Experimental Neurology最新文献_第7页

A new microinfarcts model produces widespread bilateral infarcts and persistent cognitive deficits in middle-aged mice 一种新的微梗死模型在中年小鼠中产生广泛的双侧梗死和持续的认知缺陷。

IF 4.2 2区医学 Q1 NEUROSCIENCES

Experimental Neurology

Pub Date : 2025-12-16 DOI: 10.1016/j.expneurol.2025.115598

Zhongwu Liu , Mikkala Mccann , Brianna Powell , Julie Landschoot-Ward , Zheng Gang Zhang , Michael Chopp

Background

Multi-infarct dementia (MID), a severe form of vascular cognitive impairment, results from cumulative impact of multiple cerebral microinfarcts (MMIs). Current preclinical models primarily rely on unilateral induction of MMIs, which fails to reproduce bilateral lesion distribution and persistent cognitive decline characteristic of human disease.

Objective

To develop and characterize a modified bilateral MMI model that more accurately reflects the clinical and pathological features of MID.

Methods

Twelve-month-old male C57BL/6J mice underwent either unilateral or bilateral MMI induction by microsphere embolization via the internal carotid artery. Bilateral induction was achieved by transiently occluding the contralateral common carotid artery during microsphere infusion. Behavioral assessments using novel object recognition (NOR) and elevated plus maze (EPM) were conducted on days 7, 14, and 28 post-surgery. Histological Hematoxylin and Eosin staining and immunohistochemical analyses using antibodies against Iba1 and GFAP were performed to evaluate lesion distribution and neuroinflammation.

Results

The modified bilateral procedure successfully induced widespread infarcts across both hemispheres. Bilateral MMI mice exhibited significantly greater and persistent cognitive impairment, demonstrated by a reduced NOR discrimination index and decreased open-arm exploration in the EPM persisting through day 28, than did unilateral MMI mice. Histological analysis confirmed bilateral microinfarcts and significant increase in Iba1- and GFAP-positive staining, indicating robust and sustained bilateral neuroinflammation.

Conclusion

This modified bilateral MMI procedure reproduces key pathological and functional features of human MID, overcoming the limitations of traditional unilateral models. The new model provides a clinically relevant platform for investigating mechanisms underlying vascular cognitive impairment and evaluating potential disease-modifying therapies.

背景：多发性脑梗死性痴呆（MID）是一种严重的血管性认知障碍，由多发性脑微梗死（mmi）的累积影响引起。目前的临床前模型主要依赖于单侧诱导mmi，无法再现人类疾病特征的双侧病变分布和持续认知能力下降。方法：12月龄雄性C57BL/6J小鼠经颈内动脉微球栓塞诱导单侧或双侧MMI。双侧诱导是通过微球输注期间短暂闭塞对侧颈总动脉实现的。术后第7、14和28天分别采用新目标识别（NOR）和升高+迷宫（EPM）进行行为评估。组织苏木精染色和伊红染色，免疫组化分析抗Iba1和GFAP抗体，以评估病变分布和神经炎症。结果：改良的双侧手术成功地诱导了两脑半球广泛的梗死。与单侧MMI小鼠相比，双侧MMI小鼠表现出更大且持续的认知障碍，这表现在持续28天的EPM中NOR辨别指数降低和张开臂探索减少。组织学分析证实双侧微梗死，Iba1和gfap阳性染色显著增加，表明双侧神经炎症强劲且持续。结论：这种改良的双侧MMI手术再现了人类MID的关键病理和功能特征，克服了传统单侧模型的局限性。新模型为研究血管性认知障碍的机制和评估潜在的疾病改善疗法提供了一个临床相关的平台。

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引用次数: 0

Post-acute phase Rac1 activation promotes long-term recovery of ischemic stroke via the Pak1/p38/β-catenin pathway 急性期后Rac1激活通过Pak1/p38/β-catenin通路促进缺血性卒中的长期恢复。

IF 4.2 2区医学 Q1 NEUROSCIENCES

Experimental Neurology

Pub Date : 2025-12-15 DOI: 10.1016/j.expneurol.2025.115594

Fan Wu , Yan Min , Zihan Xu , Luyuan Zhang, Lihui Zhou, Jianbo Yu, Ganglei Li, Hongwei Lin, Jie Shen, Zongchi Liu, Jian Shen, Renya Zhan, Jiangbiao Gong, Yu Zhu

Tremendous advances have been made in the understanding of neurogenesis in the adult brain, which offers hope for therapeutic strategies that target neurogenesis in the repair of nerve damage after stroke. Rac1 plays a key role in the neurogenesis of the central nervous system as one of the small GTPase members of the Rho family. However, the role of Rac1 after ischemic stroke remains controversial. This may be due to its role in mediated production of harmful substances such as ROS during the acute phase. Therefore, we are trying to explore whether it can play a role in nerve repair after the acute phase. Our research indicates that the activation of Rac1 in the post-acute phase supports ischemic recovery. Specifically, intraventricular injection of a Rac1 activator one week after middle cerebral artery occlusion (MACO) improved brain atrophy and neurological function. Rac1 activation induced the migration of neural stem cells in vitro and promoted their migration in vivo, aiding in their differentiation into mature neurons. Results from Western blotting and Co-immunoprecipitation (Co-IP) assaysuggest that Rac1 activation promotes the migration and differentiation of neural stem cells through the downstream Pak1/p38/β-catenin signaling pathway. Furthermore, Rac1 activation promotes post-stroke vascular regeneration and synaptic remodeling, In conclusion, the activation of Rac1 in the post-acute phase promotes neural repair following stroke, indicating its potential as a therapeutic target during the recovery phase of ischemic stroke.

在对成人大脑神经发生的理解方面取得了巨大的进展，这为中风后神经损伤的修复提供了以神经发生为目标的治疗策略。Rac1作为Rho家族的小GTPase成员之一，在中枢神经系统的神经发生中起着关键作用。然而，Rac1在缺血性脑卒中中的作用仍存在争议。这可能是由于其在急性期介导有害物质如活性氧的产生中的作用。因此，我们正在探索它是否能在急性期后的神经修复中发挥作用。我们的研究表明，急性期后Rac1的激活支持缺血恢复。具体来说，在大脑中动脉闭塞（MACO）后一周，脑室内注射Rac1激活剂可改善脑萎缩和神经功能。激活Rac1可诱导神经干细胞在体外迁移并促进其在体内迁移，有助于其向成熟神经元分化。Western blotting和Co-immunoprecipitation （Co-IP）实验结果表明，Rac1的激活通过下游Pak1/p38/β-catenin信号通路促进神经干细胞的迁移和分化。Rac1的激活促进脑卒中后血管再生和突触重构。综上所述，Rac1在脑卒中后急性期的激活促进脑卒中后神经修复，表明其可能成为缺血性脑卒中恢复期的治疗靶点。

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引用次数: 0

miR-15b-5p impairs myelin repair and cognitive recovery after ischemic stroke by targeting the E2F7/CXCL2 axis miR-15b-5p通过靶向E2F7/CXCL2轴损害缺血性卒中后髓磷脂修复和认知恢复。

IF 4.2 2区医学 Q1 NEUROSCIENCES

Experimental Neurology

Pub Date : 2025-12-14 DOI: 10.1016/j.expneurol.2025.115589

Yizhen Weng , Jialei Zhou , Lulu Zhang , Xinyi He , Hui Guo , Quanquan Zhang , Haiying Li , Xiang Tang , Xiang Li Sr

Ischemic stroke often causes demyelination and cognitive impairment. Emerging evidence suggests that microRNAs regulate gene expression and influence myelin repair and cognitive recovery after stroke. Here, transcriptomic analysis and RT-qPCR validation revealed marked upregulation of miR-15b-5p expression in the hippocampal regions of MCAO/R rats. Similarly, elevated serum miR-15b-5p levels were observed in stroke patients and positively correlated with NIHSS scores and infarct volumes. Functional studies involving intracerebroventricular administration of miR-15b-5p agomirs or antagomirs revealed that inhibition of miR-15b-5p markedly enhanced cognitive performance and facilitated myelin repair, as demonstrated by immunofluorescence and transmission electron microscopy. In contrast, overexpression of miR-15b-5p through agomir administration aggravated cognitive impairments and demyelination. Mechanistically, E2F7 was identified as a direct target of miR-15b-5p via dual-luciferase reporter assays. Suppression of E2F7 led to increased expression of the pro-inflammatory chemokine CXCL2, thereby exacerbating neuroinflammation and demyelination. In contrast, inhibition of miR-15b-5p restored E2F7 expression and significantly reduced CXCL2 levels, as confirmed by Western blotting and enzyme-linked immunosorbent assay. Collectively, these findings reveal a novel miR-15b–E2F7–CXCL2 axis that modulates myelin repair and cognitive recovery after ischemic stroke, highlighting miR-15b-5p as a potential therapeutic target.

缺血性中风常引起脱髓鞘和认知障碍。新出现的证据表明，microRNAs调节基因表达并影响脑卒中后髓磷脂修复和认知恢复。本研究中，转录组学分析和RT-qPCR验证显示MCAO/R大鼠海马区miR-15b-5p表达显著上调。同样，脑卒中患者血清miR-15b-5p水平升高，且与NIHSS评分和梗死体积呈正相关。脑室内给予miR-15b-5p阿戈米或安塔戈米的功能研究显示，免疫荧光和透射电镜显示，抑制miR-15b-5p显着增强认知能力并促进髓磷脂修复。相反，通过阿戈米尔过表达miR-15b-5p加重了认知障碍和脱髓鞘。在机制上，通过双荧光素酶报告基因检测，E2F7被确定为miR-15b-5p的直接靶标。抑制E2F7导致促炎趋化因子CXCL2的表达增加，从而加剧神经炎症和脱髓鞘。相比之下，经Western blotting和酶联免疫吸附试验证实，抑制miR-15b-5p可恢复E2F7表达并显著降低CXCL2水平。总的来说，这些发现揭示了一种新的miR-15b-E2F7-CXCL2轴，它调节缺血性卒中后髓磷脂修复和认知恢复，突出了miR-15b-5p作为潜在的治疗靶点。

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引用次数: 0

Cellular insights into hydrocephalus: The diverse roles and intricate crosstalk of multiple cell types 脑积水的细胞洞察：多种细胞类型的不同作用和复杂的串扰。

IF 4.2 2区医学 Q1 NEUROSCIENCES

Experimental Neurology

Pub Date : 2025-12-13 DOI: 10.1016/j.expneurol.2025.115596

Xu Li , Yuxiang Zhou , Yang Han , Xun Chen , Qian Ouyang

Hydrocephalus is characterized by the abnormal accumulation of cerebrospinal fluid (CSF) within the brain's ventricular system, which can lead to ventricular dilation. This condition affects individuals across all age groups but is particularly prevalent in infants and the elderly. The etiology of hydrocephalus is multifactorial, involving excessive CSF secretion, obstruction of CSF pathways, and impairment of CSF reabsorption. Recent evidence supports the CSF permeation theory, which emphasizes the exchange of CSF with blood and interstitial fluid throughout the brain, mediated by perivascular spaces, astrocytes, and brain parenchyma. This review focuses on the role and interactions of various cell types in CSF circulation and the development of hydrocephalus, including choroid plexus cells, choroid plexus macrophages, vascular endothelial cells, neural progenitor cells, perivascular macrophages, mast cells, astrocytes, ependymal cells, and meningeal lymphatic endothelial cells(mLECs). We discuss the mechanisms by which these cells contribute to hydrocephalus, such as the disruption of blood-CSF-barrier integrity, inflammation, and alterations in CSF dynamics. Additionally, we explore potential therapeutic strategies targeting these cellular interactions, such as the inhibition of chemokine signaling and the modulation of complement pathways. Understanding the complex interplay between different cell types is crucial for developing novel treatments for hydrocephalus. This review provides a comprehensive overview of the current knowledge regarding cellular contributions to hydrocephalus and highlights areas for future research.

脑积水的特点是脑脊液（CSF）在脑室系统内的异常积聚，可导致脑室扩张。这种情况影响所有年龄组的人，但在婴儿和老年人中尤为普遍。脑积水的病因是多因素的，包括脑脊液分泌过多、脑脊液通路阻塞和脑脊液重吸收受损。最近的证据支持脑脊液渗透理论，该理论强调脑脊液与血液和间质液在整个脑内的交换，由血管周围间隙、星形胶质细胞和脑实质介导。本文就脉络膜丛细胞、脉络膜丛巨噬细胞、血管内皮细胞、神经祖细胞、血管周围巨噬细胞、肥大细胞、星形胶质细胞、室管膜细胞和脑膜淋巴内皮细胞在脑脊液循环和脑积水发生中的作用和相互作用作一综述。我们讨论了这些细胞导致脑积水的机制，如血-CSF屏障完整性的破坏、炎症和CSF动力学的改变。此外，我们还探索了针对这些细胞相互作用的潜在治疗策略，如抑制趋化因子信号传导和调节补体途径。了解不同细胞类型之间复杂的相互作用对于开发脑积水的新治疗方法至关重要。这篇综述提供了关于脑积水细胞贡献的当前知识的全面概述，并强调了未来研究的领域。

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引用次数: 0

Influence of the estrous cycle on seizure activity in a model of mesial temporal lobe epilepsy 中颞叶癫痫模型发情周期对癫痫发作活动的影响。

IF 4.2 2区医学 Q1 NEUROSCIENCES

Experimental Neurology

Pub Date : 2025-12-13 DOI: 10.1016/j.expneurol.2025.115597

Fei Ran Li , Maxime Lévesque , Siyan Wang , Massimo Avoli

Catamenial epilepsy is characterized by seizure exacerbation during specific phases of the menstrual cycle and affects up to 70 % of epileptic women. These seizures are often non-responsive to medication and our understanding of the relationship between menstrual cycle and seizure generation remains limited. Previous experiments using the in vitro 4-aminopyridine model of epileptiform synchronization demonstrated that the proestrus and estrus, which are associated to high blood estrogen levels, favor seizure generation; this effect presumably results from enhanced parvalbumin (PV)-positive interneuron excitability caused by estrogen receptor β-mediated activity. Here, we used the in vivo kainic acid (KA) model of mesial temporal lobe epilepsy in PV-ChR2 mice to establish the influence of the estrous cycle on: (i) the induction of status epilepticus (SE), and (ii) the severity of spontaneous seizures and interictal spikes in female mice that were treated with systemic KA (i.p) injection. We found that SE induced during proestrus results in irregular estrous cycles without affecting SE severity, the occurrence/duration of spontaneous seizures and of interictal spike rates during the chronic phase. Moreover, chronic seizures were more frequent and significantly longer during the estrous phases compared to the non-estrous phases. Overall, our findings demonstrate that the hormonal state at the time of SE induction influences the estrous cycle regularity without affecting seizure or interictal spike burden during the chronic epileptic period. However, during the chronic period, seizure severity is promoted through the 4–5 days fluctuation in sex hormones coinciding with the estrous cycle, and specifically during the estrous phases.

发作性癫痫的特点是在月经周期的特定阶段发作加剧，影响高达70% %的癫痫妇女。这些癫痫发作通常对药物无反应，我们对月经周期和癫痫发作之间关系的理解仍然有限。先前使用体外4-氨基吡啶模型的实验表明，与高血雌激素水平相关的发情前期和发情期有利于癫痫发作的发生；这种效应可能是由雌激素受体β介导的活性引起的小白蛋白（PV）阳性神经元间兴奋性增强引起的。在此，我们使用PV-ChR2小鼠内侧颞叶癫痫的体内kainic酸（KA）模型来建立发情周期对：(i)诱导癫痫持续状态（SE），以及（ii）全身KA （i.p）注射处理的雌性小鼠自发性癫痫发作的严重程度和间期尖峰的影响。我们发现，在发情前期诱导的SE导致不规则的发情周期，但不影响SE的严重程度、自发性癫痫发作的发生/持续时间和慢性期的间歇峰率。此外，与非发情期相比，发情期的慢性癫痫发作更频繁，时间更长。总之，我们的研究结果表明，在慢性癫痫期间，SE诱导时的激素状态影响发情周期规律，而不影响癫痫发作或间歇峰负荷。然而，在慢性期，癫痫发作的严重程度是通过4-5 天的性激素波动与发情周期一致，特别是在发情期。

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引用次数: 0

The phenotypic transformation of astrocytes after AIS can be regulated by microglial GSDMD-mediated pyroptosis AIS后星形胶质细胞的表型转化可受gsdmd介导的小胶质细胞热凋亡的调控。

IF 4.2 2区医学 Q1 NEUROSCIENCES

Experimental Neurology

Pub Date : 2025-12-11 DOI: 10.1016/j.expneurol.2025.115595

Yige Zhang , Yifang Zhou , Wan Zhang , Yiwei Qian , Zixin Chen , Lulu Pei , Ding Zhang , Wanxuan Cheng , Mengke Tian , Ce Zong , Xin Wang , Yamin Wang , Jiaxin Wang , MingMing Ning , Jun Tan , Zongping Xia , Yuming Xu , Yuan Cao , Bo Song

Background

Microglial pyroptosis contributes to the pathogenesis of ischemic stroke through multiple pathways. However, it is unclear how it contributes to the phenotype switching of neuroinflammatory/ neuroprotective astrocytes.

Methods

This study established a mouse MCAO model and utilized microglial Gsdmd gene knockout mice to examine neuroinflammatory/neuroprotective astrocyte-related protein expression, infarct volume, mNSS scores, and other metrics. Additionally, a transwell co-culture model of microglia and astrocytes was constructed, followed by treatment with IL-1β, pyroptosis inhibitor DSF, and IL-1R1 inhibitor IL-1RA.

Results

The findings confirm that microglial GSDMD protein-mediated pyroptosis influences the phenotypic transformation of neuroinflammatory/neuroprotective astrocytes. Specifically, GSDMD-mediated pyroptosis in microglia releases IL-1β, which binds to the IL-1R1 receptor, reversing neuroinflammatory / neuroprotective astrocyte polarization.

Conclusion

This mechanism improves AIS prognosis and may serve as a promising therapeutic candidate in AIS.

背景：小胶质细胞焦亡通过多种途径参与缺血性卒中的发病机制。然而，尚不清楚它如何促进神经炎性/神经保护性星形胶质细胞的表型转换。方法：本研究建立小鼠MCAO模型，利用小胶质Gsdmd基因敲除小鼠检测神经炎症/神经保护星形胶质细胞相关蛋白表达、梗死体积、mNSS评分等指标。建立小胶质细胞和星形胶质细胞的transwell共培养模型，然后用IL-1β、焦腐抑制剂DSF和IL-1R1抑制剂IL-1RA处理。结果：证实小胶质细胞GSDMD蛋白介导的焦亡影响神经炎性/神经保护性星形胶质细胞的表型转化。具体来说，gsdmd介导的小胶质细胞焦亡释放IL-1β， IL-1β与IL-1R1受体结合，逆转神经炎症/神经保护星形胶质细胞极化。结论：该机制改善了AIS的预后，可能是治疗AIS的有希望的候选药物。

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引用次数: 0

Cholinergic modulation of hippocampal CA1 pyramidal cell excitability in ArxGCG+7 mice ArxGCG+7小鼠海马CA1锥体细胞兴奋性的胆碱能调节。

IF 4.2 2区医学 Q1 NEUROSCIENCES

Experimental Neurology

Pub Date : 2025-12-11 DOI: 10.1016/j.expneurol.2025.115591

Christopher M. Johnson , Joseph Dong , Peace Senkungu , Jahnvi Chandar , Natalia Ochoa-Sepulveda , Almedia J. Myers , Eric D. Marsh

Developmental and Epileptic Encephalopathies (DEE) are rare neurodevelopmental disorders defined by seizures, developmental delays, and abnormal EEG patterns. Infantile Spasms Syndrome (ISS), the most common DEE, was one of the first linked to single-gene variants, including polyalanine expansions in the Aristaless Related Homeobox (ARX) gene. The Arx^GCG+7 mouse, which models the human mutation, exhibits behavioral phenotypes, epileptiform hippocampal activity, and reduced cholinergic input to the hippocampus. The role of the disrupted cholinergic signaling has not been explored in this model and may be contributing to hippocampal dysfunction and DEE pathogenesis. Hence, we investigated the impact of the ARX GCG expansion on the septo-hippocampal network by first reproducing the changes in Choline acetyltransferase (ChAT) protein levels in the medial septum (MS) and diagonal band of Broca (DBB). Next, we performed ex vivo patch-clamp recordings in CA1 pyramidal neurons and measured responses to cholinergic agonists. Finally, we assessed acetylcholine receptor expression by western blot across the hippocampus to assess for homeostatic changes in receptors. Our data demonstrated a ∼ 60 % reduction in ChAT expression in the MS and DBB of Arx^GCG+7 mice. The Arx^GCG+7 CA1 pyramidal neurons exhibited increased firing activity and reduced sag potential. Despite reduced ChAT, carbachol- and pilocarpine-induced firing responses were preserved, while nicotinic receptor-mediated excitation was abolished. Carbachol-induced depolarization block threshold was elevated in mutants. Molecular analysis revealed increased muscarinic receptor 1 expression and decreased β4 nicotinic receptor expression in CA1.Together, these findings demonstrate histological, electrophysiological, and molecular alterations in the septo-hippocampal network of Arx^GCG+7 mice. Together, they suggest impaired cholinergic signaling contributes to ISS pathogenesis and highlight the cholinergic system as a potential therapeutic target.

发展性和癫痫性脑病（DEE）是罕见的神经发育障碍，由癫痫发作、发育迟缓和异常脑电图模式定义。婴儿痉挛综合征（ISS）是最常见的DEE，是最早与单基因变异相关的疾病之一，包括阿里斯塔less相关同源盒（ARX）基因中的多丙氨酸扩增。模拟人类突变的ArxGCG+7小鼠表现出行为表型、癫痫样海马活动和海马胆碱能输入减少。在这个模型中，破坏的胆碱能信号的作用尚未被探索，可能有助于海马功能障碍和DEE的发病机制。因此，我们首先通过再现中隔（MS）和Broca斜带（DBB）中胆碱乙酰转移酶（ChAT）蛋白水平的变化来研究ARX GCG扩张对中隔-海马网络的影响。接下来，我们对CA1锥体神经元进行了离体膜片钳记录，并测量了对胆碱能激动剂的反应。最后，我们通过western blot评估海马中乙酰胆碱受体的表达，以评估受体的稳态变化。我们的数据显示，ArxGCG+7小鼠MS和DBB中的ChAT表达降低 ~ 60 ~ %。ArxGCG+ 7ca1锥体神经元放电活性增加，凹陷电位降低。尽管ChAT减少，但碳醇和匹罗卡品诱导的放电反应得以保留，而尼古丁受体介导的兴奋被消除。突变体中碳甾醇诱导的去极化阻滞阈值升高。分子分析显示CA1中毒蕈碱受体1表达增加，烟碱受体β4表达减少。总之，这些发现证明了ArxGCG+7小鼠中隔-海马网络的组织学、电生理和分子改变。总之，他们认为受损的胆碱能信号有助于ISS的发病机制，并强调胆碱能系统是一个潜在的治疗靶点。

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引用次数: 0

Novel PREP ligand, HUP-46, ameliorates behavioral deficits in an alpha-synuclein based Parkinson's disease model 新型PREP配体HUP-46改善了基于α -突触核蛋白的帕金森病模型中的行为缺陷。

IF 4.2 2区医学 Q1 NEUROSCIENCES

Experimental Neurology

Pub Date : 2025-12-11 DOI: 10.1016/j.expneurol.2025.115593

Tommi Kilpeläinen , Rui Yang , Jyri Toivio , Tony Eteläinen , Francesca De Lorenzo , Bianca Fastré , Cheng Zuo , Johanna K. Uhari-Väänänen , Ulrika Julku , Hengjing Cui , Timo T. Myöhänen

Parkinson's disease (PD) is the most common neurodegenerative movement disorder, and current therapies cannot stop or delay the neuronal death. Therefore, novel therapies having disease-modifying effects are urgently needed. Small-molecular ligands for prolyl oligopeptidase (PREP) have shown disease-modifying effects in various α-synuclein (aSyn) based PD mouse models. We have recently developed novel, more effective PREP ligand series that aim to regulate PREP-related protein-protein interactions, such as with aSyn and protein phosphatase 2 A (PP2A). The most promising novel PREP ligand, HUP-46, was now tested in a PD mouse model based on unilateral AAV-A53T-aSyn virus vector injection on substantia nigra. Our results show that HUP-46, but not reference PREP inhibitor, KYP-2047, was able to restore the behavioral deficit caused by the virus vector injection in the cylinder test. 4-week treatment with PREP ligands reduced the soluble and insoluble aSyn oligomers, and iNOS-positive microglial cells in the substantia nigra. When the effect on microglial activity was further studied in the BV2 microglial cell culture activated by lipopolysaccharide and interferon-γ, the results revealed that HUP-46 but not KYP-2047 significantly reduced TNF-α production. Analysis revealed that HUP-46 reduced p38 phosphorylation and restored autophagic flux in the activated BV2 cells that may contribute to the reduced pro-inflammatory activation of BV2 cells. Taken together, our results suggest that novel PREP ligands, such as HUP-46, can have disease-modifying effect on PD mouse model.

帕金森病（PD）是最常见的神经退行性运动障碍，目前的治疗方法不能阻止或延缓神经元的死亡。因此，迫切需要具有疾病修饰作用的新疗法。脯氨酸寡肽酶（PREP）小分子配体在多种α-突触核蛋白（aSyn）为基础的PD小鼠模型中显示出疾病改善作用。我们最近开发了新的，更有效的PREP配体系列，旨在调节PREP相关蛋白-蛋白相互作用，如与aSyn和蛋白磷酸酶2 A （PP2A）。目前，最具前景的新型PREP配体HUP-46在PD小鼠模型中进行了测试，该模型基于单侧黑质注射AAV-A53T-aSyn病毒载体。结果表明，在柱体试验中，HUP-46能够恢复病毒载体注射引起的行为缺陷，而参考PREP抑制剂KYP-2047则不能。4周的PREP配体治疗减少了黑质中可溶性和不可溶性的aSyn低聚物和inos阳性的小胶质细胞。在脂多糖和干扰素-γ激活的BV2小胶质细胞培养中进一步研究其对小胶质细胞活性的影响，结果表明，HUP-46而非kypp -2047显著降低TNF-α的产生。分析显示，HUP-46降低了活化BV2细胞的p38磷酸化并恢复了自噬通量，这可能有助于降低BV2细胞的促炎激活。综上所述，我们的研究结果表明，新型PREP配体，如HUP-46，可以对PD小鼠模型产生疾病改善作用。

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引用次数: 0

Noninvasive deep brain stimulation using theta-burst transcranial magnetic-acoustic coupling to modulate cortical rhythms in Parkinsonian mice 利用经颅磁声耦合无创深部脑刺激来调节帕金森小鼠的皮质节律。

IF 4.2 2区医学 Q1 NEUROSCIENCES

Experimental Neurology

Pub Date : 2025-12-10 DOI: 10.1016/j.expneurol.2025.115592

Ruixu Liu , Ruru Wang , Xiaoqing Zhou , Fangxuan Chu , Yuheng Wang , Kai Zhu , Shunqi Zhang , Ren Ma , Zhipeng Liu

Modulating the subthalamic nucleus (STN) through neural circuits can suppress abnormal discharge rhythms in the primary motor cortex (M1) in Parkinson's disease (PD), thereby enhancing motor function. However, a clinically viable noninvasive deep brain stimulation method for PD has yet to be realized. We developed a noninvasive transcranial magnetic-acoustic coupling stimulation (TMAS) system, employing a theta burst stimulation (TBS) mode, to examine its effects of simulated electrical parameters on cortical rhythms in PD. The theta burst-TMAS (TBTMAS) system was established, and its physical performance parameters were evaluated. The STN of MPTP-induced Parkinsonian mice was targeted using both continuous TBTMAS (cTBTMAS) and intermittent TBTMAS (iTBTMAS) modes. Local field potentials (LFPs) in the M1 were recorded before and after stimulation to assess pathological biomarkers associated with PD. Results showed that both TBTMAS protocols significantly suppressed abnormal beta oscillations and reduced beta power spectral density (PSD) in the M1 of PD mice. In addition, both modes decreased the beta–ripple phase–amplitude coupling (PAC) index and disrupted PAC locking. Notably, the iTBTMAS mode exhibited a more substantial inhibitory effect on beta PSD and enhanced the downmodulation and decoupling of beta–high gamma PAC phase-locking. These findings suggest that TBTMAS can effectively regulate pathological oscillatory activity in the M1 of PD models, offering a promising non-invasive approach for deep brain stimulation therapy.

通过神经回路调节丘脑下核（STN）可以抑制帕金森病（PD）原发性运动皮层（M1）异常放电节律，从而增强运动功能。然而，一种临床可行的无创PD深部脑刺激方法尚未实现。我们开发了一种无创经颅磁声耦合刺激（TMAS）系统，采用θ波爆发刺激（TBS）模式，研究其模拟电参数对PD皮质节律的影响。建立了theta burst-TMAS （TBTMAS）系统，并对其物理性能参数进行了评价。采用连续TBTMAS （cTBTMAS）和间歇TBTMAS （iTBTMAS）两种模式靶向mptp诱导的帕金森小鼠STN。在刺激前后记录M1的局部场电位（LFPs），以评估PD相关的病理生物标志物。结果表明，两种TBTMAS方案均能显著抑制PD小鼠M1中β振荡异常，降低β功率谱密度（PSD）。此外，两种模式都降低了β纹波相幅耦合（PAC）指数，并破坏了PAC锁定。值得注意的是，iTBTMAS模式对β - PSD表现出更明显的抑制作用，并增强了β -高γ - PAC锁相的降调制和去耦。这些发现表明TBTMAS可以有效调节PD模型M1的病理振荡活动，为深部脑刺激治疗提供了一种有前途的无创方法。

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引用次数: 0

Hydrogen gas promotes neuroprotection and upregulates ATF5 expression in neonatal hypoxic-ischemic brain injury 在新生儿缺氧缺血性脑损伤中，氢气促进神经保护并上调ATF5表达。

IF 4.2 2区医学 Q1 NEUROSCIENCES

Experimental Neurology

Pub Date : 2025-12-10 DOI: 10.1016/j.expneurol.2025.115590

Shinji Nakamura , Yasuhisa Nakamura , Hideo Jinnou , Yasuhiro Nakao , Htun Yinmon , Tsutomu Mitsuie , Kosuke Koyano , Masaki Ueno , Takanori Miki , Kazunobu Sawamoto , Shinji Saitoh , Takashi Kusaka

Neonatal brain injury, typically caused by hypoxia-ischemia (HI), results in irreversible cortical and white matter damage, leading to severe neurological sequelae. Therapeutic hypothermia, the only available clinical intervention, has limited effectiveness and is not suitable for all patients. Molecular hydrogen gas exerts neuroprotective effects due to its antioxidant properties and is gaining attention as a potential therapeutic strategy. However, its cellular and molecular effects in the injured neonatal brain are poorly understood. Using a robust HI brain injury model in neonatal piglets, whose brain structure and development closely resemble those of human neonates, we investigated the cell type-specific impact of hydrogen gas following neonatal HI injury and examined the potential molecular mediators underlying its neuroprotective effects. Hydrogen gas treatment significantly attenuated HI-induced apoptosis in both cortical neurons and white matter oligodendrocytes, thereby preserving their cell densities to levels comparable to uninjured controls. These neuroprotective effects were accompanied by reduced microglial activation, astrocyte expansion and myelin loss. RNAscope analyses revealed that hydrogen gas upregulated the expression of the anti-apoptotic factor activating transcription factor 5 (ATF5) in both neurons and mature oligodendrocytes, suggesting a cell-specific protective mechanism. These findings demonstrate that hydrogen gas exerts robust neuroprotection for cortical neurons and white matter oligodendrocytes following neonatal HI injury, and ATF5 is a potential mediator of its anti-apoptotic effects. Our study highlights the clinical feasibility of hydrogen gas as a novel therapeutic strategy for neonatal brain injury.

新生儿脑损伤通常由缺氧缺血（HI）引起，可导致不可逆的皮质和白质损伤，导致严重的神经系统后遗症。治疗性低温是唯一可用的临床干预措施，其有效性有限，并不适用于所有患者。分子氢气由于其抗氧化特性而具有神经保护作用，作为一种潜在的治疗策略正受到关注。然而，其在新生儿脑损伤中的细胞和分子作用尚不清楚。利用脑结构和发育与人类新生儿非常相似的新生儿仔猪脑损伤模型，我们研究了新生儿HI损伤后氢气对细胞类型的特异性影响，并研究了其神经保护作用的潜在分子介质。氢气处理显著减弱了hi诱导的皮质神经元和白质少突胶质细胞的凋亡，从而使它们的细胞密度保持在与未损伤对照相当的水平。这些神经保护作用伴随着小胶质细胞激活减少、星形胶质细胞扩张和髓磷脂损失。RNAscope分析显示，氢气上调了神经元和成熟少突胶质细胞中抗凋亡因子激活转录因子5 （ATF5）的表达，提示细胞特异性保护机制。这些发现表明，新生儿HI损伤后，氢气对皮质神经元和白质少突胶质细胞具有强大的神经保护作用，而ATF5是其抗凋亡作用的潜在介质。我们的研究强调了氢气作为新生儿脑损伤新治疗策略的临床可行性。

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引用次数: 0