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Testing an increasing social working memory load in the female rat 测试增加雌性大鼠的社会工作记忆负荷。
IF 2.6 4区 医学 Q3 NEUROSCIENCES Pub Date : 2025-11-09 DOI: 10.1016/j.brainres.2025.150042
Camryn R. Lizik , Kyria Kelley-Wolfe , Elizabeth S. Wu , Sadaf Asadifar , Jessica L. Verpeut , Federico Sanabria , Heather A. Bimonte-Nelson
Across animal taxa, the ability to recognize members of one’s species individually is a critical form of memory, mediating social interactions necessary for individual and species survival. A variety of laboratory behavioral tasks quantify conspecific social memory ability based on the premise of novelty exploration, in which the time spent exploring a novel, never-met conspecific is greater than the time spent exploring a familiar, previously-met animal. Here, we present a novel behavioral protocol that was designed for the systematic evaluation of social memory with an increasing memory load in the rat. This protocol considers and builds upon currently used behavioral tasks quantifying social memory between a load of two animals: one novel and one familiar. Two versions of the protocol were compared, one in which increases in memory load were progressive across trials (Progressive), and one in which the load challenge of each trial was semi-randomized (Nonprogressive). We found that young, gonadally-intact female rats demonstrated social memory of numerous conspecifics simultaneously. Specifically, rats could differentiate a novel conspecific from one, two, or three familiar conspecifics. At higher social working memory demands, in which there were more animals to remember and differentiate, social discrimination ability was absent. Additionally, the Progressive and Nonprogressive load conditions did not yield different patterns in social memory abilities. This social memory load task provides a relevant tool for the experimental evaluation of social memory in female rats, a memory type that is clinically relevant, conserved, and distinct from other memory types in neurobiological and neuroendocrine mechanisms.
在动物分类群中,个体识别物种成员的能力是一种重要的记忆形式,调解个体和物种生存所必需的社会互动。在探索新奇事物的前提下,各种实验室行为任务量化了同种动物的社会记忆能力,在这种前提下,探索一种新的、从未见过的同种动物所花费的时间要大于探索一种熟悉的、以前见过的动物所花费的时间。在此,我们提出了一种新的行为仪器和方案,旨在系统地评估啮齿动物在增加记忆负荷时的社会记忆。该协议考虑并建立在目前使用的行为任务的基础上,量化两种动物之间的社会记忆:一种是新的,一种是熟悉的。比较了两种版本的方案:一种是记忆负荷的增加在试验中是渐进的(渐进),另一种是每次试验的负荷挑战是半随机的(非渐进)。我们发现,性腺完整的年轻雌性大鼠同时表现出对许多同种个体的社会记忆。具体来说,大鼠可以将一种新的同种动物与一种、两种或三种熟悉的同种动物区分开来。在较高的社会工作记忆要求下,需要记忆和区分的动物较多,社会辨别能力缺失。此外,进行性和非进行性负荷条件在社会记忆能力方面没有产生不同的模式。这个社会记忆负荷任务为社会记忆的实验评估提供了一个相关的工具,社会记忆是一种临床相关的、保守的记忆类型,在神经生物学和神经内分泌机制上与其他记忆类型不同。
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引用次数: 0
Intranasally delivered colostrum-derived small extracellular vesicles mitigate acute neuroinflammation in periventricular leukomalacia 鼻内递送初乳来源的细胞外小泡减轻脑室周围白质软化症的急性神经炎症。
IF 2.6 4区 医学 Q3 NEUROSCIENCES Pub Date : 2025-11-07 DOI: 10.1016/j.brainres.2025.150041
Beyza Ture , Funda Erdogan , Coskun Armagan , Bora Tastan , Ceren Perihan Gonul , Yusuf Guducu , Can Akyildiz , Nuray Duman , Sermin Genc , Hasan Ozkan

Background

Periventricular leukomalacia (PVL) is a predominant white matter injury in preterm infants, leading to lifelong neurodevelopmental disability, and yet disease-modifying therapies are lacking. Breast milk, especially colostrum, contains bioactive components with potential neuroprotective properties, among which extracellular vesicles (EVs) have recently attracted increasing attention. This study aimed to evaluate the neurorestorative efficacy of intranasally administered colostrum-derived small EVs (sEVs) in a lipopolysaccharide (LPS)-induced PVL model.

Methods

sEVs were isolated from Sprague-Dawley rats’ colostrum and characterized by Nanoparticle Tracking Analysis (NTA) and Western blot (WB). To assess brain delivery following intranasal administration, sEVs were labeled with PKH67. Neonatal pups were randomly assigned to three groups: control, systemic LPS, and LPS + sEVs. A PVL-like model was induced (LPS) injection at postnatal day 5 (P5), and intranasal sEVs were administered thereafter. Brains were analyzed at P11.

Results

Labeled sEVs were detectable in the hippocampus and corpus callosum (CC) within 3 h of intranasal delivery. LPS increased microglial and astroglial markers (Iba1, GFAP) and reduced neuronal/Oligodendroglial markers (NeuN, Olig2), whereas sEVs treatment partially normalized these indices in both regions.

Conclusions

Colostrum-derived sEVs reach the neonatal brain via the intranasal route and mitigate LPS-induced neuroinflammatory changes. These findings support intranasal sEVs as a non-invasive candidate approach for neonatal white-matter injury. To our knowledge, this is the first demonstration that intranasally delivered colostrum-derived sEVs can penetrate the neonatal brain and ameliorate histological indices of PVL-like injury, suggesting that this approach could be a novel and promising treatment strategy for neonatal brain injury.
背景:脑室周围白质软化症(PVL)是一种主要的早产儿白质损伤,可导致终身神经发育障碍,但目前缺乏改善疾病的治疗方法。母乳,特别是初乳含有具有潜在神经保护作用的生物活性成分,其中细胞外囊泡(EVs)近年来引起了越来越多的关注。本研究旨在评估经鼻给药的初乳衍生的小ev (sev)在脂多糖(LPS)诱导的PVL模型中的神经修复效果。方法:从Sprague-Dawley大鼠初乳中分离sev,采用纳米颗粒跟踪分析(NTA)和免疫印迹(WB)对其进行表征。为了评估经鼻给药后的脑输送情况,sev用PKH67标记。新生幼崽随机分为三组:对照组、全身性LPS组和LPS + sev组。在出生后第5天(P5)注射LPS诱导pvl样模型,随后鼻内注射sev。在P11时分析大脑。结果:经鼻给药后3 h内,海马和胼胝体(CC)中可检测到标记sev。LPS增加了小胶质细胞和星形胶质细胞标志物(Iba1, GFAP),减少了神经元/少突胶质细胞标志物(NeuN, Olig2),而sev治疗在这两个区域部分正常化了这些指标。结论:初乳衍生的sev通过鼻内途径到达新生儿大脑,并减轻lps诱导的神经炎症改变。这些发现支持鼻内sev作为新生儿白质损伤的非侵入性候选方法。据我们所知,这是首次证明经鼻给药的初乳衍生sev可以穿透新生儿大脑并改善pvl样损伤的组织学指标,这表明这种方法可能是一种新颖而有前途的新生儿脑损伤治疗策略。
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引用次数: 0
Molecular signatures of neuro-HIV and methamphetamine co-morbidity revealed by Raman spectroscopy in postmortem human brain tissue 拉曼光谱揭示了死后人脑组织中神经hiv和甲基苯丙胺共同发病的分子特征。
IF 2.6 4区 医学 Q3 NEUROSCIENCES Pub Date : 2025-11-07 DOI: 10.1016/j.brainres.2025.150036
Samaneh Ghazanfarpour , Rahul Kumar Das , Kit wai Cheung , Emma Zabel , Monireh Pourrahimi , Ravikumar Aalinkeel , Anna Sharikova , Alexander Khmaladze , Supriya D. Mahajan
HIV infection and comorbid methamphetamine (METH) use contribute significantly to neurocognitive impairment, yet the molecular brain alterations remain poorly defined. We employed confocal Raman micro-spectroscopy on formalin-fixed, paraffin-embedded cortical sections from Control (HIV-METH-), HIV + METH-, and HIV + METH + individuals, analyzing spectra (950–1800 cm−1) via SVD and classification modeling. Key Raman bands were biochemically assigned and correlated with gene expression data from QPCR. Distinct spectral profiles emerged across cohorts. HIV + and HIV + METH + brains showed reduced intensities at 1040–1140 cm−1, indicating loss of carbohydrates, phospholipids, and nucleic acid backbone integrity. Elevated spectral signals were indicative of lipid buildup, DNA damage, and increased CH2 saturation, with pronounced effects observed in tissues affected by both HIV and METH exposure. METH use exacerbated HIV-associated disruptions, including thiol depletion and nucleic acid fragmentation. SVD clustering and ROC analysis yielded high classification accuracy (F1 > 0.7). We provide evidence of convergence of transcriptomic and spectroscopic data which highlights a coordinated disruption of metabolic, inflammatory and structural pathways in HIV+METH+ subjects. The observed lipid remodeling, carbohydrate depletion, and nucleic acid damage suggest Raman spectral signatures may serve as diagnostic markers for HIV and METH-associated neuropathology. These findings demonstrate Raman spectroscopy’s sensitivity in detecting HIV and METH induced biochemical brain changes.
HIV感染和同时使用甲基苯丙胺(methamphetamine,简称冰毒)会显著导致神经认知障碍,但大脑分子改变的定义仍不明确。我们使用共聚焦拉曼显微光谱对对照(HIV-METH-)、HIV + METH-和HIV + METH + 个体的福尔马林固定、石蜡包埋的皮质切片进行分析,通过SVD和分类建模分析光谱(950-1800 cm-1)。关键的拉曼条带被生化分配,并与QPCR的基因表达数据相关。不同的光谱分布出现在队列中。HIV + 和HIV + 甲基安非他明 + 大脑在1040-1140 cm-1时强度降低,表明碳水化合物、磷脂和核酸主干完整性的损失。升高的光谱信号表明脂质积累、DNA损伤和CH2饱和度增加,在HIV和甲基安非他明暴露影响的组织中观察到明显的影响。甲基苯丙胺的使用加剧了hiv相关的破坏,包括硫醇耗竭和核酸断裂。SVD聚类和ROC分析的分类准确率较高(F1 > 0.7)。我们提供了转录组学和光谱数据趋同的证据,这些数据突出了HIV+METH+受试者中代谢,炎症和结构途径的协调破坏。观察到的脂质重塑、碳水化合物消耗和核酸损伤表明,拉曼光谱特征可以作为HIV和甲基苯丙胺相关神经病理的诊断标记。这些发现证明了拉曼光谱在检测HIV和甲基安非他明诱导的大脑生化变化方面的敏感性。
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引用次数: 0
Unraveling the therapeutic potential of triptolide in glioma: Orchestrating apoptosis and immune landscape remodeling 揭示雷公藤甲素在神经胶质瘤中的治疗潜力:调控细胞凋亡和免疫景观重塑。
IF 2.6 4区 医学 Q3 NEUROSCIENCES Pub Date : 2025-11-07 DOI: 10.1016/j.brainres.2025.150039
Tao Zhang, Cheng Fan, Yunping Liao, Xuejian Miao, Guomin Kou

Background

Glioma is a highly aggressive brain tumor marked by rapid proliferation, therapy resistance, and an immunosuppressive microenvironment. Triptolide, a bioactive compound from Tripterygium wilfordii, has demonstrated anticancer potential, yet its mechanisms in glioma remain unclear.

Methods

We integrated transcriptomic analysis, immune infiltration profiling, and experimental validation. Differentially expressed genes from GSE147352 were intersected with triptolide targets, and hub genes were identified via protein–protein interaction network analysis. Functional enrichment (GO and KEGG) and immune cell infiltration analyses were performed. Single-cell RNA sequencing validated immune-related changes, and immunohistochemistry confirmed protein-level differences. Key targets were further validated by qPCR in glioma cells.

Results

Forty-seven intersecting genes were identified, enriched in apoptosis, inflammation, and immune regulation pathways. Triptolide promoted glioma cell apoptosis by modulating BCL2L11, CASP3, MCL1, and TNF, while reprogramming the immune microenvironment by regulating IL6, IL-1β, IL10, and TGF-β1, thereby suppressing M2 macrophage polarization. Single-cell analysis confirmed these findings, and qPCR validated transcriptional changes.

Conclusion

Triptolide exerts dual anti-glioma effects by inducing apoptosis and reshaping the tumor immune microenvironment. By shifting macrophages toward a pro-inflammatory M1 phenotype and activating apoptotic pathways, triptolide emerges as a promising candidate for glioma immunotherapy.
背景:神经胶质瘤是一种高度侵袭性的脑肿瘤,其特征是快速增殖、治疗抵抗和免疫抑制微环境。雷公藤甲素是雷公藤中的一种生物活性化合物,已被证明具有抗癌潜力,但其在神经胶质瘤中的作用机制尚不清楚。方法:结合转录组学分析、免疫浸润谱分析和实验验证。GSE147352的差异表达基因与雷公藤甲素靶点相交,通过蛋白相互作用网络分析鉴定枢纽基因。功能富集(GO和KEGG)和免疫细胞浸润分析。单细胞RNA测序证实了免疫相关的变化,免疫组织化学证实了蛋白质水平的差异。在胶质瘤细胞中通过qPCR进一步验证了关键靶点。结果:鉴定出47个交叉基因,富集于细胞凋亡、炎症和免疫调节途径。雷公雷甲素通过调节BCL2L11、CASP3、MCL1、TNF促进胶质瘤细胞凋亡,同时通过调节il - 6、IL-1β、il - 10、TGF-β1对免疫微环境进行重编程,从而抑制M2巨噬细胞极化。单细胞分析证实了这些发现,qPCR证实了转录变化。结论:雷公藤甲素具有诱导细胞凋亡和重塑肿瘤免疫微环境的双重抗胶质瘤作用。通过将巨噬细胞转向促炎M1表型并激活凋亡途径,雷公藤甲素成为神经胶质瘤免疫治疗的有希望的候选者。
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引用次数: 0
Aerobic exercise modulates plasma oxidized lipid metabolites and neurotransmitters in Parkinson’s disease motor subtypes 有氧运动调节帕金森病运动亚型的血浆氧化脂质代谢物和神经递质。
IF 2.6 4区 医学 Q3 NEUROSCIENCES Pub Date : 2025-11-07 DOI: 10.1016/j.brainres.2025.150038
Yangdanyu Li , Yuning Liu , Zihao Lin , Quanqing Wei , Jie Xiang , Wei Zhang , Liguo Dong , Fujia Li , Jie Zu , Guiyun Cui , Chuanying Xu

Objective

To examine the effects of aerobic exercise on clinical symptoms in Parkinson’s disease (PD) patients with distinct motor subtypes, further explore exercise-induced alterations in oxidative lipid and neurotransmitter.

Methods

Fifty-one PD patients were randomized into the aerobic exercise group (n = 26) and the control group (n = 25). The aerobic exercise group was further divided into postural instability gait disorder (PIGD) and tremor-dominant (TD) subgroups. Clinical scales, plasma oxidized lipid, and neurotransmitter contents were assessed before and after the exercise. Paired t-tests were applied to evaluate within-group changes. Linear mixed-effects model was used to evaluate group-time interactions for metabolites. Mediation analysis was used to examine whether changes in metabolites mediated the effects of aerobic exercise on clinical symptoms.

Results

Aerobic exercise reduced UPDRS-III and SCOPA-AUT scores in both subtypes (all P-values < 0.05). And FOG-Q and RBD-HK scores decreased in TD, whereas Berg balance scale, Tinetti balance scale, MoCA scores (all P-values < 0.05) increased in PIGD following aerobic activity. Exercise altered oxidative lipids and neurotransmitters in both groups. And the linear mixed effect model shows that the differences of PGD2, arginine, glutamine, and lysine were still statistically significant among the groups (all P-values < 0.05). Notably, 20-OH-LTB4 mediated exercise-induced Tinetti Balance Scale-A improvements (indirect effect: β = 0.73, 95 % CI:0.009–1.826, P-value = 0.046) in PIGD.

Conclusions

Aerobic exercise ameliorates motor and non-motor symptoms in TD and PIGD subtypes of PD, potentially mediated by oxidative lipid. This provides further reference for the potential mechanism and clinical treatment of aerobic exercise for PD patients with different motor subtypes.
目的:探讨有氧运动对不同运动亚型帕金森病(PD)患者临床症状的影响,进一步探讨运动诱导的氧化脂质和神经递质的改变。方法:51例PD患者随机分为有氧运动组(n = 26)和对照组(n = 25)。有氧运动组进一步分为姿势不稳定步态障碍(PIGD)亚组和震颤优势(TD)亚组。在运动前后评估临床评分、血浆氧化脂质和神经递质含量。采用配对t检验评价组内变化。采用线性混合效应模型评价代谢物的群时相互作用。采用中介分析来检验代谢物的变化是否介导了有氧运动对临床症状的影响。结果:有氧运动降低了两种亚型的UPDRS-III和SCOPA-AUT评分(所有p值 )结论:有氧运动改善了TD和PIGD亚型PD的运动和非运动症状,可能是由氧化脂质介导的。这为有氧运动治疗不同运动亚型PD患者的潜在机制和临床治疗提供了进一步的参考。
{"title":"Aerobic exercise modulates plasma oxidized lipid metabolites and neurotransmitters in Parkinson’s disease motor subtypes","authors":"Yangdanyu Li ,&nbsp;Yuning Liu ,&nbsp;Zihao Lin ,&nbsp;Quanqing Wei ,&nbsp;Jie Xiang ,&nbsp;Wei Zhang ,&nbsp;Liguo Dong ,&nbsp;Fujia Li ,&nbsp;Jie Zu ,&nbsp;Guiyun Cui ,&nbsp;Chuanying Xu","doi":"10.1016/j.brainres.2025.150038","DOIUrl":"10.1016/j.brainres.2025.150038","url":null,"abstract":"<div><h3>Objective</h3><div>To examine the effects of aerobic exercise on clinical symptoms in Parkinson’s disease (PD) patients with distinct motor subtypes, further explore exercise-induced alterations in oxidative lipid and neurotransmitter.</div></div><div><h3>Methods</h3><div>Fifty-one PD patients were randomized into the aerobic exercise group (<em>n</em> = 26) and the control group (<em>n</em> = 25). The aerobic exercise group was further divided into postural instability gait disorder (PIGD) and tremor-dominant (TD) subgroups. Clinical scales, plasma oxidized lipid, and neurotransmitter contents were assessed before and after the exercise. Paired t-tests were applied to evaluate within-group changes. Linear mixed-effects model was used to evaluate group-time interactions for metabolites. Mediation analysis was used to examine whether changes in metabolites mediated the effects of aerobic exercise on clinical symptoms.</div></div><div><h3>Results</h3><div>Aerobic exercise reduced UPDRS-III and SCOPA-AUT scores in both subtypes (all <em>P</em>-values &lt; 0.05). And FOG-Q and RBD-HK scores decreased in TD, whereas Berg balance scale, Tinetti balance scale, MoCA scores (all <em>P</em>-values &lt; 0.05) increased in PIGD following aerobic activity. Exercise altered oxidative lipids and neurotransmitters in both groups. And the linear mixed effect model shows that the differences of PGD2, arginine, glutamine, and lysine were still statistically significant among the groups (all <em>P</em>-values &lt; 0.05). Notably, 20-OH-LTB4 mediated exercise-induced Tinetti Balance Scale-A improvements (indirect effect: β = 0.73, 95 % CI:0.009–1.826, <em>P</em>-value = 0.046) in PIGD.</div></div><div><h3>Conclusions</h3><div>Aerobic exercise ameliorates motor and non-motor symptoms in TD and PIGD subtypes of PD, potentially mediated by oxidative lipid. This provides further reference for the potential mechanism and clinical treatment of aerobic exercise for PD patients with different motor subtypes.</div></div>","PeriodicalId":9083,"journal":{"name":"Brain Research","volume":"1869 ","pages":"Article 150038"},"PeriodicalIF":2.6,"publicationDate":"2025-11-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145476674","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Repurposing immunomodulatory drugs targeting microglia for amyotrophic lateral sclerosis 免疫调节药物靶向小胶质细胞治疗肌萎缩性侧索硬化症。
IF 2.6 4区 医学 Q3 NEUROSCIENCES Pub Date : 2025-11-07 DOI: 10.1016/j.brainres.2025.150032
Kirsten Johanna Hendricus Maes , Jacco Jan Briedé
Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder that progressively affects upper and lower motor neurons, leading to symptoms including dysarthria, muscle weakness, and paralysis. The disease is multifactorial, with a variety of contributing pathways, including excitotoxicity, oxidative stress, and neuroinflammation. Current treatments target only two of these pathways with limited efficacy, highlighting the need for alternative approaches. Increasing evidence highlights the involvement of immune dysregulation, particularly microglial-mediated neuroinflammation, in ALS pathology. Fortunately, many immunomodulatory drugs acting on microglia are already available for other diseases, indicating promising opportunities for drug repurposing. This literature review provides an overview of existing drugs under investigation for ALS, including those that have failed, and highlights microglia-targeting compounds with emerging repurposing potential. Compounds such as ibudilast, fingolimod, and modafinil have shown encouraging initial clinical results, whereas others were well-tolerated but underpowered or failed to demonstrate efficacy. New candidates, such as azithromycin, montelukast, doxycycline, tofacitinib, quercetin, belinostat, propranolol, and several kinase inhibitors, have demonstrated positive preclinical results, supporting their advancement toward clinical evaluation. Overall, these findings emphasize the potential of microglia-targeting therapies for ALS. To realize this potential, future studies must include larger cohorts, assess effects across different disease stages and patient subgroups, and examine sex differences. This is essential to address patient heterogeneity and improve personalized treatments for ALS patients.
肌萎缩性侧索硬化症(ALS)是一种致命的神经退行性疾病,进行性影响上、下运动神经元,导致构音障碍、肌肉无力和瘫痪等症状。该疾病是多因素的,有多种致病途径,包括兴奋性毒性、氧化应激和神经炎症。目前的治疗仅针对这些途径中的两种,疗效有限,这突出了对替代方法的需求。越来越多的证据强调免疫失调,特别是小胶质细胞介导的神经炎症,在ALS病理中的参与。幸运的是,许多作用于小胶质细胞的免疫调节药物已经可以用于其他疾病,这表明药物再利用有希望的机会。本文献综述概述了正在研究的治疗ALS的现有药物,包括那些失败的药物,并强调了具有重新利用潜力的靶向小胶质细胞的新候选药物。诸如布司特、芬戈莫德和莫达非尼等化合物已显示出令人鼓舞的初步临床结果,而其他化合物耐受性良好,但效力不足或未能显示出疗效。新的候选药物,如阿奇霉素、纳曲酮、孟鲁司特、多西环素、托法替尼、槲皮素、贝利诺他和几种激酶抑制剂,已经显示出积极的临床前结果,支持它们向临床评估的进展。总的来说,这些发现强调了小胶质细胞靶向治疗ALS的潜力。为了实现这一潜力,未来的研究必须包括更大的队列,评估疾病分期和患者亚组的影响,并检查性别差异。这对于解决患者异质性和改善ALS的个性化治疗至关重要。
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引用次数: 0
RAGE signaling pathway in glioblastoma and cognitive decline: Insights into inflammatory mechanisms and therapeutic implications RAGE信号通路在胶质母细胞瘤和认知能力下降中的作用:炎症机制和治疗意义。
IF 2.6 4区 医学 Q3 NEUROSCIENCES Pub Date : 2025-11-06 DOI: 10.1016/j.brainres.2025.150026
Jemema Agnes Tripena Raj , Geofrey John , Shubham Ghanekar , Gokula Krishnan Thiruselvan , Janmay Shah , Deepak Ande , Abhishek Chatterjee , Jayant S. Goda
Glioblastoma (GBM) remains the most aggressive primary brain tumor, with standard therapies offering only modest survival benefits. A major challenge in its management is radiation therapy (RT), which, while indispensable for tumor control, often damages normal brain tissue and contributes to radiation-induced cognitive decline (RICD). This dual burden of tumor progression and treatment-associated neurotoxicity underscores the need for molecular targets that link oncogenesis and neuroinflammation.
The receptor for advanced glycation end-products (RAGE) is a multiligand pattern recognition receptor activated by HMGB1, S100 proteins, and advanced glycation end-products (AGEs), all of which are elevated in both GBM and irradiated tissues. RAGE signaling engages NF-κB, JAK/STAT, and MAPK pathways, driving glioma cell migration, angiogenesis, and immune evasion while amplifying oxidative stress and chronic neuroinflammation in the surrounding parenchyma. These effects not only promote tumor progression and resistance to RT but also impair synaptic plasticity and cognitive function, paralleling mechanisms seen in neurodegenerative disease.
Therapeutically, targeting RAGE represents a dual opportunity: suppressing GBM aggressiveness while mitigating RICD. Small-molecule inhibitors such as FPS-ZM1 and Azeliragon, biologics including sRAGE and RAGE antagonistic peptides, and phytochemicals such as curcumin, Tanshinone IIA, and berberine demonstrate the feasibility of modulating this pathway in preclinical models.
Collectively, the evidence highlights the RAGE signaling as one of the central modulators of GBM progression and RT-induced cognitive decline through NF-κB, JAK/STAT, and MAPK activation. Future strategies that selectively disrupt pathological RAGE signaling, while sparing physiological functions, may provide transformative therapeutic avenues for patients facing the dual burden of glioblastoma and radiation-induced neurotoxicity.
胶质母细胞瘤(GBM)仍然是最具侵袭性的原发性脑肿瘤,标准治疗只能提供适度的生存益处。其治疗的主要挑战是放射治疗(RT),放射治疗虽然对肿瘤控制必不可少,但往往会损害正常脑组织并导致辐射引起的认知衰退(RICD)。这种肿瘤进展和治疗相关神经毒性的双重负担强调了需要将肿瘤发生和神经炎症联系起来的分子靶点。晚期糖基化终产物受体(RAGE)是一种多配体模式识别受体,由HMGB1、S100蛋白和晚期糖基化终产物(AGEs)激活,所有这些在GBM和辐照组织中都升高。RAGE信号通路参与NF-κB、JAK/STAT和MAPK通路,驱动胶质瘤细胞迁移、血管生成和免疫逃避,同时放大周围实质的氧化应激和慢性神经炎症。这些影响不仅促进肿瘤进展和对RT的抵抗,还损害突触可塑性和认知功能,与神经退行性疾病的机制相似。在治疗上,靶向RAGE代表了双重机会:抑制GBM的侵袭性,同时减轻RICD。小分子抑制剂如FPS-ZM1和Azeliragon,生物制剂包括sRAGE和RAGE拮抗肽,植物化学物质如姜黄素、丹参酮IIA和小檗碱在临床前模型中证明了调节这一途径的可行性。总的来说,这些证据表明RAGE信号是通过NF-κB、JAK/STAT和MAPK激活的GBM进展和rt诱导的认知衰退的中心调节剂之一。未来的策略是选择性地破坏病理性RAGE信号,同时保留生理功能,可能为面临胶质母细胞瘤和辐射诱导的神经毒性双重负担的患者提供变革性的治疗途径。
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引用次数: 0
Valproate attenuates neuroinflammation and glial activation in a rat model of fibromyalgia: Evidence for antioxidant and nociceptive modulation 丙戊酸减轻纤维肌痛大鼠模型中的神经炎症和神经胶质活化:抗氧化和伤害调节的证据。
IF 2.6 4区 医学 Q3 NEUROSCIENCES Pub Date : 2025-11-04 DOI: 10.1016/j.brainres.2025.150033
Esraa A. Ahmed , Rasha B. Abd-ellatief , Marwa F. Ali , Ahmed M. Abd-Eldayem
Fibromyalgia syndrome (FMS) is a chronic, multidimensional musculoskeletal condition distinguished by severe nociceptive dysfunction, persistent fatigue, sleep disruptions, cognitive deficits, and emotional instability. Although valproic acid (VPA) has been used to treat epilepsy and bipolar disorder, its efficacy in altering neuropathic pain pathways remains unclear. In this investigation, we assessed the neuromodulatory characteristics of VPA (300 mg/kg, intraperitoneally) in an established FMS rat model, with a focus on neuroinflammation, oxidative stress, and glial activation. Behavioral evaluations for thermal hyperalgesia (paw withdrawal latency, PWL) and mechanical allodynia (paw withdrawal threshold, PWT) were performed at baseline (day 0), after induction (day 5), and at various intervals following VPA administration. Neurochemical evaluations demonstrated that VPA markedly diminished FMS-induced elevations in malondialdehyde (MDA), nitric oxide (NO), and pro-inflammatory cytokines such as tumor necrosis factor-α (TNF-α), interleukin (IL)-1β, and interleukin (IL)-6, while restoring antioxidant defenses, such as glutathione (GSH) and superoxide dismutase (SOD). Histopathological examination demonstrated reduced neuronal degeneration and decreased immunoreactivity of glial fibrillary acidic protein (GFAP). These findings indicate that VPA reduces FMS-related pain and neuroinflammatory characteristics through antioxidative and glial-modulating mechanisms, indicating its potential for therapeutic repurposing in neuropathic pain syndromes.
纤维肌痛综合征(FMS)是一种慢性、多维度肌肉骨骼疾病,以严重的伤害功能障碍、持续疲劳、睡眠中断、认知缺陷和情绪不稳定为特征。虽然丙戊酸(VPA)已被用于治疗癫痫和双相情感障碍,但其在改变神经性疼痛通路方面的功效尚不清楚。在这项研究中,我们在建立的FMS大鼠模型中评估了VPA(300 mg/kg,腹腔注射)的神经调节特性,重点关注神经炎症、氧化应激和胶质细胞激活。在基线(第0天)、诱导后(第5天)和给药后的不同时间间隔对热痛觉过敏(足部戒断潜伏期,PWL)和机械性异常痛(足部戒断阈值,PWT)进行行为评估。神经化学评估表明,VPA显著降低了fms诱导的丙二醛(MDA)、一氧化氮(NO)和促炎细胞因子如肿瘤坏死因子-α (TNF-α)、白细胞介素(IL)-1β和白细胞介素(IL)-6的升高,同时恢复抗氧化防御,如谷胱甘肽(GSH)和超氧化物歧化酶(SOD)。组织病理学检查显示神经元变性减少,胶质纤维酸性蛋白(GFAP)免疫反应性降低。这些发现表明,VPA通过抗氧化和神经胶质调节机制减轻fms相关的疼痛和神经炎症特征,表明其在神经性疼痛综合征中的治疗潜力。
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引用次数: 0
Propofol induces mitochondrial dysfunction in hippocampal neurons and postoperative cognitive dysfunction in male 3xTg-AD mice by blocking ESRRG-mediated HSD11B2 transcription 异丙酚通过阻断esrrg介导的HSD11B2转录,诱导3xTg-AD雄性小鼠海马神经元线粒体功能障碍和术后认知功能障碍。
IF 2.6 4区 医学 Q3 NEUROSCIENCES Pub Date : 2025-11-04 DOI: 10.1016/j.brainres.2025.150035
Juan Yuan, Jue Zhang, He Zhang, Yingbing Tu, Ming Li
Cognitive dysfunction is a severe issue of Alzheimer’s disease (AD). This study explores the molecular mechanisms underlying propofol-induced postoperative cognitive dysfunction (POCD) in AD mice. Triple transgenic AD (3xTg-AD) male mice or control C57BL/6J mice were subjected to propofol anesthesia and abdominal surgery for modeling. AAV-mediated gene intervention was performed on male 3xTg-AD mice prior to propofol anesthesia. Reduced estrogen-related receptor gamma (ESRRG) and hydroxysteroid 11-beta dehydrogenase 2 (HSD11B2) expression was found in the hippocampus of male 3xTg-AD mice. ESRRG overexpression mitigated POCD and hippocampal mitochondrial dysfunction in male 3xTg-AD mice exposed to propofol. This was evidenced by shorter escape latencies, longer target quadrant times, increased platform crossings, reduced malondialdehyde and mitochondrial reactive oxygen species, decreased cytosolic cytochrome C and phosphorylated dynamin-related protein 1 (p-DRP1), and higher mitochondrial membrane potential, though these effects were reversed by HSD11B2 knockdown. In vitro, propofol lowered HT22 cell mitochondrial membrane potential and elevated cytochrome C and p-DRP1, but ESRRG overexpression countered these changes. Ultimately, propofol disrupts ESRRG-mediated HSD11B2 transcription, driving mitochondrial dysfunction and POCD in male 3xTg-AD mice.
认知功能障碍是阿尔茨海默病(AD)的一个严重问题。本研究探讨异丙酚诱导AD小鼠术后认知功能障碍(POCD)的分子机制。三转基因AD (3xTg-AD)雄性小鼠或对照C57/BL6J小鼠经异丙酚麻醉后腹腔手术造模。在异丙酚麻醉前,对雄性3xTg-AD小鼠进行aav介导的基因干预。3xTg-AD雄性小鼠海马中雌激素相关受体γ (ESRRG)和羟类固醇11- β脱氢酶2 (HSD11B2)表达降低。ESRRG过表达可减轻异丙酚暴露的3xTg-AD雄性小鼠POCD和海马线粒体功能障碍。这可以通过更短的逃逸潜伏期、更长的靶象限时间、增加的平台交叉、减少的丙二醛和线粒体活性氧、减少的细胞质细胞色素C和磷酸化的动力蛋白1 (p-DRP1)以及更高的线粒体膜电位来证明,尽管这些影响被HSD11B2敲除逆转。在体外,异丙酚降低HT22细胞线粒体膜电位,升高细胞色素C和p-DRP1,但ESRRG过表达抵消了这些变化。最终,异丙酚破坏esrrg介导的HSD11B2转录,导致雄性3xTg-AD小鼠线粒体功能障碍和POCD。
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引用次数: 0
Bempedoic Acid mitigates BCG-induced depression in mice by modulating TNF-α/NF-κB signaling and restoring brain serotonin contents 酸通过调节TNF-α/NF-κB信号和恢复脑5 -羟色胺含量减轻bcg诱导的小鼠抑郁。
IF 2.6 4区 医学 Q3 NEUROSCIENCES Pub Date : 2025-11-04 DOI: 10.1016/j.brainres.2025.150031
Ritesh S. Tarwani, Sanjay N. Awathale, Sameer N. Goyal, Abdulla K. Sherikar, Pradip P. Bawane, Kartik T. Nakhate
Emerging research implicates systemic inflammation in the disruption of neuroimmune signaling, contributing to the pathogenesis of major depressive disorder. While ATP-citrate lyase (ACLY) is a key lipogenic enzyme that amplifies immune cell-mediated inflammatory responses, bempedoic acid (BA), a recently approved ACLY inhibitor for hypercholesterolemia, has demonstrated significant anti-inflammatory properties. Therefore, we investigated the antidepressant potential of BA in a mouse model of BCG-induced depression, focusing on its interaction with peripheral tumor necrosis factor-alpha (TNF-α) and the downstream modulation of brain NF-κB signaling and serotonin levels. Male Swiss Albino mice were inoculated with BCG to induce systemic inflammation-associated depressive phenotypes. BA was administered alone or with TNF-α inhibitor etanercept. Behavioral assessments included sucrose preference test (SPT), tail suspension test (TST), and locomotor activity (LMA). Levels of TNF-α in the serum, and NF-κB and serotonin contents in the brain were estimated using ELISA and HPLC techniques. BCG administration significantly reduced sucrose preference in SPT and increased immobility in TST, correlating with elevated TNF-α and NF-κB, and reduced serotonin contents. BA treatment significantly reversed these behavioral and biochemical abnormalities, and its combination with etanercept produced synergistic effects, without affecting the LMA. This study provides the first evidence of the antidepressant effect of BA, demonstrating that suppression of peripheral TNF-α by BA leads to downregulation of central NF-κB and restoration of serotonin levels. Further investigations in diverse animal models are warranted to confirm the broad-spectrum efficacy of BA, along with the evaluation of its translational potential for treating depression.
新兴的研究表明,全身性炎症与神经免疫信号的破坏有关,有助于抑郁症的发病机制。虽然atp -柠檬酸裂解酶(ACLY)是一种关键的脂质生成酶,可以放大免疫细胞介导的炎症反应,但最近被批准用于高胆固醇血症的ACLY抑制剂苯戊酸(BA)已显示出显著的抗炎特性。因此,我们在bcg诱导的抑郁症小鼠模型中研究了BA的抗抑郁潜能,重点研究了BA与周围肿瘤坏死因子-α (TNF-α)的相互作用以及下游脑NF-κB信号传导和血清素水平的调节。雄性瑞士白化病小鼠接种卡介苗诱导全身炎症相关抑郁表型。BA单独或与TNF-α抑制剂依那西普(ET)联合给药。行为评估包括蔗糖偏好测试(SPT)、悬尾测试(TST)和运动活动(LMA)。采用ELISA和HPLC法测定大鼠血清中TNF-α水平、脑内NF-κB和血清素含量。BCG显著降低了SPT的蔗糖偏好,增加了TST的不动性,与TNF-α和NF-κB升高有关,并降低了血清素含量。BA治疗显著逆转了这些行为和生化异常,并且与ET联合产生协同效应,不影响LMA。本研究首次提供了BA抗抑郁作用的证据,表明其抑制外周TNF-α导致中枢NF-κB下调和血清素水平恢复。需要在不同的动物模型中进行进一步的研究,以证实BA的广谱疗效,并评估其治疗抑郁症的转化潜力。
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Brain Research
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