Neurochemistry international最新文献_第10页

Deferoxamine prevents BBB disruption, neuroinflammation and apoptotic changes in early hours of ischemic reperfusion injury 去铁胺可预防缺血再灌注损伤早期血脑屏障破坏、神经炎症和细胞凋亡改变。

IF 4.4 3区医学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY

Neurochemistry international

Pub Date : 2025-06-13 DOI: 10.1016/j.neuint.2025.106009

Rajesh Ugale, Sneha Vatte, Punit Girdhar, Dinesh Anandani

Background

Iron contributes to brain damage in ischemia/reperfusion injury (I/R). Deferoxamine (DFX), an iron chelator, offers neuroprotective action in I/R animal models. However, its underlying mechanism is under investigation. This study aims to investigate effect of DFX on I/R damage led by BBB disruption, neuroinflammation, and apoptosis.

Methods

In adult male Wistar rats, cerebral ischemia was induced by middle cerebral artery occlusion (MCAO). Rats were treated with vehicle or DFX at 100, 200, and 300 mg/kg doses intraperitoneally (i.p.) at time intervals 1, 2, and 3 h of I/R injury. The neuroprotective effect of DFX was observed using histological staining and behavioural assessment after 24 h of I/R injury. Blood-brain barrier (BBB) integrity was evaluated by Evans blue staining & MMP9 expression. Anti-inflammatory effect of DFX was observed using immunohistochemical analysis whereas, anti-apoptotic effects via mRNA expressions of CREB, caspase-3, BDNF and Bcl-2.

Results

DFX (300 mg/kg) at 1 h of I/R injury ameliorates cerebral infarction, neurological deficits, and beam walk score. Histologically, Hoechst, hematoxylin and eosin (H & E), and cresyl violet stainings showed reduced neuronal death in DFX treated rats. It mitigates BBB disruption as observed with Evans blue staining. Additionally, DFX reduced MMP-9 expression indicative of reduced BBB disruption and improved inflammatory changes (CD86 and CD206). Besides, it inhibits mRNA expression of cleaved caspase-3 and improved expression of BDNF and Bcl-2.

Conclusions

Our findings, demonstrate that DFX prevents I/R brain damage in early hour (1 h) of I/R injury by reducing BBB disruption, inflammation, and apoptosis. DFX may exhibit potential to act as adjuvant in management of acute ischemic stroke.

背景：铁与缺血/再灌注损伤（I/R）脑损伤有关。去铁胺（DFX）是一种铁螯合剂，在I/R动物模型中具有神经保护作用。然而，其潜在机制正在调查中。本研究旨在探讨DFX对血脑屏障破坏、神经炎症和细胞凋亡导致的I/R损伤的影响。方法：采用大脑中动脉闭塞法（MCAO）诱导成年雄性Wistar大鼠脑缺血。大鼠分别在I/R损伤后1、2和3小时腹腔注射100、200和300 mg/kg剂量的载药或DFX。I/R损伤24 h后，通过组织学染色和行为学评价观察DFX的神经保护作用。Evans蓝染色及MMP9表达评价血脑屏障（BBB）完整性。通过免疫组化分析观察DFX的抗炎作用，通过CREB、caspase-3、BDNF和Bcl-2 mRNA表达观察其抗凋亡作用。结果：DFX （300 mg/kg）在I/R损伤1小时可改善脑梗死、神经功能缺损和梁行走评分。组织学上，赫斯特、苏木精和伊红（h&e）和甲氧基紫染色显示DFX治疗大鼠神经元死亡减少。埃文斯蓝染色观察到，它减轻了血脑屏障的破坏。此外，DFX降低了MMP-9的表达，表明减少了血脑屏障破坏和改善炎症变化（CD86和CD206）。抑制cleaved caspase-3 mRNA的表达，提高BDNF和Bcl-2的表达。结论：我们的研究结果表明，DFX通过减少血脑屏障破坏、炎症和细胞凋亡，在I/R损伤早期（1小时）预防I/R脑损伤。DFX可能在急性缺血性脑卒中的治疗中显示出辅助治疗的潜力。

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引用次数: 0

Epitranscriptomic shifts in M6A RNA methylation influencing transcriptional dynamics in the prefrontal cortex of chronic restraint stress rats 慢性限制性应激大鼠前额皮质M6A RNA甲基化的表观转录组改变影响转录动力学。

IF 4.4 3区医学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY

Neurochemistry international

Pub Date : 2025-06-13 DOI: 10.1016/j.neuint.2025.106008

Yu Funahashi , Bhaskar Roy , Kevin Prall , Yogesh Dwivedi

Chronic restraint stress (CRS) is a widely used model for investigating stress-induced molecular and neuronal changes. In this study, we examined transcriptome-wide m6A methylation in the prefrontal cortex of CRS rats to understand the molecular impact of stress. Elevated plasma corticosterone levels confirmed the physiological stress response in CRS rats. MeRIP-seq analysis identified 21,669 differentially methylated transcripts, with a predominant hypermethylation pattern (4,301 transcripts) compared to a smaller subset of hypomethylated transcripts (79). Chromosomal distribution revealed widespread hypermethylation across multiple chromosomes, with notable peaks on chromosomes 1, 3, and 10. Gene expression profiling indicated differential regulation of 1,424 genes, with 847 upregulated and 577 downregulated in CRS rats. Integration of m6A methylation and gene expression data revealed an inverse correlation, where hypermethylated transcripts were downregulated, suggesting a role for m6A in transcript stability and turnover. Functional analysis of hypermethylated transcripts highlighted enrichment in key neuronal processes, including synaptic plasticity, neurotransmitter signaling, and chromatin remodeling. Additionally, the 3′UTR of coding transcripts exhibited enriched m6A methylation marks, suggesting a regulatory role in mRNA stability and translation efficiency. RNA level expression analysis revealed significant downregulation of key m6A methylation-related enzymes (METTL3, METTL14, and ALKBH5), further supporting m6A dysregulation under CRS. Pathway analysis underscored the involvement of differentially methylated transcripts in RNA metabolism, chromatin remodeling, and neurobiological pathways linked to stress-related psychiatric disorders. Altogether, the study provides insight into the epitranscriptomic mechanisms underlying stress responses and their implications in neuropsychiatric disorders such as major depression.

慢性抑制应激（CRS）是一种广泛应用于研究应激诱导的分子和神经元变化的模型。在这项研究中，我们检测了CRS大鼠前额叶皮层转录组范围内的m6A甲基化，以了解应激的分子影响。血浆皮质酮水平升高证实了CRS大鼠的生理应激反应。MeRIP-seq分析确定了21,669个差异甲基化转录本，与较小的低甲基化转录本子集相比，主要是高甲基化模式（4301个转录本）。染色体分布显示，高甲基化在多条染色体上广泛存在，在染色体1、3和10上有显著的高峰。基因表达谱显示，CRS大鼠有1424个基因差异调控，其中847个基因上调，577个基因下调。整合m6A甲基化和基因表达数据显示出负相关，其中高甲基化转录本下调，表明m6A在转录本稳定性和周转中起作用。高甲基化转录本的功能分析强调了关键神经元过程中的富集，包括突触可塑性、神经递质信号传导和染色质重塑。此外，编码转录本的3'UTR表现出丰富的m6A甲基化标记，表明其在mRNA稳定性和翻译效率中具有调节作用。表达分析显示m6A关键甲基化相关酶（METTL3、METTL14和ALKBH5）显著下调，进一步支持CRS下m6A失调。通路分析强调了RNA代谢、染色质重塑和与压力相关精神疾病相关的神经生物学通路中差异甲基化转录物的参与。总之，该研究提供了应激反应的表转录组学机制及其在神经精神疾病（如重度抑郁症）中的意义。

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引用次数: 0

DNA methylation and hydroxymethylation dynamics in the aging brain and its impact on ischemic stroke 衰老脑中的DNA甲基化和羟甲基化动力学及其对缺血性脑卒中的影响

IF 4.4 3区医学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY

Neurochemistry international

Pub Date : 2025-06-11 DOI: 10.1016/j.neuint.2025.106007

Vijay Arruri , Pallavi Joshi , Raghu Vemuganti

DNA methylation and hydroxymethylation patterns at the 5th carbon of cytosine (5mC and 5hmC) in CpG dinucleotides tightly regulate gene transcription in normal physiology, aging, and associated diseases, including ischemic stroke. Resilience to ischemic brain injury depends on the interplay of diverse neural and non-neural cell types, whose gene expression and identity are predominantly regulated by brain-enriched epigenetic mechanisms, particularly the dynamics of 5mC and 5hmC in response to changing transcriptional demands under ischemic stress. In this review, we discussed the role of 5mC and 5hmC in aging and the pathophysiology of stroke. Given the high degree of inter-individual variability in stroke studies and its multifactorial etiology, we emphasize the need for personalized, temporally controlled, epigenome-based therapies to improve stroke outcomes.

CpG二核苷酸中胞嘧啶第5碳（5mC和5hmC）的DNA甲基化和羟甲基化模式密切调节正常生理、衰老和相关疾病（包括缺血性中风）的基因转录。对缺血性脑损伤的恢复取决于多种神经和非神经细胞类型的相互作用，其基因表达和身份主要由脑富集的表观遗传机制调节，特别是5mC和5hmC在缺血应激下响应转录需求变化的动态。本文就5mC和5hmC在衰老和脑卒中病理生理中的作用进行综述。鉴于卒中研究的高度个体间变异性及其多因素病因学，我们强调需要个性化、暂时控制、基于表观基因组的治疗来改善卒中预后。

引用次数: 0

Neurochemical in vivo microdialysis and postmortem tissue analysis of amygdala endocannabinoid levels after MAGL- and FAAH-inhibition in rodents MAGL-和faah抑制后啮齿动物杏仁核内源性大麻素水平的神经化学体内微透析和死后组织分析。

IF 4.4 3区医学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY

Neurochemistry international

Pub Date : 2025-06-08 DOI: 10.1016/j.neuint.2025.106006

Mariette S. Heins , Marc D. Ferger , Patrizia Voehringer , Thomas I.F.H. Cremers , Boris Ferger

This study is the first to investigate the target modulation of the MAGL inhibitor elcubragistat (ABX-1431; Lu-AG06466) and the FAAH inhibitor JNJ-42165279 in the amygdala, a brain region involved in stress-induced psychiatric disorders.

We aimed to assess dynamic changes in the endocannabinoid ligands 2-arachidonoylglycerol (2-AG) and anandamide (AEA) following pharmacological inhibition of MAGL and FAAH, enzymes regulating their metabolism.

Freely moving rats received oral doses of elcubragistat or JNJ-42165279. Microdialysis probes in the basolateral amygdala and nucleus accumbens measured extracellular 2-AG and AEA levels over 240 min using LC-MS/MS. A supplementary mouse study analyzed postmortem endocannabinoid levels in the basolateral amygdala.

MAGL inhibition by elcubragistat selectively increased extracellular and tissue 2-AG levels in the basolateral amygdala in a dose-related manner without affecting AEA. Conversely, FAAH inhibition by JNJ-42165279 selectively elevated AEA levels without altering 2-AG. Highest endocannabinoid concentration in basolateral amygdala tissue was between 2 and 4 h after MAGL or FAAH inhibition.

In vivo microdialysis is a sensitive method to study target modulation of both MAGL and FAAH inhibitors in the amygdala of freely moving rats. The results of the microdialysis study are in general agreement with postmortem tissue analysis of both 2-AG and AEA and suitable to support the preclinical drug discovery process in concert with disease related animal models.

这项研究首次研究了MAGL抑制剂elcubragistat (ABX-1431；lug - ag06466)和FAAH抑制剂JNJ-42165279在杏仁核中的作用，杏仁核是一个涉及应激性精神疾病的大脑区域。我们旨在评估内源性大麻素配体2-花生四烯醇甘油（2-AG）和anandamide （AEA）在药物抑制MAGL和FAAH（调节其代谢的酶）后的动态变化。自由活动的大鼠口服elcubragistat或JNJ-42165279。基底外侧杏仁核和伏隔核的微透析探针在240分钟内使用LC-MS/MS测量细胞外2-AG和AEA水平。一项补充小鼠研究分析了死后杏仁核基底外侧的内源性大麻素水平。elcubragistat对MAGL的抑制作用以剂量相关的方式选择性地增加了杏仁核基底外侧细胞外和组织2-AG水平，而不影响AEA。相反，JNJ-42165279抑制FAAH选择性地提高了AEA水平，而不改变2-AG。在MAGL或FAAH抑制后2 - 4小时内，杏仁核基底外侧组织内源性大麻素浓度最高。体内微透析是一种灵敏的方法来研究MAGL和FAAH抑制剂在自由运动大鼠杏仁核中的靶调节。微透析研究的结果与2-AG和AEA的死后组织分析基本一致，适合支持与疾病相关动物模型一致的临床前药物发现过程。

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引用次数: 0

Epigenetic regulation of immune cells in central nervous system: from steady state to pathology 中枢神经系统免疫细胞的表观遗传调控：从稳态到病理。

IF 4.4 3区医学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY

Neurochemistry international

Pub Date : 2025-06-06 DOI: 10.1016/j.neuint.2025.106005

Lei Zhao, Cheyenne L. Schepp, Mona Iskandar, Yilong Tao, Mahua Dey

The central nervous system (CNS) and immune system interact on a regular basis in homeostasis and in pathology. The immune system's response to CNS pathology is intricately regulated by epigenetic regulation of various immune cells that allows these cells to perform diverse and complex functions in a context-dependent manner. Epigenetics refers to modulation of gene expression that is influenced by environmental factors and doesn't depend on alteration of DNA sequence. Epigenetic regulation, such as DNA methylation, histone modification and non-coding RNA, lies at the heart of immune cell biology, integrating intrinsic transcriptional programs with extrinsic signals to dictate different immune cell behaviors. Dysregulation of epigenetic mechanisms largely affects the immune response in various diseases. Understanding epigenetic regulation provides a promising approach to manipulate immune cells behaviors in various disease contexts, thus offering therapeutic benefit window. Here, we review recent findings regarding immune cell behavior and epigenetic regulation in the context of CNS physiology and pathology. We also discuss how epigenetic mechanism contributes to cancer immunotherapy response, as well as ways to utilize combination therapy using epigenetic modifiers and personalized medicine approach to manipulate immune cell function to improve immunotherapy outcomes.

中枢神经系统（CNS）和免疫系统在体内平衡和病理中有规律地相互作用。免疫系统对中枢神经系统病理的反应是由各种免疫细胞的表观遗传调控复杂地调节的，这些免疫细胞允许这些细胞以上下文依赖的方式执行多样化和复杂的功能。表观遗传学是指受环境因素影响而不依赖于DNA序列改变的基因表达调控。表观遗传调控，如DNA甲基化、组蛋白修饰和非编码RNA，是免疫细胞生物学的核心，将内在转录程序与外在信号结合起来，决定不同的免疫细胞行为。表观遗传机制失调在很大程度上影响各种疾病的免疫反应。理解表观遗传调控提供了一种有希望的方法来操纵免疫细胞在各种疾病背景下的行为，从而提供治疗效益窗口。在这里，我们回顾了在中枢神经系统生理学和病理学背景下有关免疫细胞行为和表观遗传调控的最新发现。我们还讨论了表观遗传机制如何影响癌症免疫治疗反应，以及如何利用表观遗传修饰剂和个性化药物方法联合治疗来操纵免疫细胞功能以改善免疫治疗结果。

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引用次数: 0

Gastrin-releasing peptide in the paraventricular nucleus exerts hypertensive effects in preeclampsia 室旁核胃泌素释放肽在子痫前期有高血压作用

IF 4.4 3区医学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY

Neurochemistry international

Pub Date : 2025-06-01 DOI: 10.1016/j.neuint.2025.106004

Xiaomin Wang , Md Ahasan Ali , Xiaoxu Liu , Ming Zeng , Zhaoshu Zeng , Meng Yuan , Abdoulaye Issotina Zibrila , Shumin Liu , Nana Ping , Yuming Kang , Xuelan Li , Jinjun Liu

Background

Preeclampsia (PE) is a pregnancy complication associated with hypertension, whose central mechanism remains unclear. Gastrin-releasing peptide (GRP) is involved in the regulation of central blood pressure, however, whether GRP and its receptor, GRPR, in the paraventricular nucleus of the hypothalamus (PVN) are involved in blood pressure regulation in PE is unknown.

Methods

In this study, we initially assessed GRP/GRPR expression levels and their cellular distribution within the PVN of a PE rat model with reduced uterine perfusion pressure (RUPP). We investigated the effect of five-day antagonism of GRPR with ICI-216140 (1 mM/side/day, PVN microinjection) on PVN activity in this model. On gestational day 19 (GD19), the mean arterial pressure (MAP) was recorded, and samples were collected for analysis. We also investigated the effect of losartan on RUPP-induced changes in MAP and GRP/GRPR expression in the PVN.

Results

RUPP rats exhibited increased MAP, and GRP and GRPR expression in the PVN. GRPR antagonism with ICI-216140 attenuated RUPP intervention-increased MAP and expression of oxidative stress markers including NOX2, NOX4, and reactive oxygen species, NF-κB, and tyrosine hydroxylase in the PVN. While ICI-216140 did not affect the expression of angiotensin II receptor type 1 (AT1R), the blockade of AT1R with losartan decreased MAP 2and GRP expression in RUPP rats.

Conclusions

Our findings suggest that GRP expression in the PVN mediates placental ischemia-induced hypertension and may depend on AT1R activity, which provides new pharmacological avenues for animal models of PE.

背景子痫前期（PE）是一种与高血压相关的妊娠并发症，其主要机制尚不清楚。胃泌素释放肽（GRP）参与中枢血压的调节，但下丘脑室旁核GRP及其受体GRPR是否参与PE的血压调节尚不清楚。方法在子宫灌注压降低（RUPP）的PE大鼠模型中，我们初步评估了GRP/GRPR在PVN内的表达水平及其细胞分布。我们研究了ICI-216140 （1 mM/侧/天，PVN显微注射）对GRPR 5天的拮抗作用对PVN活性的影响。在妊娠第19天（GD19）记录平均动脉压（MAP），并采集标本进行分析。我们还研究了氯沙坦对rupp诱导的PVN中MAP和GRP/GRPR表达变化的影响。结果rupp大鼠PVN中MAP、GRP、GRPR表达增加。ICI-216140对GRPR的拮抗作用减弱了RUPP干预，增加了PVN中MAP和氧化应激标志物（包括NOX2、NOX4和活性氧）、NF-κB和酪氨酸羟化酶的表达。虽然ci -216140不影响血管紧张素II受体1型（AT1R）的表达，但氯沙坦阻断AT1R可降低RUPP大鼠MAP 2和GRP的表达。结论PVN中GRP的表达介导了胎盘缺血致高血压，并可能依赖于AT1R活性，为PE动物模型的建立提供了新的药理途径。

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引用次数: 0

A multiscale atlas of Oprm1-expressing neurons in the central nervous system: Brain-wide distribution, circuit functions, and translational therapeutic implications 中枢神经系统表达oprm1神经元的多尺度图谱：全脑分布、回路功能和翻译治疗意义

IF 4.4 3区医学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY

Neurochemistry international

Pub Date : 2025-05-28 DOI: 10.1016/j.neuint.2025.105998

Zixu Zhang , Shengru Hu , Shuyan Geng , Tianxiang Xu , Xing Liu , Zixuan Lei , Chuanyao Sun , Haoyu Sun , Wei Xie , Mingdao Mu

The mu-opioid receptor (MOR), encoded by the Oprm1 gene, critically modulates diverse physiological processes including pain perception, reward behaviors, emotional regulation, and autonomic control. The genetic complexity and region-specific distribution of Oprm1-expressing neurons underpin both the therapeutic actions and adverse effects of opioid drugs. In this comprehensive review, we systematically construct a multiscale atlas of Oprm1-expressing neurons throughout the central nervous system (CNS) by integrating genetic labeling, neuroanatomical mapping, functional circuit analyses, and translational perspectives. We highlight three interconnected aspects: (1) brain-wide regional distribution patterns, revealing enriched Oprm1 expression across sensory, limbic, and autonomic circuits; (2) functional heterogeneity of Oprm1-expressing neurons, elucidating their distinct roles in nociception, reward processing, emotional and neuroendocrine regulation, with a particular emphasis on sex differences and adaptive plasticity under stress; (3) translational opportunities for therapeutic interventions, focusing on innovative strategies such as circuit-specific opioid modulation and biased agonism, designed to optimize analgesic benefits while minimizing addiction liability and respiratory depression. Furthermore, we critically examine existing challenges and knowledge gaps, including receptor trafficking mechanisms, dynamic changes in Oprm1 expression under conditions such as chronic opioid exposure or stress, interspecies differences, and network-level opioid signaling dynamics. This integrative framework provides essential insights into MOR neurobiology, facilitating the development of next-generation opioid therapeutics that leverage precise modulation of neural circuits and molecular pharmacological advancements. The translational implications of understanding these aspects are emphasized throughout this review, aiming to bridge basic neurobiological findings with clinical applications.

由Oprm1基因编码的mu-阿片受体（MOR）对疼痛感知、奖励行为、情绪调节和自主控制等多种生理过程具有重要的调节作用。表达oprm1的神经元的遗传复杂性和区域特异性分布是阿片类药物治疗作用和不良反应的基础。在这篇综合综述中，我们通过整合遗传标记、神经解剖图谱、功能电路分析和翻译观点，系统地构建了整个中枢神经系统（CNS）表达oprm1神经元的多尺度图谱。我们强调了三个相互关联的方面：(1)全脑区域分布模式，揭示了在感觉、边缘和自主神经回路中丰富的Oprm1表达；(2)表达oprm1的神经元的功能异质性，阐明了它们在伤害感受、奖励加工、情绪和神经内分泌调节中的独特作用，特别强调了性别差异和应激下的适应可塑性；(3)治疗干预的转化机会，重点是创新策略，如电路特异性阿片类药物调节和偏倚激动作用，旨在优化镇痛效果，同时最大限度地减少成瘾倾向和呼吸抑制。此外，我们批判性地研究了现有的挑战和知识空白，包括受体运输机制，慢性阿片类药物暴露或应激条件下Oprm1表达的动态变化，物种间差异和网络水平阿片类药物信号动力学。这一综合框架提供了对MOR神经生物学的重要见解，促进了利用神经回路精确调节和分子药理学进步的下一代阿片类药物的发展。理解这些方面的翻译意义强调在整个审查，旨在桥梁基础神经生物学的发现与临床应用。

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引用次数: 0

Bioactive ROS-responsive nanotherapeutics attenuate intermittent hypoxia-induced cognitive impairment via NRF2/KEAP1/HO-1 signaling 生物活性ros反应纳米疗法通过NRF2/KEAP1/HO-1信号通路减弱间歇性缺氧诱导的认知障碍

IF 4.4 3区医学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY

Neurochemistry international

Pub Date : 2025-05-26 DOI: 10.1016/j.neuint.2025.105997

Yinpei Huang , Hailun Xie , Lian Liu , Heng Zhao , Bing Li , Feng Zhang

Obstructive sleep apnea (OSA) is characterized by chronic intermittent hypoxia (IH), which induces oxidative stress and neuronal apoptosis, ultimately leading to progressive cognitive impairment. This study investigated the neuroprotective potential of a reactive oxygen species (ROS)-responsive nanotherapeutic, namely TPCD nanoparticles (TPCD NP), synthesized through the conjugation of Tempol and phenylboronic acid pinacol ester to β-cyclodextrin, in both in vivo and in vitro models. In rats, intravenous administration of TPCD NP improved memory performance as assessed by the Morris water maze test, and preserved hippocampal neuronal morphology. TPCD NP significantly reduced intracellular ROS content and malondialdehyde (MDA) levels while restoring antioxidant capacity, including superoxide dismutase (SOD) and glutathione (GSH). Apoptosis was attenuated, as evidenced by the downregulation of Bax and cleaved caspase-3, and the upregulation of Bcl-2 expression. Mechanistically, TPCD NP enhanced the nuclear translocation of nuclear factor erythroid 2–related factor 2 (NRF2), suppressed Kelch-like ECH-associated protein 1 (KEAP1), and increased heme oxygenase-1 (HO-1) expression. The protective effects were abolished by ML385, a selective NRF2 inhibitor, confirming the essential role of NRF2 activation in mediating the antioxidant and anti-apoptotic effects of TPCD NP. In conclusion, TPCD NP attenuates oxidative stress and apoptosis induced by IH in the hippocampus by activating the NRF2/KEAP1/HO-1 pathway. These findings highlight TPCD NP as a promising therapeutic strategy for OSA-associated neurodegeneration.

阻塞性睡眠呼吸暂停（OSA）以慢性间歇性缺氧（IH）为特征，诱导氧化应激和神经元凋亡，最终导致进行性认知功能障碍。本研究在体内和体外模型中研究了一种活性氧（ROS）反应的纳米治疗药物，即TPCD纳米颗粒（TPCD NP），该纳米治疗药物是通过Tempol和苯硼酸蒎醇酯与β-环糊精偶联合成的。Morris水迷宫实验显示，大鼠静脉注射TPCD NP改善了记忆表现，并保留了海马神经元形态。TPCD NP显著降低细胞内ROS含量和丙二醛（MDA）水平，同时恢复抗氧化能力，包括超氧化物歧化酶（SOD）和谷胱甘肽（GSH）。细胞凋亡减弱，Bax和cleaved caspase-3下调，Bcl-2表达上调。机制上，TPCD NP增强核因子红细胞2相关因子2 （NRF2）的核易位，抑制kelch样ech相关蛋白1 (KEAP1)，增加血红素氧合酶1 （HO-1）的表达。选择性NRF2抑制剂ML385消除了这种保护作用，证实了NRF2激活在介导TPCD NP的抗氧化和抗凋亡作用中的重要作用。综上所述，TPCD NP通过激活NRF2/KEAP1/HO-1通路，减轻IH诱导的海马氧化应激和凋亡。这些发现强调了TPCD NP作为一种有希望的治疗osa相关神经变性的策略。

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引用次数: 0

Activation or blockade of prelimbic 5-HT4 receptors improves working memory in hemiparkinsonian rats 激活或阻断边缘前5-HT4受体可改善半帕金森大鼠的工作记忆。

IF 4.4 3区医学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY

Neurochemistry international

Pub Date : 2025-05-23 DOI: 10.1016/j.neuint.2025.105996

Jie Yang , Li Chen , Xiaoying Li , Yuan Guo , Hao Hu , Fan Li , Tao Wang , Yong Wang , Lu Yao , Li Zhang , Jian Liu

Working memory deficits commonly occur in Parkinson's disease. 5-hydroxytryptamine₄ (5-HT₄) receptors are widely distributed in the prelimbic cortex (PrL) and involved in cognition. Here we tested the effects of activation and blockade of PrL 5-HT₄ receptors on working memories by T-maze rewarded alternation and Morris water maze tests in rats with unilateral 6-hydroxydopamine (6-OHDA) lesion of the medial forebrain bundle. The lesion induced working memory deficits, decreased dopamine levels in the limbic-related brain regions, changed normalized δ, high θ, α, β, low and high γ power of the PrL, and upregulated expression of PrL 5-HT₄ receptor. Intra-PrL injection of 5-HT₄ receptor agonist BIMU8 or antagonist GR113808 did not impact working memories in sham rats, but improved working memory deficits in the lesioned rats. Intra-PrL injection of BIMU8 or GR113808 had no effect on monoamine levels in the limbic-related brain regions or normalized low and high γ power of the PrL in sham rats. However, in the lesioned rats, intra-PrL injection of BIMU8 significantly increased dopamine and 5-HT levels in the medial prefrontal cortex, amygdala and dorsal hippocampus, while intra-PrL injection of GR113808 significantly increased dopamine levels in these brain regions and increased normalized low and high γ power of the PrL. These results suggest that 6-OHDA lesion in rats induces working memory deficits, while activation or blockade of PrL 5-HT₄ receptors improves the deficits in the lesioned rats, which possibly due to the changes of monoamine levels in the limbic-related brain regions and network activity of neurons in the PrL.

工作记忆缺陷通常发生在帕金森氏症中。5-羟色胺4 （5-HT4）受体广泛分布于大脑前边缘皮层（PrL），参与认知活动。采用t -迷宫奖励交替和Morris水迷宫实验，对单侧6-羟多巴胺（6-OHDA）损伤大鼠进行了prl5 - ht4受体激活和阻断对工作记忆的影响。损伤导致大鼠工作记忆缺失，边缘相关脑区多巴胺水平降低，PrL δ、高θ、α、β、低γ和高γ能量发生改变，PrL 5-HT4受体表达上调。prl内注射5-HT4受体激动剂BIMU8或拮抗剂GR113808不影响假手术大鼠的工作记忆，但改善了损伤大鼠的工作记忆缺陷。PrL内注射BIMU8或GR113808对假大鼠边缘相关脑区的单胺水平或PrL的正常低γ和高γ功率均无影响。然而，在损伤大鼠中，PrL内注射BIMU8显著增加了内侧前额叶皮层、杏仁核和海马背侧的多巴胺和5-HT水平，而PrL内注射GR113808显著增加了这些脑区域的多巴胺水平，并增加了PrL的正常低γ和高γ功率。这些结果表明，6-OHDA损伤大鼠可诱发工作记忆缺陷，而激活或阻断PrL 5-HT4受体可改善损伤大鼠的工作记忆缺陷，这可能与大脑边缘相关区域单胺水平和PrL神经元网络活动的改变有关。

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引用次数: 0

Impact of NLRP6 inflammasome on neuroinflammation in temporal lobe epilepsy NLRP6炎性小体对颞叶癫痫神经炎症的影响

IF 4.4 3区医学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY

Neurochemistry international

Pub Date : 2025-05-19 DOI: 10.1016/j.neuint.2025.105994

Yiming Guo , Jiaqi Song , Yingxi Chen , Yang Lü , Weihua Yu

Epilepsy is one of the most common and severe chronic brain diseases, affecting up to 70 million people worldwide. Neuroinflammation plays a central role in the progression of the disease. The Nod-Like Receptor Protein 6 (NLRP6) inflammasome assembles with apoptosis-associated speck-like protein (ASC) to cleave pro-caspase-1 into caspase-1, thus forming the NLRP6 inflammasome. This process promotes the maturation and release of downstream interleukins (IL)-18 and IL-1β, exacerbating pathological processes in various diseases. In this study, we demonstrated significantly enhanced NLRP6 expression in the cortex and hippocampus of epileptic mice, suggesting a role for the inflammasome in epilepsy. Immunofluorescence staining further revealed that NLRP6 was predominantly expressed in hippocampal neurons of these mice. Additionally, knockdown of NLRP6 reduced susceptibility to epilepsy, alleviated post-seizure neuronal damage, and decreased levels of pro-inflammatory cytokines, including IL-18, IL-1β, and IL-6. Conversely, NLRP6 overexpression produced opposite effects, which were effectively reversed by treatment with the caspase-1 inhibitor VX765. To the best of our knowledge, this is the first study to demonstrate a link between NLRP6 and the activation of the caspase-1/IL-1β/IL-18 signaling pathway in a kainic acid (KA)-induced epilepsy mouse model. Administration of VX765 alleviated pathological alterations and exerted neuroprotective effects. These findings suggest that NLRP6 plays a critical role in the initiation and progression of epilepsy.

癫痫是最常见和最严重的慢性脑部疾病之一，影响全世界多达7000万人。神经炎症在疾病的发展中起着核心作用。nod样受体蛋白6 （NLRP6）炎性小体与凋亡相关斑点样蛋白（ASC）结合，将前caspase-1切割成caspase-1，从而形成NLRP6炎性小体。这一过程促进下游白细胞介素(IL)-18和IL-1β的成熟和释放，加剧了各种疾病的病理过程。在本研究中，我们发现NLRP6在癫痫小鼠的皮层和海马中的表达显著增强，提示炎症小体在癫痫中的作用。免疫荧光染色进一步显示NLRP6在小鼠海马神经元中主要表达。此外，NLRP6的敲低降低了癫痫的易感性，减轻了癫痫后的神经元损伤，降低了促炎细胞因子的水平，包括IL-18、IL-1β和IL-6。相反，NLRP6过表达产生相反的效果，用caspase-1抑制剂VX765治疗可有效逆转。据我们所知，这是第一个在kainic酸（KA）诱导的癫痫小鼠模型中证明NLRP6与caspase-1/IL-1β/IL-18信号通路激活之间存在联系的研究。VX765可减轻病理改变，发挥神经保护作用。这些发现表明NLRP6在癫痫的发生和发展中起着关键作用。

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