CNS Neuroscience & Therapeutics最新文献

Lycium barbarum Extract Enhanced Neuroplasticity and Functional Recovery in 5xFAD Mice via Modulating Microglial Status of the Central Nervous System 枸杞提取物通过调节中枢神经系统的小胶质细胞状态增强 5xFAD 小鼠的神经可塑性和功能恢复能力

IF 4.8 1区医学 Q1 NEUROSCIENCES

CNS Neuroscience & Therapeutics

Pub Date : 2024-11-20 DOI: 10.1111/cns.70123

Zhongqing Sun, Jinfeng Liu, Zihang Chen, Kwok-Fai So, Yong Hu, Kin Chiu

Objective

Alzheimer's disease (AD) is the most prevalent neurodegenerative disease with limited treatment options. This study aimed to investigate the effects of Lycium barbarum extract (LBE), a Chinese herb, on the central nervous system (CNS)—including the retina, brain, and spinal cord—in 5xFAD transgenic mice after the onset of AD.

Methods

Starting at 6 months of age, 5xFAD mice received daily intragastric gavage of LBE (2 g/kg) for 2 months. At 8 months, behavioral tests were conducted to assess cognition, motor function, and visual function. These included the Morris water maze, novel object recognition, and Y-maze tests for cognition; the beam walking balance and clasping tests for motor function; and electroretinogram (ERG) for visual function. Immunohistochemistry, western blotting, and ELISA were used to evaluate Aβ deposition, microglial morphology, neuroinflammation, and neuroprotective signaling pathways. Primary microglia and the IMG cell line were used to study LBE's effects on Aβ uptake and degradation in vitro.

Results

After 2 months of LBE treatment, the decline in cognition, motor, and visual functions in 5xFAD mice was significantly slowed. Microglia in the brain, spinal cord, and retina exhibited a neuroprotective state, with reduced Aβ deposition, decreased inflammatory cytokine levels (e.g., TNF-α, IL-1β, IL-6), increased Arg-1/iNOS ratio, and enhanced phagocytic capacity. LBE also promoted Aβ uptake and degradation in primary microglia and the IMG cell line. Neuroprotective signals such as p-Akt, p-Erk1/2, and p-CREB were elevated. Additionally, LBE treatment restored synaptic protein expression and enhanced neuroplasticity.

Conclusion

The findings suggest that LBE treatment can enhance neuroplasticity, reduce systemic inflammation, and improve phagocyte clearance of Aβ deposition via inducing a neuroprotective microglial phenotype throughout CNS. As an upper-class Chinese medicine, appropriate intake of LBE may serve as a beneficial antiaging strategy for AD.

目的阿尔茨海默病（Alzheimer's disease，AD）是最普遍的神经退行性疾病，但治疗方法有限。本研究旨在探讨中草药枸杞提取物（LBE）对 5xFAD 转基因小鼠中枢神经系统（CNS）（包括视网膜、大脑和脊髓）的影响。方法从 5xFAD 小鼠 6 个月大开始，每天灌胃 2 克/千克的 LBE，持续 2 个月。8个月大时，进行行为测试以评估认知、运动功能和视觉功能。这些测试包括针对认知的莫里斯水迷宫、新物体识别和Y迷宫测试；针对运动功能的横梁行走平衡和紧握测试；以及针对视觉功能的视网膜电图（ERG）。免疫组化、Western 印迹和 ELISA 被用来评估 Aβ 沉积、小胶质细胞形态、神经炎症和神经保护信号通路。原代小胶质细胞和 IMG 细胞系被用来研究 LBE 对体外 Aβ 吸收和降解的影响。结果 LBE 治疗 2 个月后，5xFAD 小鼠认知、运动和视觉功能的下降明显减缓。大脑、脊髓和视网膜中的小胶质细胞表现出神经保护状态，Aβ沉积减少，炎性细胞因子水平（如 TNF-α、IL-1β、IL-6）降低，Arg-1/iNOS 比率增加，吞噬能力增强。LBE 还能促进原代小胶质细胞和 IMG 细胞系对 Aβ 的摄取和降解。神经保护信号（如 p-Akt、p-Erk1/2 和 p-CREB）升高。此外，LBE 治疗还能恢复突触蛋白表达并增强神经可塑性。结论 LBE 治疗可通过诱导中枢神经系统的神经保护性小胶质细胞表型，增强神经可塑性，减轻全身炎症反应，改善吞噬细胞对 Aβ 沉积的清除。作为一种上等中药，适当摄入枸杞子可作为一种有益的抗衰老策略，用于治疗AD。

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引用次数: 0

The Abnormal Proliferation of Midbrain Dopamine Cells From Human Pluripotent Stem Cells Is Induced by Exposure to the Tumor Microenvironment 肿瘤微环境诱导人多能干细胞中脑多巴胺细胞异常增殖

IF 4.8 1区医学 Q1 NEUROSCIENCES

CNS Neuroscience & Therapeutics

Pub Date : 2024-11-19 DOI: 10.1111/cns.70117

Jun Xue, Dongyan Wu, Yuting Bao, Yifan Wu, Xin Zhang, Liang Chen

Aims

Tumorigenicity is a significant concern in stem cell-based therapies. However, traditional tumorigenicity tests using animal models often produce inaccurate results. Consequently, a more sensitive method for assessing tumorigenicity is required. This study aimed to enhance sensitivity by exposing functional progenitors derived from human pluripotent stem cells (hPSCs) to the tumor microenvironment (TME) in vitro before transplantation, potentially making them more prone to abnormal proliferation or tumorigenicity.

Methods

Midbrain dopamine (mDA) cells derived from hPSCs were exposed to the TME by coculturing with medulloblastoma. The cellular characteristics of these cocultured mDA cells were evaluated both in vitro and in vivo, and the mechanisms underlying the observed alterations were investigated.

Results

Our findings demonstrated increased proliferation of cocultured mDA cells both in vitro and in vivo. Moreover, these proliferating cells showed a higher expression of Ki67 and SOX1, suggesting abnormal proliferation. The observed abnormal proliferation in cocultured mDA cells was attributed to the hyperactivation of proliferation-related genes, the JAK/STAT3 pathway, and cytokine stimulation.

Conclusion

This study indicates that exposing functional progenitors to the TME in vitro before transplantation can induce abnormal proliferation, thereby increasing the sensitivity of tumorigenicity tests.

目的致癌性是干细胞疗法的一个重要问题。然而，使用动物模型进行的传统致瘤性测试往往产生不准确的结果。因此，需要一种更灵敏的方法来评估致瘤性。本研究旨在通过在移植前将源自人类多能干细胞（hPSCs）的功能性祖细胞暴露于体外肿瘤微环境（TME），使其更容易异常增殖或致瘤，从而提高灵敏度。方法通过与髓母细胞瘤共培养，将源自 hPSCs 的中脑多巴胺（mDA）细胞暴露于肿瘤微环境。在体外和体内评估了这些共培养的 mDA 细胞的细胞特性，并研究了观察到的变化的机制。结果我们的研究结果表明，体外和体内共同培养的 mDA 细胞的增殖均有所增加。此外，这些增殖细胞的 Ki67 和 SOX1 表达量较高，表明增殖异常。在共培养的 mDA 细胞中观察到的异常增殖可归因于增殖相关基因、JAK/STAT3 通路和细胞因子刺激的过度激活。结论本研究表明，在移植前将功能性祖细胞暴露于体外 TME 可诱导异常增殖，从而提高致瘤性检测的敏感性。

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引用次数: 0

9-Methylfascaplysin Prevents Neuroinflammation and Synaptic Damage via Cell-Specific Inhibition of Kinases in APP/PS1 Transgenic Mice 9-甲基蛙皮素通过抑制细胞特异性激酶预防APP/PS1转基因小鼠的神经炎症和突触损伤

IF 4.8 1区医学 Q1 NEUROSCIENCES

CNS Neuroscience & Therapeutics

Pub Date : 2024-11-19 DOI: 10.1111/cns.70100

Jingyang Le, Chenglong Xia, Jiayi Xu, Jinhan Cai, Chenwei Hu, Yu Bai, Huiyue Chen, Wenni Rong, Yujie Jiang, Xinming Wu, Yongmei Li, Qiyao Wang, C. Benjamin Naman, Hua Wei, Jili Zhang, Hao Liu, Xiaowei Chen, Fufeng Liu, Hongze Liang, Wei Cui

Background

Alzheimer's disease (AD) is a leading neurodegenerative disorder without effective treatments. The nonlinear dynamic nature of AD pathophysiology suggested that multiple pharmacological actions of anti-AD drugs should be elucidated. 9-Methylfascaplysin (9-MF) was previously designed and synthesized as a novel anti-AD candidate.

Methods and Results

In this study, 9-MF at low concentrations significantly prevented cognitive impairments with similar efficacy as donepezil in APP/PS1 transgenic mice. In addition, 9-MF potently reduced β-amyloid (Aβ)-associated neuroinflammation and tau-associated synaptic damage in vivo. 9-MF-regulated microglia-specific differentially phosphorylated proteins (DPPs) were mainly enriched in neuroinflammation, while 9-MF-regulated neuron-specific DPPs were enriched in synaptic regulation, as revealed by a quantitative phosphoproteomic approach. A phosphoproteome-kinome algorithm further identified that rho-associated coiled-coil kinase 2 (ROCK2) and glycogen synthase kinase 3β (GSK3β) ranked high in 9-MF-downregulated kinase perturbations. 9-MF possessed high affinities for ROCK2 and GSK3β, which was confirmed by in vitro kinase activity assay. The protective effects of 9-MF were abolished by ROCK2 knockdown in Aβ-treated BV2 microglial cells, and by GSK3β knockdown in glyceraldehyde-treated SH-SY5Y neuronal cells, respectively.

Conclusions

All these results supported that 9-MF produced anti-AD effects via cell-specific inhibition of ROCK2 and GSK3β in microglia and neurons, respectively.

背景阿尔茨海默病（AD）是一种主要的神经退行性疾病，目前尚无有效的治疗方法。阿尔茨海默病病理生理学的非线性动态性质表明，应阐明抗阿尔茨海默病药物的多种药理作用。此前，研究人员设计并合成了 9-Methylfascaplysin (9-MF) 作为新型抗 AD 候选药物。方法与结果在这项研究中，低浓度的9-MF能显著预防APP/PS1转基因小鼠的认知障碍，其疗效与多奈哌齐相似。此外，9-MF 还能有效减少体内与 β 淀粉样蛋白（Aβ）相关的神经炎症和与 tau 相关的突触损伤。定量磷酸化蛋白组学方法显示，9-MF调控的小胶质细胞特异性差异磷酸化蛋白（DPPs）主要在神经炎症中富集，而9-MF调控的神经元特异性差异磷酸化蛋白则在突触调节中富集。磷蛋白组-激酶组算法进一步确定，在9-MF下调的激酶扰动中，rho相关盘绕线圈激酶2（ROCK2）和糖原合酶激酶3β（GSK3β）的作用较强。9-MF对ROCK2和GSK3β具有高亲和力，体外激酶活性测定证实了这一点。在 Aβ 处理的 BV2 小神经胶质细胞中敲除 ROCK2，以及在甘油醛处理的 SH-SY5Y 神经元细胞中敲除 GSK3β，9-MF 的保护作用均被取消。结论所有这些结果都证明，9-MF 通过抑制小胶质细胞和神经元中的 ROCK2 和 GSK3β，分别在细胞特异性上产生抗逆转录酶抑制作用。

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引用次数: 0

Selective Inhibition of P2Y1 and P2Y12 Receptor Signal Pathways in Platelet Aggregation in Transgenic Cell Lines and Rats by Potassium 2-(1-Hydroxypentyl)-Benzoate, Puerarin and Salvianolic Acid B 2-（1-羟基戊基）苯甲酸钾、葛根素和丹酚酸 B 对转基因细胞系和大鼠血小板聚集中 P2Y1 和 P2Y12 受体信号通路的选择性抑制作用

IF 4.8 1区医学 Q1 NEUROSCIENCES

CNS Neuroscience & Therapeutics

Pub Date : 2024-11-19 DOI: 10.1111/cns.70089

Yiying Li, Weiping Wang, Jie Cai, Nan Feng, Shaofeng Xu, Ling Wang, Xiaoliang Wang

Aim

Potassium 2-(1-hydroxypentyl)-benzoate (dl-PHPB), puerarin and salvianolic acid B are three natural products or derivatives that can inhibit platelet aggregation. However, the mechanisms of dl-PHPB, puerarin and salvianolic acid B to inhibit platelet aggregation are still not clear.

Method

Here, 2-methylthioadenosine diphosphate (2-MeSADP) was used as an inducer to confirm the effects of three drugs on platelet aggregation and illustrate the corresponding mechanisms.

Result

The results indicated that dl-PHPB, puerarin and salvianolic acid B significantly inhibited platelet aggregation both in vivo and in vitro. In addition, the content of IP₃, cAMP and intracellular [Ca²⁺]_i were measured in HEK293 cell lines overexpressing P2Y₁ and P2Y₁₂. Dl-PHPB and puerarin could obviously reduce 2-MeSADP-induced IP₃ increase, but salvianolic acid B showed no effects. Unlike dl-PHPB and puerarin, which had no effects on 2-MeSADP-induced cAMP decrease, salvianolic acid B significantly reversed the reduction of cAMP. Both dl-PHPB and puerarin could decrease the enhanced intracellular [Ca²⁺]_i induced by 2-MeSADP; however, salvianolic acid B showed no effect on intracellular [Ca²⁺]_i elevation.

Conclusion

These results suggested that dl-PHPB and puerarin inhibited platelet aggregation via targeting at P2Y₁ receptor and P2Y₁-Gq-IP₃-Ca²⁺ signal pathway. Differently, salvianolic acid B inhibited platelet aggregation via targeting at P2Y₁₂ receptor and via Gi-AC-cAMP signal pathway.

目的 2-（1-羟基戊基）-苯甲酸钾（dl-PHPB）、葛根素和丹酚酸 B 是三种能够抑制血小板聚集的天然产物或衍生物。然而，dl-PHPB、葛根素和丹酚酸B抑制血小板聚集的机制尚不清楚。方法以2-甲硫基腺苷二磷酸（2-MeSADP）为诱导剂，证实三种药物对血小板聚集的影响，并说明相应的机制。结果结果表明，dl-PHPB、葛根素和丹酚酸 B 均能显著抑制体内和体外血小板聚集。此外，在过表达 P2Y1 和 P2Y12 的 HEK293 细胞系中测量了 IP3、cAMP 和细胞内 [Ca2+]i 的含量。结果表明，Dl-PHPB 和葛根素能明显降低 2-MeSADP 诱导的 IP3 升高，但丹参酚酸 B 没有影响。dl-PHPB和葛根素对2-MeSADP诱导的cAMP减少没有影响，而丹参酚酸B却能显著逆转cAMP的减少。dl-PHPB和葛根素都能降低2-MeSADP诱导的细胞内[Ca2+]i的升高，但丹参酚酸B对细胞内[Ca2+]i的升高没有影响。结论这些结果表明，dl-PHPB 和葛根素通过靶向 P2Y1 受体和 P2Y1-Gq-IP3-Ca2+ 信号通路抑制血小板聚集。不同的是，丹酚酸 B 通过靶向 P2Y12 受体和 Gi-AC-cAMP 信号途径抑制血小板聚集。

{"title":"Selective Inhibition of P2Y1 and P2Y12 Receptor Signal Pathways in Platelet Aggregation in Transgenic Cell Lines and Rats by Potassium 2-(1-Hydroxypentyl)-Benzoate, Puerarin and Salvianolic Acid B","authors":"Yiying Li, Weiping Wang, Jie Cai, Nan Feng, Shaofeng Xu, Ling Wang, Xiaoliang Wang","doi":"10.1111/cns.70089","DOIUrl":"https://doi.org/10.1111/cns.70089","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Aim</h3>\u0000 \u0000 <p>Potassium 2-(1-hydroxypentyl)-benzoate (<i>dl</i>-PHPB), puerarin and salvianolic acid B are three natural products or derivatives that can inhibit platelet aggregation. However, the mechanisms of <i>dl</i>-PHPB, puerarin and salvianolic acid B to inhibit platelet aggregation are still not clear.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Method</h3>\u0000 \u0000 <p>Here, 2-methylthioadenosine diphosphate (2-MeSADP) was used as an inducer to confirm the effects of three drugs on platelet aggregation and illustrate the corresponding mechanisms.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Result</h3>\u0000 \u0000 <p>The results indicated that <i>dl</i>-PHPB, puerarin and salvianolic acid B significantly inhibited platelet aggregation both in vivo and in vitro. In addition, the content of IP<sub>3</sub>, cAMP and intracellular [Ca<sup>2+</sup>]<sub>i</sub> were measured in HEK293 cell lines overexpressing P2Y<sub>1</sub> and P2Y<sub>12</sub>. <i>Dl</i>-PHPB and puerarin could obviously reduce 2-MeSADP-induced IP<sub>3</sub> increase, but salvianolic acid B showed no effects. Unlike <i>dl</i>-PHPB and puerarin, which had no effects on 2-MeSADP-induced cAMP decrease, salvianolic acid B significantly reversed the reduction of cAMP. Both <i>dl</i>-PHPB and puerarin could decrease the enhanced intracellular [Ca<sup>2+</sup>]<sub>i</sub> induced by 2-MeSADP; however, salvianolic acid B showed no effect on intracellular [Ca<sup>2+</sup>]<sub>i</sub> elevation.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusion</h3>\u0000 \u0000 <p>These results suggested that <i>dl</i>-PHPB and puerarin inhibited platelet aggregation via targeting at P2Y<sub>1</sub> receptor and P2Y<sub>1</sub>-Gq-IP<sub>3</sub>-Ca<sup>2+</sup> signal pathway. Differently, salvianolic acid B inhibited platelet aggregation via targeting at P2Y<sub>12</sub> receptor and via Gi-AC-cAMP signal pathway.</p>\u0000 </section>\u0000 </div>","PeriodicalId":154,"journal":{"name":"CNS Neuroscience & Therapeutics","volume":"30 11","pages":""},"PeriodicalIF":4.8,"publicationDate":"2024-11-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/cns.70089","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142674093","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}

引用次数: 0

Olaparib Enhances the Efficacy of Third-Generation Oncolytic Adenoviruses Against Glioblastoma by Modulating DNA Damage Response and p66shc-Induced Apoptosis 奥拉帕利通过调节DNA损伤反应和p66shc诱导的细胞凋亡增强第三代肿瘤溶解性腺病毒对胶质母细胞瘤的疗效

IF 4.8 1区医学 Q1 NEUROSCIENCES

CNS Neuroscience & Therapeutics

Pub Date : 2024-11-18 DOI: 10.1111/cns.70124

Yida Liu, Sheng Fang, Peiwen Wang, Junwen Zhang, Fusheng Liu

Aims

Patients with glioblastoma multiforme (GBM) do not benefit from current cancer treatments, and their prognosis is dismal. This study aimed to investigate the potential synergistic effects of TS-2021, a third-generation oncolytic adenovirus, combined with the PARP inhibitor olaparib in GBM.

Methods

TS-2021’s impact on p66shc-induced apoptosis, DNA damage response, and poly (ADP-ribose) polymerase (PARP) activation was evaluated in GBM cells. The synergistic effect of TS-2021 and olaparib was examined in GBM cell lines and an immunocompetent mouse model of GBM. Mechanistic studies focused on the role of p66shc phosphorylation in the observed effects.

Results

TS-2021 triggered p66shc-induced apoptosis, DNA damage response, and PARP activation. The combination of TS-2021 and olaparib synergistically increased cell apoptosis and DNA damage and reduced PARP expression compared to monotherapy. Olaparib promoted TS-2021 replication and release in GBM cells. Mechanistically, olaparib combined with TS-2021 upregulated p66shc phosphorylation, enhancing tumor cell apoptosis. In vivo, the combination therapy inhibited tumor growth and prolonged survival, confirming the synergistic effect.

Conclusion

This study is the first to suggest that TS-2021 sensitizes GBM cells with wild-type BRCA1/2 to olaparib. The combination of TS-2021 and olaparib shows a synergistic therapeutic effect against GBM, providing a promising treatment strategy.

目的：多形性胶质母细胞瘤（GBM）患者无法从目前的癌症治疗中获益，其预后令人沮丧。本研究旨在探讨第三代溶瘤腺病毒TS-2021与PARP抑制剂奥拉帕利（olaparib）联合治疗GBM的潜在协同作用：方法：在GBM细胞中评估了TS-2021对p66shc诱导的细胞凋亡、DNA损伤反应和聚（ADP-核糖）聚合酶（PARP）激活的影响。在 GBM 细胞系和免疫功能正常的 GBM 小鼠模型中考察了 TS-2021 和奥拉帕利的协同作用。机理研究的重点是 p66shc 磷酸化在观察到的效应中的作用：结果：TS-2021可引发p66shc诱导的细胞凋亡、DNA损伤反应和PARP激活。与单药治疗相比，TS-2021 和奥拉帕利联合用药可协同增加细胞凋亡和 DNA 损伤，减少 PARP 表达。奥拉帕利促进了TS-2021在GBM细胞中的复制和释放。从机理上讲，奥拉帕利与 TS-2021 联用可上调 p66shc 磷酸化，从而增强肿瘤细胞凋亡。在体内，联合疗法抑制了肿瘤生长并延长了生存期，证实了其协同作用：本研究首次表明，TS-2021能使野生型BRCA1/2的GBM细胞对奥拉帕尼敏感。TS-2021和奥拉帕利的联合疗法对GBM具有协同治疗效果，是一种很有前景的治疗策略。

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引用次数: 0

Steroids' Neuroprotective Potential in Severe Cerebral Venous Thrombosis: Experimental and Clinical Exploration of NLRP3 Inflammasome Inhibition 类固醇在严重脑静脉血栓中的神经保护潜力：抑制 NLRP3 炎症球体的实验和临床探索。

IF 4.8 1区医学 Q1 NEUROSCIENCES

CNS Neuroscience & Therapeutics

Pub Date : 2024-11-17 DOI: 10.1111/cns.70125

Shuyuan Hu, Yaqin Gu, Limin Hou, Jia Liu, Haiping Zhao, Yumin Luo, Chunxiu Wang, Xunming Ji, Guiyou Liu, Jiangang Duan

Background

NLRP3 inflammasome-related inflammation might play an important role in the pathophysiology of severe CVT. The use of steroids as anti-inflammatory agents in improving severe CVT prognosis remains controversial.

Methods

A total of 94 male Sprague–Dawley rats were used. We evaluated the dynamic and association between NLRP3 inflammasome in brain, blood, and CSF and severity in severe CVT rats and/or patients. We also explored the effect of steroids on NLRP3 activation, neurological injury, and CSF circulation disturbance after CVT in animals and/or patients.

Results

In rats, compared with the sham group, NLRP3-related factors rose on day 1, peaked on day 2 (NLRP3, Sham: 0.79 ± 0.22; day 2: 1.25 ± 0.08, p < 0.01; pro-Caspase-1, Sham: 0.58 ± 0.13, day 2: 1.20 ± 0.44, p < 0.05; GSDMD, Sham: 0.94 ± 0.22, day 2: 1.72 ± 0.46, p < 0.05; pro-IL-1β, Sham: 0.74 ± 0.15, day 2: 1.35 ± 0.09, p < 0.01), decreased on day 7 in rats (n = 4 per group). Thrombus (Sham: 0.00 ± 0.00, day 2: 3.44 ± 0.70, p < 0.0001), infarct size (Sham: 0.00 ± 0.00, day 2: 11.99 ± 6.26, p < 0.01) and neurological deficits appeared similar trend. In 50 patients, serum NLRP3 and IL-6 levels correlated positively with NIHSS (r = 0.4273, p = 0.0020; r = 0.4938, p = 0.0029) and mRS (r = 0.5349, p = 0.0125; r = 0.6213, p = 0.026), while CSF IL-6 correlated positively with mRS on admission (r = 0.5349, p = 0.0125). Compared with baseline, NLRP3 (0.36 (0.36, 0.36) vs. 0.41 (0.37, 0.84), p < 0.0001) and IL-6 decreased (4.06 ± 1.48 vs. 12.03 ± 7.80, p < 0.05), accompanying by improvement of neurological deficits and CSF circulation (all p < 0.01) after steroids therapy in severe CVT patients at discharge and 3 months follow-up. No significant steroid-related adverse effects were observed.

Conclusion

Short-term steroid therapy may improve prognosis of severe CVT by suppressing NLRP3 inflammasome-related inflammation.

背景：NLRP3炎症体相关炎症可能在重症CVT的病理生理学中扮演重要角色。使用类固醇作为抗炎药物改善重度 CVT 预后仍存在争议：方法：共使用了 94 只雄性 Sprague-Dawley 大鼠。我们评估了严重 CVT 大鼠和/或患者大脑、血液和脑脊液中 NLRP3 炎性体的动态变化及其与严重程度之间的关联。我们还探讨了类固醇对动物和/或患者 CVT 后 NLRP3 活化、神经损伤和 CSF 循环障碍的影响：结果：与假组相比，大鼠的 NLRP3 相关因子在第 1 天升高，在第 2 天达到峰值（NLRP3，假组：0.79 ± 0.22；第 2 天：1.25 ± 0.08，p 结论：短期类固醇治疗可改善大鼠和/或患者的前体损伤：短期类固醇治疗可抑制 NLRP3 炎症相关炎症，从而改善重症 CVT 的预后。

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引用次数: 0

Endothelial Dysfunctions in Blood–Brain Barrier Breakdown in Alzheimer's Disease: From Mechanisms to Potential Therapies 阿尔茨海默病血脑屏障破裂的内皮功能障碍：从机制到潜在疗法。

IF 4.8 1区医学 Q1 NEUROSCIENCES

CNS Neuroscience & Therapeutics

Pub Date : 2024-11-15 DOI: 10.1111/cns.70079

Qian Yue, Xinyue Leng, Ningqing Xie, Zaijun Zhang, Deguang Yang, Maggie Pui Man Hoi

Recent research has shown the presence of blood–brain barrier (BBB) breakdown in Alzheimer's disease (AD). BBB is a dynamic interface consisting of a continuous monolayer of brain endothelial cells (BECs) enveloped by pericytes and astrocytes. The restricted permeability of BBB strictly controls the exchange of substances between blood and brain parenchyma, which is crucial for brain homeostasis by excluding blood-derived detrimental factors and pumping out brain-derived toxic molecules. BBB breakdown in AD is featured as a series of BEC pathologies such as increased paracellular permeability, abnormal levels and functions of transporters, and inflammatory or oxidative profile, which may disturb the substance transportation across BBB, thereafter induce CNS disorders such as hypometabolism, Aβ accumulation, and neuroinflammation, eventually aggravate cognitive decline. Therefore, it seems important to protect BEC properties for BBB maintenance and neuroprotection. In this review, we thoroughly summarized the pathological alterations of BEC properties reported in AD patients and numerous AD models, including paracellular permeability, influx and efflux transporters, and inflammatory and oxidative profiles, and probably associated underlying mechanisms. Then we reviewed current therapeutic agents that are effective in ameliorating a series of BEC pathologies, and ultimately protecting BBB integrity and cognitive functions. Regarding the current drug development for AD proceeds extremely hard, this review aims to discuss the therapeutic potentials of targeting BEC pathologies and BBB maintenance for AD treatment, therefore expecting to shed a light on the future AD drug development by targeting BEC pathologies and BBB protection.

最近的研究表明，阿尔茨海默病（AD）中存在血脑屏障（BBB）的破坏。血脑屏障是一个动态界面，由连续的单层脑内皮细胞（BEC）和包膜细胞及星形胶质细胞组成。BBB 的有限通透性严格控制着血液和脑实质之间的物质交换，通过排除血液中的有害因子和泵出脑源性毒性分子，对脑平衡至关重要。AD 中的 BBB 破坏表现为一系列 BEC 病变，如细胞旁通透性增加、转运体水平和功能异常、炎症或氧化特征等，这些病变可能会扰乱物质跨 BBB 转运，进而诱发代谢低下、Aβ 积累和神经炎症等中枢神经系统疾病，最终加重认知功能衰退。因此，保护 BEC 的特性对于维护 BBB 和保护神经似乎非常重要。在这篇综述中，我们全面总结了在 AD 患者和众多 AD 模型中报道的 BEC 特性的病理改变，包括细胞旁通透性、流入和流出转运体、炎症和氧化特征，以及可能相关的潜在机制。然后，我们回顾了目前能有效改善一系列 BEC 病理变化并最终保护 BBB 完整性和认知功能的治疗药物。鉴于目前治疗AD的药物开发进展极为缓慢，本综述旨在讨论针对BEC病理变化和BBB维护治疗AD的治疗潜力，从而为未来针对BEC病理变化和BBB保护的AD药物开发提供启示。

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引用次数: 0

Phospholipase D Family Member 4 Regulates Microglial Phagocytosis and Remyelination via the AKT Pathway in a Cuprizone-Induced Multiple Sclerosis Mouse Model 磷脂酶 D 家族成员 4 在铜绿素诱导的多发性硬化症小鼠模型中通过 AKT 通路调控小胶质细胞的吞噬作用和再髓鞘化作用

IF 4.8 1区医学 Q1 NEUROSCIENCES

CNS Neuroscience & Therapeutics

Pub Date : 2024-11-15 DOI: 10.1111/cns.70111

Ran Sun, Tengyun Ma, Zheng Zhao, Yan Gao, Juan Feng, Xue Yang

Aims

Remyelination is an endogenous repair process that is often deficient in multiple sclerosis (MS). Stimulation of remyelination is thought to help limit the progression of MS. This study aimed to investigate the expression pattern and function of a microglial phagocytosis-related gene, phospholipase D family member 4 (PLD4), in a cuprizone (CPZ)-induced MS mouse model.

Methods

The extent of remyelination was assessed using LFB staining. Myelin phagocytosis assay was used to investigate the effect of Pld4 on microglial phagocytic activity.

Results

Pld4 was upregulated in the corpus callosum during demyelination and remyelination. AAV9-mediated Pld4 deficiency impaired remyelination and reduced the number of Olig2-positive cells. In the corpus callosum of Pld4-deficient mice, the microglial phagocytosis marker MAC2 was reduced, accompanied by inhibition of TrkA/AKT signaling. Similarly, the phagocytosis assay showed that Pld4 knockdown significantly inhibited myelin debris phagocytosis by BV2 cells. The AKT activator SC79 reversed the Pld4 deficiency-induced inhibition of microglial phagocytic activity and rescued the impaired remyelination in Pld4-deficient mice.

Conclusion

PLD4 is upregulated in CPZ-induced MS and modulates microglial phagocytosis and remyelination via the AKT pathway. Our findings provide experimental evidence for a better understanding of the molecular mechanism of MS.

目的：再髓鞘化是一种内源性修复过程，多发性硬化症（MS）患者通常缺乏这一过程。刺激再髓鞘化被认为有助于限制多发性硬化症的进展。本研究旨在调查小胶质细胞吞噬相关基因磷脂酶D家族成员4（PLD4）在铜试剂（CPZ）诱导的多发性硬化症小鼠模型中的表达模式和功能：方法：用LFB染色法评估髓鞘再形成的程度。方法：用LFB染色法评估髓鞘再形成的程度，用髓鞘吞噬试验研究Pld4对小胶质细胞吞噬活性的影响：结果：在脱髓鞘和再髓鞘化过程中，Pld4在胼胝体中上调。AAV9介导的Pld4缺乏会影响髓鞘再形成，并减少Olig2阳性细胞的数量。在Pld4缺陷小鼠的胼胝体中，小胶质细胞吞噬标记物MAC2减少，同时TrkA/AKT信号也受到抑制。同样，吞噬试验显示，Pld4 基因敲除显著抑制了 BV2 细胞对髓鞘碎片的吞噬。AKT激活剂SC79逆转了Pld4缺陷诱导的小胶质细胞吞噬活性抑制，并挽救了Pld4缺陷小鼠受损的髓鞘再形成：结论：PLD4在CPZ诱导的多发性硬化症中上调，并通过AKT途径调节小胶质细胞的吞噬和髓鞘再形成。我们的发现为更好地理解多发性硬化症的分子机制提供了实验证据。

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引用次数: 0

Individualized rTMS Intervention Targeting Sleep Deprivation-Induced Vigilance Decline: Task fMRI-Guided Approach 针对睡眠不足引起的警觉性下降的个性化经颅磁刺激干预：任务fMRI引导的方法。

IF 4.8 1区医学 Q1 NEUROSCIENCES

CNS Neuroscience & Therapeutics

Pub Date : 2024-11-13 DOI: 10.1111/cns.70087

Yuanqiang Zhu, Chen Wang, Ziliang Xu, Fan Guo, Yingjuan Chang, Jiali Liu, WenMing Liu, Peng Fang, Minwen Zheng

Study Objectives

Sleep deprivation (SD) is prevalent in our increasingly round-the-clock society. Optimal countermeasures such as ample recovery sleep are often unfeasible, and brief naps, while helpful, do not fully restore cognitive performance following SD. Thus, we propose that targeted interventions, such as repetitive transcranial magnetic stimulation (rTMS), may enhance cognitive performance recovery post-SD.

Methods

We recruited 50 participants for two SD experiments. In the first experiment, participants performed a psychomotor vigilance task (PVT) under three conditions: normal sleep (resting wakefulness), after 24 h of SD, and following a subsequent 30-min nap. We analyzed dynamic changes in PVT outcomes and cerebral responses across conditions to identify the optimal stimulation target. Experiment 2 adopted the same protocol except that, after the nap, 10-Hz, sham-controlled, individualized rTMS was administrated. Then, an analysis of variance was conducted to investigate the ability of stimulation to improve the PVT reaction times.

Results

Through task-related functional magnetic resonance imaging, we identified cerebral responses within the right middle frontal gyrus (MFG) as the optimal stimulation target. Subsequent application of individualized 10-Hz rTMS over the right MFG attenuated SD-induced deterioration of vigilance.

Conclusion

Our findings suggest that combining a brief nap with individualized rTMS can significantly aid the recovery of vigilance following SD. This approach, through modulating neural activity within functional brain networks, is a promising strategy to counteract the cognitive effects of SD.

研究目的：睡眠不足（SD）在我们这个日夜颠倒的社会中十分普遍。充足的恢复性睡眠等最佳对策往往不可行，而短暂的小睡虽然有帮助，但并不能完全恢复睡眠不足后的认知能力。因此，我们建议采取有针对性的干预措施，如重复经颅磁刺激（rTMS），以促进自毁后认知能力的恢复：方法：我们招募了 50 名参与者进行两项 SD 实验。在第一项实验中，参与者在三种条件下完成了精神运动警觉任务（PVT）：正常睡眠（静息清醒）、SD 24 小时后以及随后的 30 分钟小睡。我们分析了不同条件下PVT结果和大脑反应的动态变化，以确定最佳刺激目标。实验 2 采用了相同的实验方案，但在小睡后，我们进行了 10 赫兹、假控制、个性化的经颅磁刺激。然后，进行方差分析，研究刺激对改善 PVT 反应时间的能力：结果：通过任务相关功能磁共振成像，我们确定右侧额叶中回（MFG）内的大脑反应为最佳刺激目标。结论：我们的研究结果表明，将短暂的午睡与右侧额叶中回（MFG）的刺激结合在一起，能有效缓解SD引起的警觉性下降：我们的研究结果表明，将短暂的午睡与个体化经颅磁刺激相结合，可显著帮助自毁后的警觉性恢复。这种方法通过调节大脑功能网络内的神经活动，是对抗自毁性脑损伤认知影响的一种有前途的策略。

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引用次数: 0

Automated Hematoma Detection and Outcome Prediction in Patients With Traumatic Brain Injury 创伤性脑损伤患者血肿的自动检测和预后。

IF 4.8 1区医学 Q1 NEUROSCIENCES

CNS Neuroscience & Therapeutics

Pub Date : 2024-11-12 DOI: 10.1111/cns.70119

Yang Xu, Qiuyu Fu, Mengqi Qu, Junyao Chen, Jianqi Fan, Shike Hou, Lu Lu

Purpose

To develop a tool for automated subtype classification and segmentation of intracranial hemorrhages (ICH) on CT scans of patients with traumatic brain injury (TBI). Furthermore, outcome prediction for patients can effectively facilitate patient management.

Methods

This study presents a cascade framework for two-stage segmentation and multi-label classification. The hematoma region of interest (ROI) is localized, and then the ROI is cropped and resized to the original pixel size before being input into the model again to obtain the segmentation results. In multilabel classification, the mask obtained from automatic segmentation is superimposed onto the corresponding ROI and CT slices, respectively, to constitute the input image. Subsequently, the ROI image is employed as the local network input to obtain local features. Third, the CT image is utilized to construct a feature extraction network to obtain global features. Ultimately, the local and global features are fused dimensions in the pooling layer, and calculated to generate the final retrieval results. For the prediction of 14-day in-hospital mortality, automatically extracted hematoma subtype and volume features were integrated to enhance the widely used CRASH model.

Results

The proposed segmentation method achieves the best estimates on the Dice similarity coefficient and Jaccard Similarity Index. The proposed multilabel classification method achieved an average accuracy of 95.91%. For mortality prediction, the best model achieved an average area under the receiver operating characteristic curve (AUC) of 0.91 by 5-fold cross-validation.

Conclusions

The proposed method enhances the precision of hematoma segmentation and subtype classification. In clinical settings, the method can streamline the evaluation of ICH for radiologists, and the automatically extracted features are anticipated to facilitate prognosis assessment.

目的：开发一种工具，用于对创伤性脑损伤（TBI）患者 CT 扫描中的颅内出血（ICH）进行自动亚型分类和分割。此外，对患者的预后预测可有效促进患者管理：本研究提出了一种用于两阶段分割和多标签分类的级联框架。首先对血肿感兴趣区域（ROI）进行定位，然后将 ROI 裁剪并调整为原始像素大小，最后再次输入模型以获得分割结果。在多标签分类中，自动分割得到的掩膜分别叠加到相应的 ROI 和 CT 切片上，构成输入图像。然后，将 ROI 图像作为局部网络输入，以获得局部特征。第三，利用 CT 图像构建特征提取网络，以获得全局特征。最后，局部特征和全局特征在池化层中进行维度融合，并通过计算得出最终检索结果。在预测 14 天院内死亡率时，自动提取的血肿亚型和体积特征被整合到广泛使用的 CRASH 模型中：结果：提出的分割方法实现了对 Dice 相似系数和 Jaccard 相似指数的最佳估计。所提出的多标签分类方法的平均准确率达到 95.91%。在死亡率预测方面，通过 5 倍交叉验证，最佳模型的接收者工作特征曲线下的平均面积（AUC）达到了 0.91：结论：所提出的方法提高了血肿分割和亚型分类的精确度。结论：所提出的方法提高了血肿分割和亚型分类的精确度，在临床环境中，该方法可简化放射科医生对 ICH 的评估，自动提取的特征有望促进预后评估。

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引用次数: 0