CNS Neuroscience & Therapeutics最新文献_第5页

Multi-Site Theta-tACS Improves Memory and Language Performance and Associated Local and Remote Functional Connectivity in Mild Cognitive Impairment 多位点Theta-tACS改善轻度认知障碍患者的记忆和语言表现以及相关的局部和远程功能连接。

IF 5 1区医学 Q1 NEUROSCIENCES

CNS Neuroscience & Therapeutics

Pub Date : 2025-12-18 DOI: 10.1002/cns.70707

Zhiwei Guo, Yi Jiang, Jiayuan He, Ning Jiang

Background

While multi-site noninvasive brain stimulation demonstrates enhanced cognitive benefits in mild cognitive impairment (MCI), the efficacy of transcranial alternating current stimulation (tACS) in this paradigm remains unestablished. The study aims were to investigate the therapeutic effects of multi-site tACS on MCI patients and its underlying neural mechanism.

Methods

A parallel, sham-controlled trial was conducted with 60 MCI participants assigned to multi-site tACS (prefrontal gyrus and precuneus), single-site tACS (precuneus), or sham groups. All participants underwent 20 days of 7 Hz tACS concurrent with working memory training. Cognitive assessments and fMRI examinations were performed pre- and post- intervention. Local and remote functional connectivity changes were evaluated using regional homogeneity (Reho) and resting-state network (RSN) analyses, respectively.

Results

Multi-site tACS demonstrated superior cognitive improvements, particularly in verbal fluency (p = 0.006) and recognition memory (p = 0.025), compared to sham stimulation. Significant ReHo changes were observed in the superior frontal gyrus (SFG) and superior temporal gyrus (STG) exclusively in the multi-site group (p < 0.05). Additionally, multi-site tACS induced broader functional connectivity alterations in the default mode network (DMN), executive control network (ECN), and left frontoparietal network (FPN). Correlations were found between the Reho changes in SFG and STG and the score changes of immediate memory (r = 0.367, p = 0.039) and language naming (r = 0.371, p = 0.037), respectively. Functional connectivity changes in the right inferior parietal lobe were also significantly correlated with the score changes of language naming (r = −0.374, p = 0.035). Moreover, more functional connectivity changes between the prefrontal gyrus stimulation site and the salience network and DMN were also detected in the multi-site group relative to the single-site group.

Conclusions

Multi-site tACS is more effective than single-site tACS in enhancing cognitive functions and modulating cognition-related brain networks in MCI patients. These superior neuromodulatory effects of multi-site tACS may be attributed to its capacity to modulate functional networks across the prefrontal gyrus more extensively.

背景：虽然多部位无创脑刺激在轻度认知障碍（MCI）中显示出增强的认知益处，但经颅交流电刺激（tACS）在这一范式中的疗效仍未确定。本研究旨在探讨多点tACS对MCI患者的治疗效果及其潜在的神经机制。方法：将60名MCI参与者分为多部位tACS（前额叶回和楔前叶）、单部位tACS（楔前叶）或假手术组，进行平行、假对照试验。所有参与者在进行工作记忆训练的同时，接受了20天的7赫兹tACS。在干预前后分别进行认知能力评估和功能磁共振成像检查。采用区域同质性（Reho）和静息状态网络（RSN）分析分别评价了局部和远程功能连通性的变化。结果：与假刺激相比，多位点tACS表现出了更好的认知改善，特别是在语言流畅性（p = 0.006）和识别记忆（p = 0.025）方面。结论：多位点tACS在MCI患者认知功能增强和认知相关脑网络调节方面比单位点tACS更有效。多位点tACS的这些优越的神经调节作用可能归因于其更广泛地调节前额叶回功能网络的能力。

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引用次数: 0

Genetic and Clinical Characteristics of Chinese Adult Patients With Krabbe Disease 中国成人蟹黄病的遗传与临床特点

IF 5 1区医学 Q1 NEUROSCIENCES

CNS Neuroscience & Therapeutics

Pub Date : 2025-12-18 DOI: 10.1002/cns.70708

Yi Zhang, Hui-Fen Huang, Juan-Juan Xie, Wang Ni, Hao Yu, Zhi-Ying Wu

Aim

This study aims to expand the clinical and genetic spectrum of Krabbe disease (KD) in Chinese adult patients and to improve diagnosis and understanding of its phenotypic diversity.

Methods

Patients clinically suspected of leukodystrophy were recruited between 2015 and 2025. Clinical features were collected, and whole-exome sequencing (WES) was performed to identify potential variants. The pathogenicity of detected variants was classified according to the American College of Medical Genetics and Genomics (ACMG) standards and guidelines. Functional assays assessing protein expression, processing, secretion, subcellular localization, and enzymatic activity were conducted to further validate variant pathogenicity.

Results

Fourteen unrelated patients were genetically diagnosed with KD, and their genetic and clinical features were summarized. Eleven variants in GALC were identified, including a novel missense variant c.1019C>T (p.P340L) which is not reported in the Human Gene Mutation Database (HGMD). Unlike most adult patients who typically present with spastic paraplegia, the patient carrying this variant exhibited initial symptoms of peripheral neuropathy. Functional experiments demonstrated that the variant led to impaired protein processing and localization, as well as reduced GALC enzymatic activity. Other variants including p.D56H, p.L377X, p.L441X, and p.L634S also affected GALC functions to varying degrees.

Conclusion

This study enhances the genotypic and phenotypic characterization of KD in China, aiding in differential diagnosis and genetic counseling. Functional data reinforce the pathogenicity of identified variants.

目的：本研究旨在扩大中国成人克拉伯病（KD）的临床和遗传谱，提高对其表型多样性的诊断和认识。方法：招募2015 ~ 2025年间临床疑似脑白质营养不良的患者。收集临床特征，并进行全外显子组测序（WES）以确定潜在的变异。检测到的变异的致病性按照美国医学遗传与基因组学学院（ACMG）的标准和指南进行分类。功能分析评估蛋白表达、加工、分泌、亚细胞定位和酶活性，以进一步验证变异的致病性。结果：14例无亲缘关系的患者被遗传学诊断为KD，并总结其遗传学和临床特征。在GALC中鉴定出11种变异，包括一种新的错义变异c.1019C>T (p.P340L)，该变异未在人类基因突变数据库（HGMD）中报道。与大多数典型表现为痉挛性截瘫的成年患者不同，携带该变异的患者表现为周围神经病变的初始症状。功能实验表明，该变异导致蛋白质加工和定位受损，并降低GALC酶活性。其他变异包括p.D56H、p.L377X、p.L441X和p.L634S也不同程度地影响GALC功能。结论：本研究增强了KD在中国的基因型和表型特征，有助于鉴别诊断和遗传咨询。功能数据强化了已鉴定变异的致病性。

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引用次数: 0

Sevoflurane Exposure Exacerbates Memory Impairment and Pathological Manifestation by Inhibiting AKT/mTOR-Mediated Autophagy in P301L Tau Transgenic Mice 七氟醚暴露通过抑制AKT/ mtor介导的自噬加剧P301L Tau转基因小鼠的记忆损伤和病理表现

IF 5 1区医学 Q1 NEUROSCIENCES

CNS Neuroscience & Therapeutics

Pub Date : 2025-12-17 DOI: 10.1002/cns.70694

Kaiwu He, Zhijing Zhang, Youzhi Li, Wei Xiong, Yanmei Xing, Wenli Gao, Wei Kong, Lixin Chen, Xifei Yang, Zhongliang Dai

Background

Alzheimer's disease (AD) is a global health event with progressive cognitive decline affecting millions of elderly people worldwide. Emerging evidence indicates that sevoflurane may be associated with AD progression. However, the underlying mechanism remains poorly understood. Herein, we explored the potential role of sevoflurane exposure in cognitive ability and the possible mechanisms of action in the early stage of Tg4510 (P301L tau) transgenic mice.

Methods

Using the novel object recognition test and Y-maze test, we assessed the change in cognitive abilities in 3-month-old male WT mice and Tg4510 mice with or without 3% sevoflurane exposure. By histological analysis and western blot, we determined the effect of sevoflurane exposure on tau pathology, synaptic function, and neuroinflammatory response. TMT-labeled proteomics technique coupled with bioinformatics analysis was performed to identify the potential key pathways or proteins involved in sevoflurane-induced cognitive deterioration.

Results

Behavioral test showed that sevoflurane exposure exacerbated cognitive impairment of young Tg4510 mice. Pathologically, immunofluorescence demonstrated that sevoflurane exposure increased tau phosphorylation, synaptic defects, and neuroinflammatory response, which were further supported by the result of immunoblotting in Tg4510 mice exposed to sevoflurane. Proteomic analysis revealed an obvious decrease in autophagy-related proteins including Sort1, Vps28, and Atg3 in the hippocampus of sevoflurane-exposed Tg4510 mice compared to the nonexposed group. As an upstream signaling of autophagy, the AKT/mTOR pathway was found to be inhibited in sevoflurane-exposed Tg4510 mice. Moreover, our data also validated an inhibition of autophagy signaling associated with sevoflurane exposure in the context of tau pathology, as indicated by the upregulated expression of p62 and the downregulated expression of Sort1, Vps28, and Atg3.

Conclusion

These findings suggest that autophagy signaling appears to be a promising target for intervention in sevoflurane-induced cognitive impairment in the early tau pathology, which lays the foundation for further study of the underlying mechanisms.

背景：阿尔茨海默病（AD）是一种全球性的健康事件，其进行性认知能力下降影响着全世界数百万老年人。新出现的证据表明，七氟醚可能与AD的进展有关。然而，其潜在的机制仍然知之甚少。本研究探讨了七氟醚暴露对Tg4510 （P301L tau）转基因小鼠早期认知能力的潜在作用及其可能的作用机制。方法：采用新颖的物体识别测试和y -迷宫测试，评估3月龄雄性WT小鼠和Tg4510小鼠在3%七氟醚暴露和不暴露条件下认知能力的变化。通过组织学分析和western blot，我们确定了七氟醚暴露对tau病理、突触功能和神经炎症反应的影响。tmt标记的蛋白质组学技术结合生物信息学分析，确定了七氟醚诱导认知衰退的潜在关键途径或蛋白质。结果：行为学测试显示，七氟醚暴露加重了幼年Tg4510小鼠的认知障碍。病理学上，免疫荧光显示七氟醚暴露增加了tau磷酸化，突触缺陷和神经炎症反应，免疫印迹结果进一步支持了七氟醚暴露的Tg4510小鼠。蛋白质组学分析显示，与未暴露组相比，七氟醚暴露的Tg4510小鼠海马中自噬相关蛋白Sort1、Vps28和Atg3明显减少。作为自噬的上游信号通路，AKT/mTOR通路在七氟醚暴露的Tg4510小鼠中被抑制。此外，我们的数据还证实了tau病理背景下七氟醚暴露相关的自噬信号的抑制，如p62表达上调和Sort1、Vps28和Atg3表达下调所示。结论：这些发现提示自噬信号可能是干预七氟醚诱导的早期tau病理认知障碍的一个有希望的靶点，为进一步研究其潜在机制奠定了基础。

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引用次数: 0

Trimethylamine N-Oxide Linking Gut Microbiota to Cardiocerebral Disease Is a Novel Biomarker for Stroke Subtypes With Mixed Etiology: A Prospective Cohort Study 三甲胺n -氧化物将肠道微生物群与心脑疾病联系起来是一种新的生物标志物，可用于混合病因的脑卒中亚型：一项前瞻性队列研究

IF 5 1区医学 Q1 NEUROSCIENCES

CNS Neuroscience & Therapeutics

Pub Date : 2025-12-15 DOI: 10.1002/cns.70704

Yukun Wang, Yeju Hu, Ruoyu Qin, Wei Li, Chu Zhou, Rongrong Liu, Qiyang Yuan, Ruicheng Zhang, Guiyun Cui, Shiguang Zhu

Background

The pathogenesis of ischemic stroke is multifaceted, and growing evidence highlights that mixed etiologies should be considered. This prospective cohort study investigated the relationship between plasma levels of trimethylamine N-oxide (TMAO), a cardiovascular disease risk factor, and etiologic stroke subtypes.

Methods

Plasma TMAO levels were compared in 223 patients, including 95, 73, and 55 patients with large artery atherosclerosis (LAA), cardioembolism (CE), and cardioembolism with culprit artery stenosis (CES), respectively, admitted with acute ischemic stroke complicated by large vessel occlusion and treated with endovascular therapy. At-admission clinical data and blood samples obtained during intervention were collected.

Results

After adjusting for covariates, including age, sex, hypertension, diabetes mellitus, estimated glomerular filtration rate(eGFR), smoking, and alcohol consumption, plasma TMAO levels were highest in the CES group (1.583 μmol/L), followed by the LAA and CE groups (1.064 and 0.583 μmol/L, respectively), with significant differences among the three groups detected (Wald χ² = 22.877, p < 0.001). By binary logistic regression analysis after adjusting for the same covariates, plasma TMAO level was an independent predictor for distinguishing the CES subtype from the CE subtype (95% CI, 2.062–8.183; p < 0.001), with an area under the curve of 0.778.

Conclusion

Plasma TMAO levels, which were highest in patients with stroke due to CES, followed by those with stroke due to LAA and CE, may serve as an independent predictor for distinguishing CE from CES as the stroke etiology.

背景：缺血性脑卒中的发病机制是多方面的，越来越多的证据表明，应考虑混合病因。这项前瞻性队列研究调查了血浆三甲胺n -氧化物（TMAO）水平（一种心血管疾病危险因素）与病因性卒中亚型之间的关系。方法：对223例急性缺血性脑卒中合并大血管闭塞并行血管内治疗的大动脉粥样硬化（LAA）、心脏栓塞（CE）、心脏栓塞合并罪魁动脉狭窄（CES）患者（分别为95例、73例和55例）的血浆TMAO水平进行比较。收集入院时的临床资料和干预期间获得的血液样本。结果：经年龄、性别、高血压、糖尿病、估计肾小球滤过率（eGFR）、吸烟、饮酒等协变量校正后，血浆TMAO水平以CES组最高（1.583 μmol/L），其次为LAA组（1.064 μmol/L）， CE组（0.583 μmol/L），三组间差异有统计学意义（Wald χ2 = 22.877, p）。血浆TMAO水平在CE引起的卒中患者中最高，其次是LAA和CE引起的卒中，这可能是区分CE和CE作为卒中病因的独立预测因子。

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引用次数: 0

Transient Receptor Potential Channels as Key Regulators of Neuroinflammation in Neurological Disorders: Mechanistic Insights, Therapeutic Potentials, and Future Directions 瞬时受体电位通道作为神经系统疾病中神经炎症的关键调节因子：机制见解，治疗潜力和未来方向。

IF 5 1区医学 Q1 NEUROSCIENCES

CNS Neuroscience & Therapeutics

Pub Date : 2025-12-15 DOI: 10.1002/cns.70700

Daji Guo, Mengjiao Cai, Yanmin Xian, Yinyin Chen, Yujun Feng, Chun Hu, Lizhang Zeng, Lei Shi, Shiqing Zhang

Background

Transient receptor potential (TRP) ion channels, a ubiquitous family of nonselective cation channels, are extensively expressed across the nervous system, immune system, and peripheral tissues. These channels serve as critical sensors for detecting temperature, mechanical forces, and chemical stimuli, thereby regulating numerous physiological and pathological processes. Over the past decade, their pivotal role in neuroimmune crosstalk and inflammatory signaling has emerged as a key focus within neuroscience research.

Methods

A comprehensive literature review was conducted in PubMed using key terms “TRP channel,” “neuroinflammation,” and each of the following neurological disorders: neuropathic pain, migraine, stroke, multiple sclerosis (MS), Alzheimer's disease (AD), Parkinson's disease (PD), autism spectrum disorder (ASD), epilepsy, and psychiatric disorders.

Results

This review synthesizes the current evidence to elucidate the dual-edged contributions of TRP channels as mediators of inflammation in neuropathic pain, migraine, stroke, MS, AD, PD, ASD, epilepsy, and psychiatric disorders. Furthermore, we also evaluate emerging therapeutic strategies targeting TRP channels, encompassing both nonpharmacological approaches and pharmacological interventions.

Conclusions

By integrating mechanistic insights with translational perspectives, this review highlights TRP channels as promising targets for precision medicine and underscores their potential in the development of novel, mechanism-based therapies for complex neurological disorders, thereby advancing a new era of targeted neuroimmunomodulation.

背景：瞬时受体电位（TRP）离子通道是一类普遍存在的非选择性阳离子通道，在神经系统、免疫系统和外周组织中广泛表达。这些通道是检测温度、机械力和化学刺激的关键传感器，从而调节许多生理和病理过程。在过去的十年中，它们在神经免疫串扰和炎症信号传导中的关键作用已成为神经科学研究的重点。方法：在PubMed上使用关键词“TRP通道”、“神经炎症”和以下神经系统疾病进行全面的文献综述：神经性疼痛、偏头痛、中风、多发性硬化症（MS）、阿尔茨海默病（AD）、帕金森病（PD）、自闭症谱系障碍（ASD）、癫痫和精神疾病。结果：本综述综合了目前的证据，阐明了TRP通道作为炎症介质在神经性疼痛、偏头痛、中风、MS、AD、PD、ASD、癫痫和精神疾病中的双重作用。此外，我们还评估了针对TRP通道的新兴治疗策略，包括非药物方法和药物干预。结论：通过将机制见解与翻译观点相结合，本综述强调了TRP通道作为精准医学的有希望的靶点，并强调了它们在开发复杂神经疾病的新型、基于机制的治疗方法方面的潜力，从而推进了靶向神经免疫调节的新时代。

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引用次数: 0

The Blood–Brain Barrier as an Integration Hub in Alzheimer's Disease: How Microbiota Metabolites Modulate Central Signal Processing 血脑屏障作为阿尔茨海默病的整合中心：微生物代谢产物如何调节中枢信号处理。

IF 5 1区医学 Q1 NEUROSCIENCES

CNS Neuroscience & Therapeutics

Pub Date : 2025-12-14 DOI: 10.1002/cns.70703

O. Giangiulio, R. Maccarone

Background

While both gut–brain axis dysfunction and blood–brain barrier (BBB) breakdown are documented in Alzheimer's disease (AD), current research treats these as separate phenomena. However, emerging evidence suggests that the BBB may function as an active integration interface that processes microbiota-derived metabolites and thereby potentially modulates how peripheral signals influence cognitive health.

Objective

This review synthesizes current evidence on microbiota metabolites as modulators of BBB integration capacity, discussing how such mechanisms may contribute to variability in cognitive outcomes despite similar gut microbiome profiles by demonstrating how BBB signal-integration mechanisms determine gut–brain communication effectiveness in AD.

Methods

We analyzed peer-reviewed literature from 2010 to 2025, focusing on BBB dynamic properties, microbiota metabolite effects on BBB function, and their integration patterns, emphasizing functional evidence supporting the BBB's active signal processing capabilities.

Results

Current evidence suggests that the BBB exhibits integration properties, including dynamic permeability regulation, context-dependent metabolite processing, and coordinated responses to complex signal streams. Short-chain fatty acids enhance integration capacity through HDAC inhibition and coordinated receptor activation, while lipopolysaccharides and trimethylamine N-oxide may overwhelm integration processes through TLR4-mediated disruption. BBB dysfunction precedes classical AD pathology and correlates with altered metabolite processing capacity. Individual variations in BBB integration capacity may help account for why individuals with similar gut microbiome profiles show different cognitive outcomes.

Conclusion

Viewing the BBB as an active integration interface offers a useful perspective for organizing current evidence on gut–brain interactions in AD. This conceptual perspective suggests that therapeutic strategies might benefit from supporting BBB integration capacity and optimizing metabolite-processing mechanisms alongside improving gut health.

背景：虽然在阿尔茨海默病（AD）中记录了肠-脑轴功能障碍和血脑屏障（BBB）破坏，但目前的研究将它们视为单独的现象。然而，新出现的证据表明，血脑屏障可能作为一个积极的整合界面，处理微生物衍生的代谢物，从而潜在地调节外周信号如何影响认知健康。目的：本综述综合了微生物代谢物作为血脑屏障整合能力调节剂的现有证据，通过展示血脑屏障信号整合机制如何决定AD患者肠-脑通讯有效性，讨论了尽管肠道微生物群特征相似，但这种机制如何导致认知结果的变变性。方法：我们分析了2010年至2025年的同行评审文献，重点关注血脑屏障的动态特性、微生物代谢产物对血脑屏障功能的影响及其整合模式，强调支持血脑屏障主动信号处理能力的功能证据。结果：目前的证据表明，血脑屏障具有整合特性，包括动态渗透性调节、环境依赖性代谢物处理和对复杂信号流的协调响应。短链脂肪酸通过抑制HDAC和协调受体激活来增强整合能力，而脂多糖和三甲胺n -氧化物可能通过tlr4介导的破坏来压倒整合过程。血脑屏障功能障碍先于经典AD病理，并与代谢产物处理能力的改变相关。血脑屏障整合能力的个体差异可能有助于解释为什么具有相似肠道微生物群特征的个体表现出不同的认知结果。结论：将血脑屏障视为一个活跃的整合接口，为整理AD中肠-脑相互作用的现有证据提供了有用的视角。这一概念观点表明，治疗策略可能受益于支持血脑屏障整合能力和优化代谢物处理机制，同时改善肠道健康。

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引用次数: 0

Development and Validation of Multiple Machine Learning Models Integrating Neutrophil-Lymphocyte Ratio for Prediction of Hemorrhagic Transformation After Intravenous Thrombolysis in Acute Ischemic Stroke 利用中性粒细胞-淋巴细胞比值预测急性缺血性卒中静脉溶栓后出血转化的多机器学习模型的开发与验证。

IF 5 1区医学 Q1 NEUROSCIENCES

CNS Neuroscience & Therapeutics

Pub Date : 2025-12-12 DOI: 10.1111/cns.70667

Fanhai Bu, Runlu Cai, Ying Hu, Xiaohong Tang, Wei Zhang, Xinxin Yang

Background

Hemorrhagic transformation (HT) is a critical complication of intravenous thrombolysis (IVT) in acute ischemic stroke (AIS). This study developed and validated machine learning (ML) models integrating inflammatory biomarkers with clinical indicators to predict post-IVT HT.

Methods

In 1272 IVT-treated AIS patients, the least absolute shrinkage and selection operator (LASSO) regression identified five predictors from 17 variables, which were subsequently utilized to construct eight ML models. The models were trained (70% data) and tested (30% data). Furthermore, external validation conducted on an independent cohort substantiated the generalizability of the optimal model. The SHapley Additive exPlanations (SHAP) method explained feature importance.

Results

LASSO screened five significant predictors: the neutrophil-to-lymphocyte ratio (NLR), admission National Institutes of Health Stroke Scale (NIHSS) score, the Alberta Stroke Program Early CT Score (ASPECTS), blood glucose, and atrial fibrillation. Logistic regression (LR) achieved optimal performance with an AUC of 0.833 internally and 0.842 externally. SHAP analysis prioritized NIHSS as the top contributor, while the nomogram elucidated the variability in HT risk.

Conclusion

Integrating NLR with stroke severity and neuroimaging biomarkers enhances the accuracy of HT predictions. The LR-based nomogram provided a practical tool for personalized IVT decisions, emphasizing the prognostic value of systemic inflammation in AIS management.

背景：出血性转化（HT）是急性缺血性卒中（AIS）静脉溶栓（IVT）的一个重要并发症。本研究开发并验证了整合炎症生物标志物和临床指标的机器学习（ML）模型，以预测ivt后的HT。方法：在1272例ivt治疗的AIS患者中，最小绝对收缩和选择算子（LASSO）回归从17个变量中识别出5个预测因子，随后用于构建8个ML模型。对模型进行训练（70%数据）和测试（30%数据）。此外，在独立队列上进行的外部验证证实了最优模型的泛化性。SHapley加性解释（SHAP）方法解释了特征的重要性。结果：LASSO筛选了五个重要的预测指标：中性粒细胞与淋巴细胞比率（NLR）、入院时美国国立卫生研究院卒中量表（NIHSS）评分、阿尔伯塔卒中计划早期CT评分（ASPECTS）、血糖和心房颤动。Logistic回归（LR）达到最佳效果，内部AUC为0.833，外部AUC为0.842。SHAP分析优先考虑NIHSS是最大的贡献者，而nomogram则阐明了HT风险的变异性。结论：将NLR与脑卒中严重程度和神经影像学生物标志物相结合可提高HT预测的准确性。基于lr的nomographic为个性化IVT决策提供了实用工具，强调了系统性炎症在AIS管理中的预后价值。

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引用次数: 0

Activation and Long-Term Maintenance of Adaptive Immunity in the Central Nervous System: A Double-Edged Sword? 中枢神经系统适应性免疫的激活和长期维持：一把双刃剑？

IF 5 1区医学 Q1 NEUROSCIENCES

CNS Neuroscience & Therapeutics

Pub Date : 2025-12-12 DOI: 10.1002/cns.70697

Luojinyun Wang, Feng Zhang, Jiehong Wu, Sibo Yang, Daqiang Zhou, Xiaodi Sun, Bohao Chang, Bo Hu, Yifan Zhou

Background

For a long time, the brain was considered an organ with “immune privilege”, where microglial cells played a phagocytic role, maintaining immune self-sufficiency. However, recent studies have revealed the presence of immune-related structures and immune cell infiltration in the brain, which participates in adaptive immunity.

Aim of Review

This review aims to synthesize recent findings on the activation and long-term maintenance of adaptive immunity in the central nervous system (CNS), exploring how adaptive immune responses function in pathogen clearance, tumor defense, and CNS inflammation. It highlights both the protective and detrimental roles of adaptive immunity in these contexts.

Key Scientific Concepts

Antigen-presenting cells (APCs) present antigen information to naive T cells, initiating adaptive immunity in the CNS. Activated T cells can differentiate into effector T cells to perform immediate immune functions or into tissue-resident memory T cells (TRMs) that persist in the CNS, providing long-term immune surveillance. Over the past 15 years, studies have shown that adaptive immunity is activated and maintained during intracranial pathogen infections, brain tumors, and CNS inflammation. While adaptive immunity can clear pathogens, eliminate tumor cells, and protect the brain, it can also lead to CNS inflammation under certain conditions, resulting in undesirable outcomes.

背景：长期以来，大脑被认为是具有“免疫特权”的器官，其中小胶质细胞发挥吞噬作用，维持免疫自给自足。然而，最近的研究表明，大脑中存在免疫相关结构和免疫细胞浸润，参与适应性免疫。综述目的：本文综述了近年来在中枢神经系统（CNS）适应性免疫的激活和长期维持方面的研究进展，探讨了适应性免疫反应在病原体清除、肿瘤防御和中枢神经系统炎症中的作用。它强调了适应性免疫在这些情况下的保护和有害作用。关键科学概念：抗原呈递细胞（APCs）向幼稚T细胞呈递抗原信息，启动中枢神经系统的适应性免疫。激活的T细胞可以分化为效应T细胞，执行即时免疫功能，也可以分化为组织驻留记忆T细胞（TRMs），持续存在于中枢神经系统中，提供长期免疫监视。在过去的15年里，研究表明适应性免疫在颅内病原体感染、脑肿瘤和中枢神经系统炎症期间被激活和维持。虽然适应性免疫可以清除病原体，消除肿瘤细胞，保护大脑，但在某些情况下，它也会导致中枢神经系统炎症，导致不良后果。

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引用次数: 0

Mechanism of Hypoxia-Induced HMGB1 Regulating NLRP3 Inflammasome/Caspase-1 Pathway-Mediated Pyroptosis in Myocardial Ischemia Reperfusion Injury Through the Nrf2/HO-1 Pathway 缺氧诱导HMGB1通过Nrf2/HO-1途径调控NLRP3炎性体/Caspase-1途径介导的心肌缺血再灌注损伤中的焦亡机制

IF 5 1区医学 Q1 NEUROSCIENCES

CNS Neuroscience & Therapeutics

Pub Date : 2025-12-11 DOI: 10.1111/cns.70661

Fuzhen Zheng, Licheng Yan, Fei Ren, Wenlong Cai, Yongrong Lan, Hong Chen, Qian Chen, Guoxing Weng

Objective

Myocardial ischemia–reperfusion injury (MIRI) represents an inevitable risk event for acute myocardial infarction. We explored the mechanism of hypoxia-induced high-mobility group box 1 (HMGB1) promoting MIRI by modulating the NLRP3 inflammasome/Caspase-1 pathway-mediated pyroptosis via the Nrf2/HO-1 pathway.

Methods

In vitro cultured mouse cardiomyocytes were exposed to hypoxia/reoxygenation (H/R) to establish an MIRI cell model, then treated with short hairpin-HMGB1, a NLRP3 agonist (Nigericin), and a Nrf2 inhibitor (ML385). Cell viability and injury were assessed via MTT and LDH assays. HMGB1 (nuclear/cytoplasm), Nrf2 (nuclear/cytoplasm), HO-1, NLRP3, ASC, cleaved Caspase-1, and GSDMD-N protein levels, and IL-1β and IL-18 levels in cell supernatants were determined by western blot and ELISA. HMGB1 and Nrf2 distribution were analyzed by immunofluorescence, with their interaction verified by co-immunoprecipitation. An MIRI mouse model was developed and treated with HMGB1 Box A for in vivo verification.

Results

H/R induction declined the nuclear HMGB1 protein level and cell viability, and intensified the cytoplasmic HMGB1 protein level, cell damage, and pyroptosis-related protein and inflammatory cytokine levels, which were averted by HMGB1 knockdown. NLRP3 activation partially reversed HMGB1 knockdown's effect on improving cardiomyocyte pyroptosis. Hypoxia-induced HMGB1 inhibited Nrf2/HO-1 activation by interacting with Nrf2. Nrf2/HO-1 suppression partly counteracted HMGB1 knockdown's suppressive effects on NLRP3 inflammasome activation and pyroptosis. HMGB1 suppressed the Nrf2/HO-1 axis to enhance NLRP3 inflammasome/Caspase-1 pathway-mediated pyroptosis, thereby exacerbating MIRI in vivo.

Conclusion

Hypoxia induces HMGB1's nucleus-to-cytoplasm translocation, which binds to Nrf2 to repress Nrf2 nuclear translocation to suppress Nrf2/HO-1 activation to promote NLRP3 inflammasome/Caspase-1-mediated pyroptosis, thereby exacerbating MIRI.

目的：心肌缺血再灌注损伤（MIRI）是急性心肌梗死不可避免的危险事件。我们通过Nrf2/HO-1通路调节NLRP3炎性体/Caspase-1通路介导的焦亡，探讨缺氧诱导的高迁移率组盒1 （HMGB1）促进MIRI的机制。方法：体外培养的小鼠心肌细胞缺氧/再氧化（H/R）建立MIRI细胞模型，然后用短发夹- hmgb1、NLRP3激动剂（Nigericin）和Nrf2抑制剂（ML385）处理。通过MTT和LDH测定细胞活力和损伤程度。western blot和ELISA法检测细胞上清液中HMGB1（核/胞质）、Nrf2（核/胞质）、HO-1、NLRP3、ASC、cleaved Caspase-1、GSDMD-N蛋白水平和IL-1β、IL-18水平。通过免疫荧光分析HMGB1和Nrf2的分布，并通过共免疫沉淀验证它们的相互作用。建立MIRI小鼠模型，用HMGB1 Box A处理进行体内验证。结果：H/R诱导使细胞核HMGB1蛋白水平下降，细胞活力下降，胞质HMGB1蛋白水平升高，细胞损伤、热释相关蛋白和炎症因子水平升高，而这些均可通过HMGB1敲除而避免。NLRP3激活部分逆转HMGB1敲低对心肌细胞焦亡的改善作用。缺氧诱导的HMGB1通过与Nrf2相互作用抑制Nrf2/HO-1的激活。Nrf2/HO-1抑制部分抵消了HMGB1敲低对NLRP3炎性小体激活和焦亡的抑制作用。HMGB1抑制Nrf2/HO-1轴，增强NLRP3炎性体/Caspase-1途径介导的焦亡，从而在体内加重MIRI。结论：缺氧诱导HMGB1核-胞质易位，与Nrf2结合抑制Nrf2核易位，抑制Nrf2/HO-1活化，促进NLRP3炎性小体/ caspase -1介导的焦亡，从而加重MIRI。

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引用次数: 0

Dl-3-n-Butylphthalide Promotes Cortical Angiogenesis via Akt/GSK-3β Signaling in Ischemic Stroke Mice dl -3-n-丁苯酞通过Akt/GSK-3β信号通路促进缺血性脑卒中小鼠皮质血管生成

IF 5 1区医学 Q1 NEUROSCIENCES

CNS Neuroscience & Therapeutics

Pub Date : 2025-12-10 DOI: 10.1002/cns.70698

Lan Zhang, Shanshan Wei, Jian Zhang, Rong Chen, Jiangyong Miao, Lina Wang, Peipei Zhang, Wenyan Shang, Renhao Xu, Xiangjian Zhang, Cong Zhang

Aims

Dl-3-n-butylphthalide (NBP) is a novel agent for acute ischemic stroke. This study aimed to investigate its effects on cortical angiogenesis and vasodilation during stroke recovery.

Methods

Mice underwent distal middle cerebral artery occlusion (dMCAO) and subsequently received NBP treatment. Therapeutic efficacy was measured by neurological deficits and infarct size. Angiogenesis was assessed by immunofluorescent staining. Laser speckle and two-photon microscopy imaging were employed to evaluate dynamic changes in cortical cerebral blood flow and vascular structure in vivo. The modulation of the Akt/GSK-3β signaling pathway was detected by western blotting.

Results

NBP administration promoted neurological recovery and reduced infarct size in the subacute phase. It facilitated cerebral blood flow and vasodilation, enhanced angiogenesis as evidenced by increased BrdU⁺/CD31⁺ cells and improved astrocyte/pericyte coverage around microvessels. Moreover, the pro-angiogenesis effect of NBP depends on the activation of the Akt/GSK-3β pathway, and this effect is blocked by LY294002.

Conclusion

In conclusion, NBP enhances recovery after ischemic stroke by promoting cortical angiogenesis and vasodilation through activation of the Akt/GSK-3β pathway. These findings highlight its therapeutic potential for delayed intervention in ischemic stroke.

目的：dl -3-正丁苯酞（NBP）是一种治疗急性缺血性脑卒中的新型药物。本研究旨在探讨其对脑卒中恢复期皮质血管生成和血管舒张的影响。方法：小鼠大脑中远端动脉闭塞（dMCAO）后给予NBP治疗。治疗效果通过神经功能缺损和梗死面积来衡量。免疫荧光染色评价血管生成。采用激光散斑成像和双光子显微成像技术观察脑皮质血流和血管结构的动态变化。western blotting检测Akt/GSK-3β信号通路的调节。结果：NBP可促进亚急性期神经功能恢复，减少梗死面积。它促进脑血流和血管舒张，促进血管生成，BrdU+/CD31+细胞增加，微血管周围星形胶质细胞/周细胞覆盖率提高。此外，NBP的促血管生成作用依赖于Akt/GSK-3β通路的激活，而这一作用被LY294002阻断。结论：NBP通过激活Akt/GSK-3β通路促进皮质血管生成和血管舒张，从而促进缺血性脑卒中后的恢复。这些发现突出了其在缺血性卒中延迟干预治疗中的潜力。

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引用次数: 0