Experimental Neurology最新文献_第4页

Imipramine improves motor impairments in a rat model of Parkinson's disease induced by 6-hydroxydopamine; the role of oxidative stress and neurotrophic factors 丙咪嗪改善6-羟多巴胺诱导的帕金森病大鼠模型的运动损伤氧化应激与神经营养因子的作用。

IF 4.2 2区医学 Q1 NEUROSCIENCES

Experimental Neurology

Pub Date : 2026-01-13 DOI: 10.1016/j.expneurol.2026.115646

Mahdi Hajibabaei , Bagher Jafarvand , Elmira Beirami , Neda Valian

Introduction

Parkinson's disease (PD) is a progressive neurological disorder characterized by the loss of dopaminergic neurons in the substantia nigra and is associated with neuroinflammation, apoptosis, oxidative stress, and motor impairment. Imipramine, a tricyclic antidepressant, has a wide range of biological effects such as anti-inflammatory, anti-apoptotic, and free radical scavenging activities. The present study was designed to investigate the neuroprotective effect of imipramine in a rat model of PD induced by 6-hydroxydopamine (6-OHDA).

Methods

Male Wistar rats were treated with daily intraperitoneal administration of imipramine (20 mg/kg, for 14 days) starting 72 h after 6-OHDA injection (20 μg/rat; 4 μl in the right medial forebrain bundle (MFB)). The motor performance was assessed using the rotarod, beam, pole, and apomorphine-induced rotation tests. The protein levels of neurotrophic factors (BDNF, GDNF, and NT3) and factors involved in oxidative stress (MDA, CAT, SOD, GST, and GSH) were measured in the striatum by ELISA technique. The neuronal survival was also evaluated by Nissl staining.

Results

Our results showed that 6-OHDA caused motor impairments and neuronal cell death. It also significantly reduced the protein levels of neurotrophic factors and induced an oxidative stress response in the striatum of rats. Whereas, imipramine treatment effectively reduced 6-OHDA-induced motor deficits and neuronal cell death. This improvement was accompanied by an increase in neurotrophic factors, especially GDNF, as well as a reduction in oxidative stress through increased SOD levels.

Conclusion

These findings provide direct evidence that imipramine treatment contributes to improve of neuronal cell death and motor deficits, perhaps by increasing the striatal levels of SOD and GDNF, which play a key role in the survival of dopaminergic neurons. Further studies are also needed to elucidate the precise underlying molecular mechanisms of neuroprotective effects of imipramine.

简介：帕金森病（PD）是一种进行性神经系统疾病，以黑质多巴胺能神经元的丧失为特征，与神经炎症、细胞凋亡、氧化应激和运动障碍有关。丙咪嗪是一种三环抗抑郁药，具有广泛的生物效应，如抗炎、抗凋亡和自由基清除活性。本研究旨在探讨丙咪嗪对6-羟多巴胺（6-OHDA）诱导的PD大鼠模型的神经保护作用。方法：雄性Wistar大鼠注射6-OHDA(20 μl /大鼠，右侧内侧前脑束4 μl) 72 h后，每天腹腔注射丙咪嗪（20 mg/kg，连续14 d）。通过旋转杆、梁、杆和阿吗啡诱导旋转试验评估运动性能。采用ELISA法测定纹状体中神经营养因子（BDNF、GDNF、NT3）和氧化应激相关因子（MDA、CAT、SOD、GST、GSH）的蛋白水平。采用尼氏染色法观察神经元存活情况。结果：6-羟多巴胺可引起运动障碍和神经元细胞死亡。它还显著降低了大鼠纹状体中神经营养因子的蛋白质水平，并诱导了氧化应激反应。然而，丙咪嗪治疗可有效减少6-羟多巴胺诱导的运动缺陷和神经元细胞死亡。这种改善伴随着神经营养因子的增加，特别是GDNF，以及通过增加SOD水平减少氧化应激。结论：这些发现为丙咪嗪治疗有助于改善神经元细胞死亡和运动缺陷提供了直接证据，可能是通过增加纹状体中SOD和GDNF的水平，这在多巴胺能神经元的存活中起关键作用。还需要进一步的研究来阐明丙咪嗪神经保护作用的确切潜在分子机制。

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引用次数: 0

CCR2 knockdown attenuates post-hemorrhagic hydrocephalus and improves glymphatic function after intraventricular hemorrhage CCR2敲低可减轻出血性脑积水，改善脑室内出血后的淋巴功能。

IF 4.2 2区医学 Q1 NEUROSCIENCES

Experimental Neurology

Pub Date : 2026-01-13 DOI: 10.1016/j.expneurol.2026.115644

Huajiang Deng , Shuang Zhang , Haoxiang Wang , Xiaoyin Liu , Kunhong Zhong , Keru Huang , Yuanyou Li , Ziang Deng , Aiping Tong , Liangxue Zhou

Post-hemorrhagic hydrocephalus (PHH) is a severe complication of intraventricular hemorrhage (IVH), yet its underlying mechanisms remain unclear. The glymphatic system (GS), a key pathway involved in cerebrospinal fluid (CSF) circulation and metabolic waste clearance, has recently been implicated in the pathogenesis of PHH. In this study, we employed a mouse model of IVH (n = 6 per group, assessed from 6 h to 28 days post-IVH) to investigate the role of the CCL2/CCR2 signaling axis in GS dysfunction and PHH progression. Behavioral tests, CSF tracer imaging, immunofluorescence, and Western blot analyses were used to assess CSF dynamics, AQP4 polarization, and relevant protein levels. The results showed that IVH induced upregulation of CCL2/CCR2, endoplasmic reticulum stress, and NF-κB activation, accompanied by the loss of AQP4 polarization and impairment of GS function. Notably, CCR2 inhibition was significantly associated with restored AQP4 polarization, improved CSF clearance, reduced ventricular enlargement, and ameliorated neurological deficits. These findings suggest that the CCL2/CCR2 signaling pathway may contribute to GS dysfunction in PHH and provide a foundation for exploring its therapeutic potential.

出血性脑积水（PHH）是脑室内出血（IVH）的严重并发症，但其潜在机制尚不清楚。glymphatic system （GS）是参与脑脊液（CSF）循环和代谢废物清除的关键途径，最近被认为与PHH的发病机制有关。在这项研究中，我们采用IVH小鼠模型（每组n = 6，IVH后6 h至28 天评估）来研究CCL2/CCR2信号轴在GS功能障碍和PHH进展中的作用。行为测试、脑脊液示踪成像、免疫荧光和Western blot分析用于评估脑脊液动力学、AQP4极化和相关蛋白水平。结果表明，IVH诱导CCL2/CCR2上调、内质网应激、NF-κB活化，同时伴有AQP4极化缺失和GS功能损伤。值得注意的是，CCR2抑制与恢复AQP4极化、改善CSF清除率、减少心室增大和改善神经功能缺陷显著相关。这些发现提示CCL2/CCR2信号通路可能参与PHH中GS功能障碍，并为探索其治疗潜力提供了基础。

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引用次数: 0

Prolonged antibiotic treatment accelerates neurological recovery and reduces long-term neuroinflammatory gene expression after experimental TBI in mice 长期抗生素治疗可加速小鼠实验性脑外伤后神经系统恢复并降低长期神经炎症基因表达。

IF 4.2 2区医学 Q1 NEUROSCIENCES

Experimental Neurology

Pub Date : 2026-01-13 DOI: 10.1016/j.expneurol.2026.115645

Katharina Ritter , Katharina Petri , Julian Denninger , Yi Zhang , Yong Wang , Michael K.E. Schäfer

Background

Neuroprotective effects of antibiotic medications are reported in the context of experimental traumatic brain injury (TBI), but the choice of substances and treatment intervals are inconsistent.

Methods

In this study, we tested whether continuous posttraumatic administration of a combined broad-spectrum antibiotic regimen of vancomycin, amoxicillin, and clavulanic acid affects neurological recovery, structural brain damage and neuroinflammation following experimental TBI by controlled cortical impact in 80 adult male C57BL/6 mice.

Results

Antibiotic treatment led to accelerated recovery from posttraumatic neuromotor impairment and exploratory behavioural disorders. Reduced astrocytic activation and neuronal loss in the ipsilesional thalamic region in the early (5 days post injury, dpi) and attenuated neuroinflammatory gene expression in the late (30 dpi) period were observed alongside a severe disruption of the intestinal microbial spectrum after five days of antibiotic treatment, while the structural brain damage remained unaffected.

Conclusion

We demonstrated accelerated neurological recovery and long-lasting effects of antibiotic treatment on the neuroinflammatory response after experimental TBI. Increased plasma levels of lipopolysaccharide-binding protein and short-chain fatty acids were evaluated, yet not identified as potential modulators. As the observed effects can not entirely be linked to the intestinal dysbiosis, direct modulation of secondary brain damage by the antibiotic substances should be considered as an alternate mechanism.

背景：在实验性创伤性脑损伤（TBI）的背景下，已有抗生素药物的神经保护作用的报道，但药物的选择和治疗间隔并不一致。方法：在这项研究中，我们测试了80只成年雄性C57BL/6小鼠创伤后持续使用万古霉素、阿莫西林和克拉维酸联合广谱抗生素方案是否会影响实验性TBI后的神经恢复、结构性脑损伤和神经炎症。结果：抗生素治疗可加速创伤后神经运动障碍和探索性行为障碍的恢复。在早期（损伤后5 天）观察到同伤丘脑区域星形细胞激活减少和神经元丢失，在晚期（30 dpi）观察到神经炎症基因表达减弱，同时在5天抗生素治疗后肠道微生物谱严重破坏，而结构性脑损伤未受影响。结论：我们证明了抗生素治疗对实验性TBI后神经炎症反应的加速恢复和持久效果。血浆中脂多糖结合蛋白和短链脂肪酸水平的升高被评估，但未被确定为潜在的调节剂。由于观察到的影响不能完全与肠道生态失调有关，抗生素物质直接调节继发性脑损伤应被视为一种替代机制。

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引用次数: 0

Spatiotemporal multi-omics profiling of secondary brain injury after intracerebral hemorrhage in an optimized autologous blood-induced mouse model with human tissue validation 优化的自体血诱导小鼠脑出血后继发性脑损伤的时空多组学分析。

IF 4.2 2区医学 Q1 NEUROSCIENCES

Experimental Neurology

Pub Date : 2026-01-13 DOI: 10.1016/j.expneurol.2026.115650

Yang Du , Guangshuo Li , Yijun Lin , Zeqiang Ji , Yiwei Shi , Xiaojing Zhang , Na Zhou , Jia Zhang , Kaijiang Kang , Xingquan Zhao , Liheng Bian

Background

Secondary brain injury (SBI) following intracerebral hemorrhage (ICH) involves complex molecular events such as oxidative stress, inflammation, and immune cell infiltration. Understanding their spatiotemporal patterns is essential for identifying therapeutic targets and optimal intervention windows.

Methods

We optimized an autologous blood-induced ICH mouse model and performed neuroimaging, behavioral testing, histological evaluation, and transcriptomic and proteomic analyses across multiple time points (Days 1, 3, 5, 8, and 12). Time-resolved analyses focused on dynamic changes in SBI-related pathways, including oxidative stress, ferroptosis, leukocyte migration, neutrophil extracellular trap (NET) formation, and phagocytic–lysosomal activity, with spatial validation by immunofluorescence and histology. Model refinements reduced blood coagulation and leakage, improving procedural success and reproducibility. In addition, imaging and perihematomal tissue from a patient 66 h after ICH onset were examined for comparison.

Results

Principal component and clustering analyses revealed a time-dependent molecular trajectory, with rapid early transcriptional changes followed by delayed but sustained protein-level responses. Markers of oxidative stress and ferroptosis (HMOX1, FTH1), adhesion molecules (VCAM1, CD11b), and phagocytic activity (CD68, CTSD) displayed distinct temporal and spatial expression patterns. NET formation peaked between Days 3 and 5 and then gradually declined. Human ICH tissue demonstrated similar activation of oxidative, inflammatory, and phagocytic pathways.

Conclusions

This study delineates the spatiotemporal dynamics of key pathways and molecules involved in secondary brain injury after ICH, revealing stage-specific molecular features and potential therapeutic windows. The optimized autologous blood-induced ICH model exhibits good stability, reproducibility, and relevance to human pathology.

背景：脑出血（ICH）后继发性脑损伤（SBI）涉及复杂的分子事件，如氧化应激、炎症和免疫细胞浸润。了解它们的时空模式对于确定治疗靶点和最佳干预窗口是必不可少的。方法：我们优化了自体血源性脑出血小鼠模型，并在多个时间点（第1、3、5、8和12天）进行神经影像学、行为测试、组织学评估以及转录组学和蛋白质组学分析。时间分辨分析侧重于sbi相关通路的动态变化，包括氧化应激、铁死亡、白细胞迁移、中性粒细胞胞外陷阱（NET）形成和吞噬细胞溶酶体活性，并通过免疫荧光和组织学进行空间验证。模型的改进减少了血液凝固和泄漏，提高了手术的成功率和可重复性。此外，影像学和血肿周围组织从患者66 h脑出血发作后检查进行比较。结果：主成分和聚类分析揭示了一个时间依赖的分子轨迹，快速的早期转录变化随后是延迟但持续的蛋白质水平反应。氧化应激和铁凋亡标志物（HMOX1, FTH1），粘附分子（VCAM1, CD11b）和吞噬活性（CD68， CTSD）表现出不同的时空表达模式。NET的形成在第3天至第5天达到顶峰，然后逐渐下降。人脑出血组织表现出类似的氧化、炎症和吞噬途径的激活。结论：本研究揭示了脑出血后继发性脑损伤关键通路和分子的时空动态，揭示了阶段性分子特征和潜在的治疗窗口。优化后的自体血源性脑出血模型具有良好的稳定性、可重复性和与人类病理的相关性。

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引用次数: 0

Machine learning for discovery of clinical pain biomarkers following spinal cord injury 用机器学习发现脊髓损伤后的临床疼痛生物标志物

IF 4.2 2区医学 Q1 NEUROSCIENCES

Experimental Neurology

Pub Date : 2026-01-13 DOI: 10.1016/j.expneurol.2026.115649

Roxana Florea , Ki-Soo Jeong , Carl Y. Saab

Chronic pain is highly prevalent in patients with spinal cord injury (SCI) and further degrades the quality of life in individuals already struggling with somatic, motor, and autonomic deficits. The management of SCI pain is challenging, mainly due to the lack of reliable, FDA-approved diagnostics, effective therapies, and incomplete understanding of the underlying mechanisms. These limitations have led to increased efforts dedicated to the identification of objective pain biomarkers. However, the FDA has yet to approve a physiologically relevant biomarker for the assessment of pain in populations with SCI. Given the multidimensional nature of pain, there is increasing recognition that composite biomarkers are needed. In this paper, we review several candidate pain signatures and discuss how the inclusion of multi-modal features such as self-reported questionnaires and behavioural measures should also be considered in the identification of comprehensive biomarkers of SCI pain. Since multi-modal, large-scale data presents a particular computational challenge, we further argue that AI and ML approaches enable novel combinatorial designs of SCI pain biomarkers. The advantages of AI and ML methods, which continue to evolve at a rapid pace, include computational efficiency, discovery of latent or embedded patterns in complex data architectures, personalized diagnostics, and minimization of potential bias. We also caution against over-reliance on physiological or neural imaging features that ignore the demographic, motivational, emotional, cognitive and cultural dimensions of pain, while advocating for AI/ML models with improved interpretability.

慢性疼痛在脊髓损伤（SCI）患者中非常普遍，并且进一步降低了已经与躯体、运动和自主神经缺陷作斗争的个体的生活质量。脊髓损伤疼痛的管理是具有挑战性的，主要是由于缺乏可靠的，fda批准的诊断，有效的治疗方法，以及对其潜在机制的不完全了解。这些限制导致越来越多的努力致力于识别客观疼痛生物标志物。然而，FDA尚未批准用于评估脊髓损伤人群疼痛的生理相关生物标志物。鉴于疼痛的多维性，人们越来越认识到需要复合生物标志物。在本文中，我们回顾了几种候选的疼痛特征，并讨论了在识别脊髓损伤的综合生物标志物时应如何考虑多模态特征，如自我报告的问卷和行为测量。由于多模态、大规模数据提出了特殊的计算挑战，我们进一步认为人工智能和机器学习方法可以实现SCI疼痛生物标志物的新型组合设计。人工智能和机器学习方法的优势继续以快速的速度发展，包括计算效率、发现复杂数据架构中的潜在或嵌入模式、个性化诊断和最小化潜在偏差。我们还警告不要过度依赖生理或神经成像特征，这些特征忽略了疼痛的人口统计学、动机、情感、认知和文化维度，同时提倡具有更好可解释性的AI/ML模型。

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引用次数: 0

Letter to the Editor. Effect of encephalomyosynangiosis procedure on post stroke recovery in a permanent model of ischemic stroke. 给编辑的信。脑肌病合并术对永久性缺血性脑卒中模型脑卒中后恢复的影响。

IF 4.2 2区医学 Q1 NEUROSCIENCES

Experimental Neurology

Pub Date : 2026-01-10 DOI: 10.1016/j.expneurol.2026.115641

Pian Gong, Yichun Zou

This correspondence comments on the methodological issues of Anthony et al. on encephalomyosynangiosis (EMS) for acute ischemic stroke in mice. The central issue is the clinically unrealistic intervention time of 4 h post-occlusion, which limits the translational relevance of the reported benefits in infarct reduction and recovery. Furthermore, the surgical design-specifically, the differential handling of the temporalis muscle between groups-introduces a potential confounder, as the excision in controls may alter baseline intracranial pressure compared to the preserved muscle in the EMS group. Details on sham procedures were also lacking. We suggest that employing a later, clinically pertinent time point and a more standardized surgical control would significantly strengthen the experimental model and the validity of its conclusions.

本文对Anthony等人关于小鼠急性缺血性中风脑肌病（EMS）的方法学问题进行了评论。中心问题是临床上不现实的4 h闭塞后干预时间，这限制了报道的梗死减少和恢复益处的转化相关性。此外，手术设计-特别是两组之间颞肌的不同处理-引入了潜在的混杂因素，因为与EMS组中保留的肌肉相比，对照组的切除可能会改变基线颅内压。虚假程序的细节也缺乏。我们建议采用更晚的临床相关时间点和更规范的手术控制将显著加强实验模型及其结论的有效性。

引用次数: 0

Effect of encephalomyosynangiosis procedure on post stroke recovery in a permanent model of ischemic stroke. 脑肌病合并术对永久性缺血性脑卒中模型脑卒中后恢复的影响。

IF 4.2 2区医学 Q1 NEUROSCIENCES

Experimental Neurology

Pub Date : 2026-01-09 DOI: 10.1016/j.expneurol.2026.115642

Anthony Diaz, Daylin Gamiotea-Turro, Sanjeev Kumar Yadav, Ketan R Bulsara, Rajkumar Verma

This correspondence responds to the comments by Gong and Zou et al., regarding our study of encephalomyosynangiosis (EMS) in an acute ischemic stroke mouse model. We clarify that the selection of a 4-h post-ischemia intervention window was intentional and aligned with the study's proof-of-concept objective to evaluate the feasibility and biological impact of EMS in a hyperacute stroke setting, rather than modeling delayed or chronic recovery paradigms. We further address concerns regarding surgical controls, detailing the rationale for temporalis muscle handling and craniectomy design to minimize intracranial pressure-related confounding while maintaining physiological relevance. The absence of additional control arms and the use of a non-surgical sham group are acknowledged as limitations inherent to the study's scope. Overall, this response contextualizes the experimental design choices and reinforces the study's primary contribution as an initial demonstration of EMS efficacy when applied early after ischemic injury, providing a foundation for future investigations using delayed or staged interventions.

这篇文章回应了Gong和Zou等人关于我们在急性缺血性脑卒中小鼠模型中研究脑肌病合并症（EMS）的评论。我们澄清，选择缺血后4小时的干预窗口是有意的，并且符合该研究的概念验证目标，即评估EMS在超急性卒中环境中的可行性和生物学影响，而不是模拟延迟或慢性恢复范式。我们进一步讨论了手术控制方面的问题，详细介绍了颞肌处理和颅骨切除术设计的基本原理，以尽量减少与颅内压相关的混淆，同时保持生理相关性。缺乏额外的对照组和使用非手术假组被认为是研究范围固有的局限性。总的来说，这一反应将实验设计选择置于背景下，并加强了该研究的主要贡献，即在缺血性损伤后早期应用EMS的效果，为未来使用延迟或分阶段干预的研究提供了基础。

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引用次数: 0

Daily intranasal resveratrol-conjugated gold nanoparticles administration promotes neuroprotection and improves neurological outcome in the R6/2 mouse model of Huntington's disease 每日鼻内白藜芦醇结合金纳米颗粒可促进亨廷顿病R6/2小鼠模型的神经保护并改善神经预后

IF 4.2 2区医学 Q1 NEUROSCIENCES

Experimental Neurology

Pub Date : 2026-01-07 DOI: 10.1016/j.expneurol.2026.115639

Emanuela Paldino , Emiliano Montalesi , Marco Fiocchetti , Flavia Dioguardi , Iole Venditti , Elena Olivieri , Maria Marino , Francesca R. Fusco

Pan-apoptosis and involvement of the inflammatory process are the hallmarks of Huntington's disease (HD). Inflammation currently represents one of the potential therapeutic targets for slowing and fighting the pathological phenotype of HD. The immunomodulatory properties of natural compounds, such as resveratrol, have been demonstrated in various disease models and human clinical trials. In the present study, we evaluated the neuroprotective and anti-inflammatory effects of the daily intranasal administration of resveratrol-conjugated gold nanoparticles in awake R6/2 mice, the genetic animal model of HD. Transgenic mice were treated daily with resveratrol-conjugated gold nanoparticles (0.1 mg/kg/day) starting from 5 weeks of age corresponding to the prodromal stage of the disease. After sacrifice, histological and immunofluorescence studies were performed. We found that resveratrol treated R6/2 mice survived longer and displayed a significant partial recovery of motor performance compared with R6/2 mice that received the nanoparticles with vehicle. Primary outcome measures such as striatal atrophy, neuronal intranuclear inclusions, and modulation of microglial reaction revealed a neuroprotective effect of resveratrol conjugated gold nanoparticles. Resveratrol provided a significant increase of neuroglobin, a neuroprotective globin, along with activated CREB and BDNF in the mice medium spiny neurons, accompanied by a down modulation of neuroinflammation, which, combined, might explain the beneficial effects observed in this model. Our findings showed that nanoparticles loaded with a specific compound which acts on the mutated protein intranuclear inclusions and inflammatory components may represent a valid therapeutic strategy in slowing down the symptoms of HD neurodegeneration.

泛细胞凋亡和炎症过程的参与是亨廷顿舞蹈病（HD）的标志。炎症目前是减缓和对抗HD病理表型的潜在治疗靶点之一。天然化合物（如白藜芦醇）的免疫调节特性已在各种疾病模型和人体临床试验中得到证实。在本研究中，我们在清醒的HD遗传动物模型R6/2小鼠中评估了每日鼻内给药白藜芦醇结合金纳米颗粒的神经保护和抗炎作用。从与疾病前驱期相对应的5周龄开始，每天用白藜芦醇偶联金纳米颗粒（0.1 mg/kg/天）治疗转基因小鼠。牺牲后，进行组织学和免疫荧光研究。我们发现白藜芦醇处理的R6/2小鼠存活时间更长，运动能力明显部分恢复。纹状体萎缩、神经元核内包涵体和小胶质细胞反应的调节等主要结局指标显示白藜芦醇共轭金纳米颗粒具有神经保护作用。白藜芦醇显著增加了小鼠中棘神经元中的神经球蛋白（一种神经保护性球蛋白），同时激活了CREB和BDNF，并伴有神经炎症的下调，这可能解释了该模型中观察到的有益效果。我们的研究结果表明，携带特定化合物的纳米颗粒可作用于突变蛋白核内包涵体和炎症成分，可能是减缓HD神经退行性疾病症状的有效治疗策略。

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引用次数: 0

NFKBIZ mediates neuroprotection and maintains blood-brain barrier integrity in cerebral ischemia/reperfusion via STAT3-regulated Nrf2/ARE signaling NFKBIZ通过stat3调控的Nrf2/ARE信号介导脑缺血/再灌注时的神经保护和维持血脑屏障完整性。

IF 4.2 2区医学 Q1 NEUROSCIENCES

Experimental Neurology

Pub Date : 2026-01-07 DOI: 10.1016/j.expneurol.2026.115638

Cheng Huang , Xiaocong Mo , Ying Liu , Di Hu , Cun Li , Yuan Zhao , Shuxin Wang , Jinjun Xia , Xiaoyan Chen , Wei Sun , Rui Xu

Ischemic stroke (IS) is a leading cause of adult disability and mortality worldwide. It is characterized by a complex series of cellular and molecular events that lead to neuronal injury and disruption of the blood-brain barrier (BBB). The BBB plays a crucial role in maintaining brain homeostasis, and its disruption during IS exacerbates secondary brain injury. However, the molecular mechanisms that preserve BBB integrity and provide neuroprotection remain poorly understood. In this study, we used mRNA sequencing to identify genes differentially expressed in IS models. To investigate the role of NFKBIZ in BBB maintenance, we conducted additional in vitro and in vivo experiments. Mechanistic studies focused on the STAT3-mediated Nrf2/ARE signaling pathway, and metabolomic profiling was used to identify metabolites associated with NFKBIZ activity. Our findings indicate that NFKBIZ is essential for maintaining BBB integrity. Overexpression of NFKBIZ reduced ischemic injury and preserved BBB function, while its downregulation significantly worsened neurological deficits and BBB damage. The STAT3-Nrf2/ARE axis, a critical pathway for antioxidant defense, was activated by NFKBIZ, contributing to its protective effects. Furthermore, metabolomic analysis identified a set of metabolites linked to NFKBIZ function, providing insight into the underlying biological mechanisms. This study underscores the potential of NFKBIZ as a therapeutic target for neuroprotection and BBB preservation in IS, suggesting new avenues for developing treatments to improve outcomes in stroke patients.

缺血性脑卒中（IS）是世界范围内导致成人残疾和死亡的主要原因。它的特点是一系列复杂的细胞和分子事件，导致神经元损伤和血脑屏障（BBB）的破坏。血脑屏障在维持大脑稳态中起着至关重要的作用，在IS期间，血脑屏障的破坏加剧了继发性脑损伤。然而，保持血脑屏障完整性和提供神经保护的分子机制仍然知之甚少。在这项研究中，我们使用mRNA测序来鉴定IS模型中差异表达的基因。为了研究NFKBIZ在血脑屏障维持中的作用，我们进行了额外的体外和体内实验。机制研究侧重于stat3介导的Nrf2/ARE信号通路，代谢组学分析用于鉴定与NFKBIZ活性相关的代谢物。我们的研究结果表明NFKBIZ对于维持血脑屏障的完整性至关重要。NFKBIZ过表达可减轻缺血性损伤，保留血脑屏障功能，而其下调可显著加重神经功能缺损和血脑屏障损伤。STAT3-Nrf2/ARE轴是抗氧化防御的关键途径，NFKBIZ激活了STAT3-Nrf2/ARE轴，有助于其保护作用。此外，代谢组学分析确定了一组与NFKBIZ功能相关的代谢物，为潜在的生物学机制提供了见解。这项研究强调了NFKBIZ作为IS神经保护和血脑屏障保存的治疗靶点的潜力，为开发改善卒中患者预后的治疗方法提供了新的途径。

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引用次数: 0

Astrocytic TPK1 mitigates amyloid pathology via TFEB-mediated endocytosis 星形细胞TPK1通过tfeb介导的内吞作用减轻淀粉样蛋白病理。

IF 4.2 2区医学 Q1 NEUROSCIENCES

Experimental Neurology

Pub Date : 2026-01-06 DOI: 10.1016/j.expneurol.2026.115640

Shu-Zhen Zhang , Yuan Ma , Yu Ding , Yan-Qing Yin , Bing-Wei Wang , Gang Hu , Jia-Wei Zhou

Alzheimer's disease (AD), the leading cause of dementia, is characterized by amyloid-beta (Aβ) plaques, neurofibrillary tangles, and progressive neurodegeneration. Deregulation of glial cell activity plays an important role in the amyloid pathology. However, it is still unclear how changes in astrocytes contribute to Aβ deposition and clearance in AD. Here, we showed that deficiency of astrocytic thiamine pyrophosphokinase 1 (Tpk1), exacerbated Aβ burden leading to exacerbated spatial memory deficits in a mouse model of AD. While selective overexpression of Tpk1 in astrocytes ameliorated cognitive decline and significantly reduced hippocampal and cortical Aβ plaque burden. Enhanced Tpk1 expression augmented astrocyte endocytic capacity. Mechanistically, Tpk1-promoted endocytic activity depended on the activation of transcription factor EB (TFEB)-mediated pathways. Collectively, our findings demonstrate that astrocytic TPK1 mitigates cognitive impairment in 5xFAD mice by upregulating TFEB expression, thereby enhancing astrocyte-mediated engulfment and degradation of neurotoxic aggregates, including Aβ. This study suggests that astrocytic TPK1/TFEB pathway is a promising target for developing disease-modifying AD therapies.

阿尔茨海默病（AD）是痴呆症的主要原因，其特征是β淀粉样蛋白（Aβ）斑块、神经原纤维缠结和进行性神经变性。神经胶质细胞活性的失调在淀粉样蛋白病理中起着重要作用。然而，目前尚不清楚星形胶质细胞的变化如何促进AD中Aβ的沉积和清除。在本研究中，我们发现星形细胞硫胺素焦磷酸激酶1 （Tpk1）的缺乏加重了阿尔茨海默病小鼠模型中的a β负荷，从而加重了空间记忆缺陷。而在星形胶质细胞中选择性过表达Tpk1可改善认知能力下降，并显著减少海马和皮质β斑块负担。Tpk1表达的增强增强了星形胶质细胞的内吞能力。在机制上，tpk1促进的内吞活性依赖于转录因子EB （TFEB）介导途径的激活。总的来说，我们的研究结果表明，星形胶质细胞TPK1通过上调TFEB表达来减轻5xFAD小鼠的认知障碍，从而增强星形胶质细胞介导的神经毒性聚集体（包括Aβ）的吞噬和降解。这项研究表明星形细胞TPK1/TFEB通路是开发疾病修饰性AD治疗的一个有希望的靶点。

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