cooperative roles of MLC subsets in brain aging. We examine the key molecular drivers of MLCs senescence and detail how subset-specific dysfunction contributes to the propagation of cellular aging and related neuropathology. Finally, we evaluate current and emerging therapeutic strategies that target MLCs senescence.</p><p><strong>Conclusion: </strong>We conclude by proposing a multidimensional management framework for brain aging. This framework positions MLCs as a central therapeutic hub, integrating advanced diagnostics and stratified interventions to preserve brain health and mitigate neurodegenerative pathology.</p>","PeriodicalId":154,"journal":{"name":"CNS Neuroscience & Therapeutics","volume":"32 4","pages":"e70873"},"PeriodicalIF":5.0,"publicationDate":"2026-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13071362/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147669323","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":"AS1842856 Reduces β-Amyloid Burden via Inhibiting PLA2G4A-Mediated Lysosomal Dysfunction in APP/PS1 Mice.","authors":"Da-Long He, Zheng Wu, Rong-Jun Jia, Ting-Yao Wu, Yi-Min Qiu, Yong-Gang Fan","doi":"10.1002/cns.70910","DOIUrl":"https://doi.org/10.1002/cns.70910","url":null,"abstract":"<p><strong>Aims: </strong>Both cytosolic phospholipase A2 (PLA2G4A)-induced lysosomal membrane disruption and glycogen synthase kinase-3α/β (GSK3α/β)-mediated lysosomal dysfunction have been implicated in neurodegeneration, with a potential regulatory relationship between these two pathways. We recently identified AS1842856 (AS) as a suppressor of GSK3α/β. This study was therefore designed to investigate whether AS mitigates Alzheimer's disease (AD) progression by targeting PLA2G4A to restore lysosomal homeostasis.</p><p><strong>Methods: </strong>The therapeutic potential of AS was investigated in APP/PS1 mice by analyzing cognitive function, β-amyloid (Aβ) load, and lysosomal integrity, with its mechanism of action further explored in N2a-sw cells.</p><p><strong>Results: </strong>AS treatment reduced GSK3α/β expression in both APP/PS1 mice and N2a-sw cells. This suppression led to decreased PLA2G4A levels, restoration of lysosomal membrane integrity, and enhanced lysosomal degradation of Aβ. Consequently, AS administration alleviated Aβ burden and improved cognitive function in APP/PS1 mice. Moreover, AS was found to inhibit NF-κB-mediated PLA2G4A expression. Knockdown experiments further revealed that reduced GSK3β-but not GSK3α-reproduced the suppressive effect on PLA2G4A.</p><p><strong>Conclusion: </strong>Our study identified the GSK3β/NF-κB/PLA2G4A signaling axis as a novel therapeutic target in AD, and AS could inhibit this axis to mitigate Aβ pathology by promoting lysosomal degradation of Aβ.</p>","PeriodicalId":154,"journal":{"name":"CNS Neuroscience & Therapeutics","volume":"32 4","pages":"e70910"},"PeriodicalIF":5.0,"publicationDate":"2026-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13123454/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147758066","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":"Feasibility and Tumor Dynamics of Daily MRI-Guided Online Adaptive Radiotherapy for Brain Glioma.","authors":"Shouliang Ding, Xiumao Yin, Mengqi Sun, Hongdong Liu, Ying Wang, Biaoshui Liu, Mengke Qi, Yuchuan Zhou, Xiaojing Du, Meiling Deng, Wanming Hu, Xiaoyan Huang, Zihuang Li, Yonggao Mou, Yuanyuan Chen","doi":"10.1002/cns.70905","DOIUrl":"https://doi.org/10.1002/cns.70905","url":null,"abstract":"<p><strong>Background: </strong>Magnetic resonance image (MRI)-guided radiotherapy can optimize the therapeutic outcomes of brain glioma patients, as it adjusts to tumor changes in the course of radiation treatment. This study evaluates the dynamic changes of tumors and the feasibility of implementing MRI-guided online adaptive radiotherapy (MRIgOART) for the treatment of brain glioma.</p><p><strong>Patients & methods: </strong>This observational prospective cohort study involved patients with brain glioma treated using 1.5 T MR-Linac from 2021 to 2023. MRIgOART can correct treatment errors and evaluate treatment response through adapt-to-position (ATP) and adapt-to-shape (ATS) strategies. Dice similarity coefficient (DSC), absolute/relative volume (Vrel), and Hausdorff distance (HD) metrics were used to quantify tumor changes. The covariables subjected to evaluation included: surgical resection extent, 1p/19q status, telomerase reverse transcriptase (TERT) mutation status, O6-methylguanine-DNA-methyltransferase (MGMT) methylation status, and isocitrate dehydrogenase (IDH) mutation status. ART and non-ART treatment plans were comparatively analyzed based on target coverage and dose constraints for normal brain tissue. The pattern of failure, as the primary endpoint, was evaluated in this study. Secondary endpoints of the study consisted of overall survival (OS) and progression-free survival (PFS), assessed according to treatment schedules.</p><p><strong>Results: </strong>The cohort comprised 57 patients. The patients with an interval longer than 10 days from simulation to the Fx1 exhibited more significant tumor changes (p < 0.001). The tumor volume showed a gradual reduction during the treatment, whereas the alterations in its location and shape became increasingly evident over time. Multivariate analyses identified associations between prognosis and HD, in addition to a relationship between the extent of surgical resection and DSC. ATS was utilized in 52.6% of patients at least once during treatment, with a higher frequency in TERT wild-type patients (p = 0.013). MRIgOART treatment plans achieved superior target conformality, adequate coverage, and effective sparing of OARs. High-grade glioma (HGG) patients exhibited median PFS of 13 months (95% CI, 10.2-15.8 months) and OS of 28 months (95% CI, 23.3-32.7 months). Failure analysis revealed 58.9% in-field, 17.6% marginal, and 23.5% distant recurrences, with IDH mutation status associated with failure patterns.</p><p><strong>Conclusion: </strong>Preliminary findings in patients with HGG suggest a lower incidence of recurrences within the radiation field and indicate promising outcomes associated with MRIgOART. However, these observations require further validation through comparative studies.</p>","PeriodicalId":154,"journal":{"name":"CNS Neuroscience & Therapeutics","volume":"32 4","pages":"e70905"},"PeriodicalIF":5.0,"publicationDate":"2026-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13112182/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147758250","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":"Retinal Microvascular Dysfunction Reflects Vascular and Alzheimer's-Related Pathology in Dementia With Lewy Bodies.","authors":"Qiuling Tong, William Robert Kwapong, Xiaoqian Luan, Suqing Hu, Yihan Hu, Yimo Guo, Chenli Ji, Ming Yang, Zhen Wang","doi":"10.1002/cns.70891","DOIUrl":"https://doi.org/10.1002/cns.70891","url":null,"abstract":"<p><strong>Background: </strong>Dementia with Lewy bodies (DLB) frequently coexists with cerebrovascular injury and Alzheimer's-related pathology, yet accessible in vivo markers of these processes remain limited. The retinal microvasculature shares structural and physiological characteristics with cerebral small vessels and may provide a non-invasive window into neurovascular and neurodegenerative pathology.</p><p><strong>Methods: </strong>In this cross-sectional study, 32 individuals with DLB and 31 age-matched cognitively unimpaired controls (CU) underwent swept-source optical coherence tomography angiography (OCTA), brain MRI, and plasma biomarker assessment. Retinal vessel densities of the superficial vascular complex (SVC), deep vascular complex (DVC), and choriocapillaris (CC) were quantified. Plasma amyloid-β, phosphorylated tau-217 (p-tau217), and glial fibrillary acidic protein were measured. Cerebral small vessel disease (SVD) burden and white matter hyperintensity (WMH) volumes were derived from MRI. Associations with cognition and mediation by WMH burden were evaluated using generalized estimating equations and bootstrapped mediation analyses.</p><p><strong>Results: </strong>Compared with CU, individuals with DLB exhibited significantly reduced SVC, DVC, and CC vessel densities (all p < 0.001). Lower retinal vessel densities were associated with higher plasma amyloid burden and elevated p-tau217, as well as greater SVD burden and periventricular WMH volume. APOE ε4 carriers demonstrated more pronounced retinal microvascular impairment, higher WMH burden, and elevated p-tau217 levels than non-carriers. Reduced SVC density was associated with worse global cognition, and this relationship was partially mediated by periventricular WMH volume.</p><p><strong>Conclusions: </strong>Retinal microvascular impairment measured by OCTA is closely linked to Alzheimer's-related plasma biomarkers, SVD, and cognitive decline in DLB. These findings support retinal OCTA as a scalable, non-invasive biomarker reflecting convergent neurodegenerative and vascular pathology in DLB.</p>","PeriodicalId":154,"journal":{"name":"CNS Neuroscience & Therapeutics","volume":"32 4","pages":"e70891"},"PeriodicalIF":5.0,"publicationDate":"2026-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13098535/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147758221","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":"Chronic Cerebral Hypoxia and Cognitive Impairment: A Systematic Review and Meta-Analysis Based on Chronic Mountain Sickness, Anemia, Chronic Obstructive Pulmonary Disease, and Obstructive Sleep Apnea.","authors":"Haishi Fei, Guirong Cheng, Yan Zeng, Feibo Zhao, Zhichao He, Shengzhong Yi","doi":"10.1002/cns.70875","DOIUrl":"10.1002/cns.70875","url":null,"abstract":"<p><strong>Background: </strong>Chronic hypoxia, a key pathological feature of chronic mountain sickness (CMS), anemia, Chronic Obstructive Pulmonary Disease (COPD), and Obstructive Sleep Apnoea (OSA), impairs cognitive function; however, their association strength, shared mechanisms, and disease-specific differences remain unsystematized, hindering early interventions.</p><p><strong>Objective: </strong>This study aimed to quantify these via a systematic review and meta-analysis to clarify the deficits and mechanisms for clinical guidance.</p><p><strong>Methods: </strong>We searched PubMed, Web of Science, Embase, and Cochrane Library for relevant studies, assessed the quality using the Newcastle-Ottawa Scale, and analyzed the data using Stata 18.0.</p><p><strong>Results: </strong>Forty-one studies involving 18 countries, 369, 619 participants (5 on CMS, 8 on anemia, 11 on OSA, and 17 on COPD) demonstrated that all four diseases were associated with an increased risk of cognitive impairment, with OR ranging from 1.370 to 6.892. In dichotomous analyses, anemia was epidemiologically linked to elevated cognitive impairment risk but showed nonsignificant, heterogeneous effects on continuous cognitive scores and no associations with specific cognitive domains, indicating its impact is moderated by population traits and measurement approaches. The other three diseases impaired global and domain-specific cognition with SMD ranging from -0.6352 to -0.2000, each with unique deficit profiles. Notably, correction for publication bias eliminated the statistical significance of the overall pooled OR for cognitive impairment risk.</p><p><strong>Conclusion: </strong>Hypoxia is the core shared mechanism linking these four diseases to cognitive impairment, involving mitochondrial dysfunction and neuroinflammation, with additional modulation by genetic and adaptive factors. However, current evidence is limited by publication bias and inconsistent findings (e.g., for anemia). These conclusions must be interpreted with extreme caution, and high-quality longitudinal studies are needed to confirm causality.</p>","PeriodicalId":154,"journal":{"name":"CNS Neuroscience & Therapeutics","volume":"32 4","pages":"e70875"},"PeriodicalIF":5.0,"publicationDate":"2026-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13087434/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147696902","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":"Inhibition of Transglutaminase 2 Preserves Blood-Brain Barrier Integrity and Improves Neurological Outcomes After Experimental Traumatic Brain Injury in Mice.","authors":"Jieru Yang, Lihan Zhang, Xiancheng Qiu, Jiyang Wang, Ruicheng Yan, Jiasen Ye, Jianhua Peng, Yong Jiang","doi":"10.1002/cns.70887","DOIUrl":"10.1002/cns.70887","url":null,"abstract":"<p><strong>Background: </strong>Traumatic brain injury (TBI) is a leading global cause of disability and mortality, with blood-brain barrier (BBB) disruption exacerbating secondary injury. Transglutaminase 2 (TGM2), a multifunctional enzyme implicated in neuroinflammation and extracellular matrix remodeling, remains underexplored in TBI-related BBB dysfunction. This study elucidates the role of TGM2 in BBB disruption following TBI and explores its therapeutic potential in mitigating BBB damage.</p><p><strong>Methods: </strong>The controlled cortical impact (CCI) and oxygen-glucose deprivation (OGD) models were used to establish in vivo and in vitro TBI models in mice. The experimental approaches comprised RNA sequencing, Western blot analysis, RT-qPCR, immunofluorescence staining, and behavioral assessments.</p><p><strong>Results: </strong>TGM2 expression peaked at 48 h after TBI, predominantly in brain endothelial cells, correlating with BBB disruption (reduced tight junction proteins, increased edema). TGM2 knockdown may attenuate MMP-9 via the IL-17 pathway, restoring BBB integrity. In vivo, TGM2 inhibition reduced Evans blue leakage, upregulated CLAUDIN-5/ZO-1, and improved motor coordination, balance, and spatial memory.</p><p><strong>Conclusion: </strong>TGM2 is a key molecule affecting the BBB after TBI. Inhibition of TGM2 can alleviate the blood-brain barrier and neurological deficits after TBI, acting through the IL-17-MMP-9 axis.</p>","PeriodicalId":154,"journal":{"name":"CNS Neuroscience & Therapeutics","volume":"32 4","pages":"e70887"},"PeriodicalIF":5.0,"publicationDate":"2026-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13092724/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147721102","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":"Transnasal Ventral Brainstem Epidural Electrical Stimulation Enhances Consciousness in Anesthetized Sheep: A Feasibility Study.","authors":"Bin Liu, Jingyu Feng, Xiaofang Zhao, Tao Yu, Zhijun Zhao, Fei Shen, Chenglong Yang, Sihui Wang, Chenyu Nong, Yu Sun, Kaiming Ma, Xin Chen, Guogang Xing, Qinggang Ge, Jun Yang","doi":"10.1002/cns.70894","DOIUrl":"https://doi.org/10.1002/cns.70894","url":null,"abstract":"<p><strong>Aim: </strong>Disorders of consciousness (DOC) remain a major clinical challenge, and the efficacy of currently available neuromodulation strategies remains limited. The brainstem reticular formation is central to arousal regulation, but approaches directly targeting it remain technically demanding. This feasibility study aimed to explore whether epidural electrical stimulation applied via a transnasal clival approach could induce arousal and the electrocorticographic (ECoG) changes.</p><p><strong>Methods: </strong>Three anesthetized sheep were implanted with epidural stimulating electrodes placed over the ventral brainstem via a transnasal clival approach and cortical recording electrodes on the fronto-parietal lobes. During the stimulation period, continuous behavioral monitoring was performed, and ECoG was recorded and later processed with spectral analysis.</p><p><strong>Results: </strong>All three sheep successfully underwent electrode implantation without intraoperative complications, including cerebrospinal fluid leakage or neurovascular injury. Short-term stimulation reliably elicited behavioral signs of arousal. Concurrently, spectral analysis of ECoG revealed a reduction in low-frequency power (δ, θ) and an increase in high-frequency power (β, γ).</p><p><strong>Conclusions: </strong>Transnasal clival epidural stimulation is technically feasible and capable of modulating arousal-related neural activity. Further investigations with optimized electrode design and larger cohorts are required to validate its safety and efficacy.</p>","PeriodicalId":154,"journal":{"name":"CNS Neuroscience & Therapeutics","volume":"32 4","pages":"e70894"},"PeriodicalIF":5.0,"publicationDate":"2026-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13112188/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147758331","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":"Circuit-Selective FAAH Inhibition Suppresses Experimental Absence Seizures.","authors":"Tatiana P Morais, Cristiano Bombardi, Vincenzo Crunelli, Giuseppe Di Giovanni","doi":"10.1002/cns.70874","DOIUrl":"10.1002/cns.70874","url":null,"abstract":"<p><strong>Background: </strong>Childhood absence epilepsy (CAE) arises from dysfunctional corticothalamic networks generating spike wave discharges (SWDs) and behavioral arrest. Despite available treatments, a significant proportion of patients remain pharmacoresistant and develop neuropsychiatric comorbidities. The endocannabinoid system (ECS), through activity-dependent signaling, is a key regulator of synaptic and network stability, but its therapeutic potential in absence epilepsy remains unresolved.</p><p><strong>Aims: </strong>To determine whether selective elevation of endogenous cannabinoid tone-particularly anandamide (AEA)-via inhibition of fatty acid amide hydrolase (FAAH) suppresses absence seizures and to define the contribution of thalamic mechanisms.</p><p><strong>Materials and methods: </strong>Video-EEG recordings were performed in Genetic Absence Epilepsy Rats from Strasbourg (GAERS), combining automated detection and blinded validation of SWDs. The irreversible FAAH inhibitor PF-04457845 was administered acutely and subchronically and also delivered via bilateral microinfusion into the ventrobasal (VB) thalamus. Seizure number, total seizure time, and seizure duration were quantified.</p><p><strong>Results: </strong>FAAH inhibition produced a robust and sustained reduction in absence seizures, primarily by decreasing seizure number and cumulative seizure time, with minimal effects on seizure duration. These effects were observed following both acute and repeated systemic administrations, without evidence of tolerance. Importantly, focal VB microinfusion of PF-04457845 reproduced the anti-absence effects, demonstrating that thalamic enhancement of endocannabinoid signaling is sufficient to attenuate pathological network activity. These effects are consistent with increased brain AEA levels and enhanced activity-dependent CB1 receptor signaling.</p><p><strong>Discussion: </strong>Our findings indicate that selective amplification of endogenous cannabinoid signaling-likely driven by increased AEA availability-suppresses absence-like activity by modulating thalamocortical network dynamics. In contrast to direct CB1 receptor agonists, which exacerbate absence seizures, FAAH inhibition preserves the spatial and temporal specificity of ECS, enabling circuit-restricted modulation of excitability. The VB thalamus emerges as a critical locus for ECS-mediated control of seizure generation.</p><p><strong>Conclusion: </strong>FAAH inhibition represents a mechanistically distinct and circuit-selective strategy to suppress absence seizures, likely through elevation of endogenous AEA and targeted modulation of thalamocortical networks. These findings support further translational development of FAAH inhibitors as potential therapies for CAE.</p>","PeriodicalId":154,"journal":{"name":"CNS Neuroscience & Therapeutics","volume":"32 4","pages":"e70874"},"PeriodicalIF":5.0,"publicationDate":"2026-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13071753/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147669342","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":"Zinc Overload in Microvessels Contributes to Blood-Brain Barrier Disruption by Activating the JAK2 Pathway After Cerebral Ischemia/Reperfusion.","authors":"Zhengran Guo, Wenjuan Shi, Xiaodong Chen, Shuhua Yuan, Xunming Ji, Zhifeng Qi","doi":"10.1002/cns.70885","DOIUrl":"10.1002/cns.70885","url":null,"abstract":"<p><strong>Aims: </strong>Stroke is one of the leading causes of adult disability and death worldwide. Inflammation-induced microvascular dysfunction and increased blood-brain barrier (BBB) permeability are major contributors to cerebral ischemia/reperfusion (I/R) injury. Previous studies have shown that zinc accumulation in microvessels contributes to BBB disruption following I/R. However, the mechanisms linking zinc accumulation to microvascular inflammation remain poorly understood.</p><p><strong>Methods: </strong>We investigated whether the Janus kinase 2/signal transducer and activator of transcription 3 (JAK2/STAT3) inflammatory pathway mediates microvascular zinc overload-induced BBB damage, using the model of I/R rats, endothelial cells and neuron-specific zinc transporter 3 knockout (ZnT3-cKO) mice.</p><p><strong>Results: </strong>Our findings in I/R rats and endothelial cells revealed that zinc accumulation in microvessels activated JAK2, promoting mitochondrial translocation of phosphorylated STAT3 (p-STAT3) and exacerbating BBB disruption. These effects were significantly suppressed by zinc chelation. Furthermore, inhibition of neuronal zinc release in ZnT3-cKO mice markedly reduced zinc accumulation and JAK2 activation in ischemic microvessels. ZnT3 knockout also prevented mitochondrial translocation of p-STAT3, attenuated mitochondrial dysfunctions, and abolished zinc overload-induced BBB permeability following I/R.</p><p><strong>Conclusion: </strong>This study suggests that zinc accumulation in microvessels contributes to I/R-induced BBB damage through JAK2/STAT3 signaling and highlights a potential therapeutic target for preserving vascular integrity after stroke.</p>","PeriodicalId":154,"journal":{"name":"CNS Neuroscience & Therapeutics","volume":"32 4","pages":"e70885"},"PeriodicalIF":5.0,"publicationDate":"2026-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13085896/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147696883","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":"Teriflunomide Attenuates Demyelination and Enhances Remyelination in Organotypic Brain Slice Cultures Through Modulation of Glial Cell Dynamics.","authors":"Jessica Kronenberg, Lara-Jasmin Schröder, Henriette Reinsberg, Thomas Skripuletz, Sandra Heckers, Florian Hansmann, Wolfgang Baumgärtner, Martin Stangel, Viktoria Gudi","doi":"10.1002/cns.70857","DOIUrl":"10.1002/cns.70857","url":null,"abstract":"<p><strong>Objectives: </strong>Teriflunomide has been proven to be effective in the therapy of relapsing-remitting multiple sclerosis (RMS). In an approach to better elucidate the mode of action of teriflunomide in the central nervous system (CNS), we aimed here to clarify the role of teriflunomide on glial cells using an ex vivo demyelination model.</p><p><strong>Methods: </strong>Organotypic cerebellar slice cultures (OSC) were cultivated from 10-day-old mice and left to fully myelinate for another 7 days. Demyelination was induced by lysolecithin (LPC) and was studied by immunohistochemistry against myelin proteins and electron microscopy. Glial cell responses were investigated by immunohistochemistry. Intra-glia interactions were studied using primary rodent glial cell cultures.</p><p><strong>Results: </strong>Teriflunomide treatment did not affect developmental myelination but attenuated myelin degradation induced by LPC, as assessed by myelin basic protein and myelin oligodendrocyte glycoprotein immunoreactivity. During demyelination, teriflunomide treatment was associated with reduced microglial cell density and proliferation. Partial depletion of microglia using the CSF-1R inhibitor BLZ945 resulted in a similar preservation of myelin, supporting a functional association between microglial abundance and the extent of myelin loss in this model. Quantitative ultrastructural analysis further supported preserved myelin structures in teriflunomide-treated slices. Spontaneous remyelination was improved and enhanced numbers of oligodendrocytes were detected following teriflunomide treatment in OSC. However, direct cytoprotective/pro-proliferative effects of teriflunomide on oligodendroglia were not observed in primary glial cultures. There were also no indirect effects of teriflunomide-treated microglia on oligodendrocyte progenitor cells in vitro.</p><p><strong>Conclusions: </strong>Teriflunomide exerts beneficial effects on myelin preservation and remyelination in an ex vivo demyelination model, potentially through modulation of glial cell dynamics rather than direct effects on oligodendroglial cells.</p>","PeriodicalId":154,"journal":{"name":"CNS Neuroscience & Therapeutics","volume":"32 4","pages":"e70857"},"PeriodicalIF":5.0,"publicationDate":"2026-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13072056/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147669356","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}