Molecular and Cellular Neuroscience最新文献_第4页

Rethinking Parkinson's: The role of proteostasis networks and autophagy in disease progression 重新思考帕金森病：蛋白质平衡网络和自噬在疾病进展中的作用。

IF 2.6 3区医学 Q3 NEUROSCIENCES

Molecular and Cellular Neuroscience

Pub Date : 2025-06-07 DOI: 10.1016/j.mcn.2025.104023

Akhil Sharma, Ashi Mannan, Thakur Gurjeet Singh

Protein dyshomeostasis is identified as the hallmark of many age-related NDDs including Parkinson's disease (PD). PD is a progressive neurodegenerative disorder (NDD) characterized by the accumulation of misfolded proteins, particularly α-synuclein (α-syn) leading to formation of Lewy bodies and cause degeneration of dopaminergic neurons in substantia nigra pars compacta (SNpc). Disruption of the cell's normal protein balance, which occurs when cells experience stress, plays a key role in causing the formation of harmful protein clumps. Functional proteostasis relies on coordinated mechanisms involving posttranslational modifications (PTMs), molecular chaperones, the unfolded protein response (UPR), the ubiquitin-proteasome system (UPS), and the autophagy-lysosome pathway (ALP). These networks maintain proper synthesis, folding, confirmation and degradation of protein such as α-syn protein in PD. These approaches include enhancing lysosomal function, promoting autophagy and modulating the unfolded protein response. Understanding the complex interactions between these pathways is essential for developing effective treatments. This review synthesizes current knowledge of various genes and molecular mechanisms underlying proteostasis disruption in PD and evaluates emerging therapeutic strategies that target multiple genes and pathways simultaneously. The finding highlights the potential of integrated approaches to restore protein homeostasis and prevent neurodegeneration, offering new directions for PD treatment development.

蛋白质失衡被认为是许多与年龄相关的ndd的标志，包括帕金森病（PD）。PD是一种进行性神经退行性疾病（NDD），其特征是错误折叠蛋白，特别是α-突触核蛋白（α-syn）的积累导致路易小体的形成，并导致黑质致密部（SNpc）多巴胺能神经元的变性。当细胞受到压力时，细胞正常的蛋白质平衡就会被破坏，这在导致有害蛋白质团块的形成中起着关键作用。功能性蛋白质静止依赖于包括翻译后修饰（PTMs）、分子伴侣、未折叠蛋白反应（UPR）、泛素-蛋白酶体系统（UPS）和自噬-溶酶体途径（ALP）在内的协调机制。这些网络维持PD中α-syn蛋白等蛋白质的正常合成、折叠、确认和降解。这些方法包括增强溶酶体功能，促进自噬和调节未折叠蛋白反应。了解这些途径之间复杂的相互作用对于开发有效的治疗方法至关重要。这篇综述综合了目前关于PD中蛋白质平衡破坏的各种基因和分子机制的知识，并评估了同时针对多个基因和途径的新兴治疗策略。这一发现突出了综合方法在恢复蛋白质稳态和预防神经退行性变方面的潜力，为PD治疗的发展提供了新的方向。

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引用次数: 0

Apelin-13 can regulate adipose-derived mesenchymal stem cells to improve traumatic brain injury Apelin-13可调节脂肪源性间充质干细胞改善外伤性脑损伤。

IF 2.6 3区医学 Q3 NEUROSCIENCES

Molecular and Cellular Neuroscience

Pub Date : 2025-06-06 DOI: 10.1016/j.mcn.2025.104016

Min Huang , Yong Zhang , Yanyang Shen, Yiqin Xu, Xuehong Liu

Traumatic brain injury (TBI) is one of the most serious neurological diseases worldwide. At present, there is no effective treatment for TBI. The regenerative effects of adipose-derived mesenchymal stem cells (ADSCs) on neuronal injury have garnered considerable concern in the scientific community over the past decade. Apelin-13, a key member of the apelin family, has anti-apoptotic, anti-inflammatory, and antioxidative stress effects. ADSCs can modify the microenvironment to enhance neuronal survival through secreting regulatory factors. Apelin-13 can regulate the microenvironment of ADSC differentiation to promote the growth and differentiation of ADSCs. This review delves into ADSCs' therapeutic potential in brain injury pathogenesis, explores apelin-13 protective mechanism against neurological damage, and analyzes how apelin-13 regulates ADSCs to achieve the modulatory effect on neurological recovery.

创伤性脑损伤（TBI）是世界范围内最严重的神经系统疾病之一。目前，还没有有效的治疗方法。在过去的十年中，脂肪源性间充质干细胞（ADSCs）对神经元损伤的再生作用在科学界引起了相当大的关注。apelin -13是apelin家族的重要成员，具有抗凋亡、抗炎和抗氧化应激作用。ADSCs可以通过分泌调节因子来改变微环境，提高神经元的存活率。Apelin-13可以调节ADSC分化的微环境，促进ADSC的生长分化。本文将深入探讨ADSCs在脑损伤发病机制中的治疗潜力，探讨apelin-13对神经损伤的保护机制，分析apelin-13如何调控ADSCs实现对神经功能恢复的调节作用。

引用次数: 0

Regulation of hippocampal excitatory synapse development by the adhesion G-protein coupled receptor brain-specific angiogenesis inhibitor 2 (BAI2/ADGRB2) 粘附g蛋白偶联受体脑特异性血管生成抑制剂2 （BAI2/ADGRB2）对海马兴奋性突触发育的调控

IF 2.6 3区医学 Q3 NEUROSCIENCES

Molecular and Cellular Neuroscience

Pub Date : 2025-05-30 DOI: 10.1016/j.mcn.2025.104015

Christina M. Meyer, Olga Vafaeva, Henry Low, David J. Speca, Elva Díaz

Glutamatergic synapses and their associated dendritic spines are critical information processing sites within the brain. Proper development of these specialized cellular junctions is important for normal brain functionality. Synaptic adhesion G protein-coupled receptors (aGPCRs) have been identified as regulators of synapse development and function. While two members of the Brain-specific angiogenesis inhibitor (BAI/ADGRB) subfamily of synaptic aGPCRs, BAI1/ADGRB1 and BAI3/ADGRB3, have been found to mediate synapse and spine formation, BAI2/ADGRB2 function remains uncharacterized at the synapse. Here, we show that endogenous ADGRB2 is expressed throughout the nervous system with prominent expression in synapse dense regions of the hippocampus. In dissociated hippocampal cultures, ADGRB2 is highly enriched at large postsynaptic sites, defined by the size of the postsynaptic scaffold PSD95. Loss of ADGRB2 negatively impacts glutamatergic synapses across development in dissociated hippocampal cultures. In contrast, GABAergic synapse density is unchanged. Furthermore, ADGRB2 deficient neurons have significant alterations in spine morphology with decreased density of mature PSD95-containing mushroom-shaped spines compared with wild-type neurons. Interestingly, no major alterations in dendritic complexity were observed in ADGRB2 deficient neurons, in contrast to previous results for the other BAIs/ADGRBs. The reduction in mature mushroom-shaped spines is commensurate with a reduction in spine volume and head diameter. Altogether, these results demonstrate that the aGPCR ADGRB2 is an important regulator of glutamatergic synapse and PSD95-associated spine development in cultured hippocampal neurons. These results expand the knowledge of the BAI/ADGRB subfamily of aGPCRs in mediating excitatory synapse and spine development and highlight differences unique to ADGRB2.

谷氨酸突触及其相关的树突棘是大脑中重要的信息处理位点。这些特化细胞连接的适当发育对正常的脑功能很重要。突触粘附G蛋白偶联受体（agpcr）已被确定为突触发育和功能的调节因子。虽然脑特异性血管生成抑制剂（BAI/ADGRB）突触agpcr亚家族的两个成员BAI1/ADGRB1和BAI3/ADGRB3已被发现介导突触和脊柱形成，但BAI2/ADGRB2在突触中的功能仍未被表征。在这里，我们发现内源性ADGRB2在整个神经系统中表达，在海马突触密集区表达突出。在分离的海马培养物中，ADGRB2在大突触后位点高度富集，这是由突触后支架PSD95的大小决定的。在分离的海马培养中，ADGRB2的缺失会对谷氨酸突触的发育产生负面影响。相比之下，gaba能突触密度不变。此外，与野生型神经元相比，ADGRB2缺陷神经元的脊柱形态发生了显著改变，含psd95的成熟蘑菇状脊柱密度降低。有趣的是，与其他BAIs/ adgrb相比，ADGRB2缺陷神经元的树突复杂性没有发生重大变化。成熟蘑菇状脊柱的减少与脊柱体积和头部直径的减少是相称的。总之，这些结果表明，aGPCR ADGRB2是培养海马神经元中谷氨酸突触和psd95相关脊柱发育的重要调节因子。这些结果扩大了对介导兴奋性突触和脊柱发育的agpcr的BAI/ADGRB亚家族的认识，并突出了ADGRB2特有的差异。

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引用次数: 0

Peroxisome, neuropeptide, and inflammation signaling pathways uniquely impacted by opioid exposure in the hypothalamus of males and females 过氧化物酶体、神经肽和炎症信号通路受阿片类物质暴露在男性和女性下丘脑中的独特影响。

IF 2.6 3区医学 Q3 NEUROSCIENCES

Molecular and Cellular Neuroscience

Pub Date : 2025-05-30 DOI: 10.1016/j.mcn.2025.104014

G.R. Sunderland , B.R. Southey , M.B. Villamil , S.L. Rodriguez-Zas

Synaptic plasticity is a recognized neuroadaptation of the brain in response to environmental cues. In addition, differences between females and males in neuronal plasticity in response to opioids have been reported. However, the response to opioids in the hypothalamus, a structure that encompasses sexually dimorphic nuclei, is partially characterized. Furthering the characterization of the sex-dependent dysregulation of gene networks, the hypothalamus transcriptome was profiled in female and male pigs that were exposed to morphine relative to controls. Among the 923 genes that were differentially expressed (FDR-adjusted p-value <0.05) across treatments and sexes, 179 genes were identified between saline and morphine-treated females, and 129 genes were identified between saline-treated females and males. The under-expression of genes in the morphine-exposed relative to the saline groups in both sexes characterized the enrichment of the peroxisome pathway and neuropeptide signaling process whereas the opposite pattern characterized the enrichment of the glutamatergic synapse pathway in females. The neuropeptide pathway included differentially expressed neuropeptide and corresponding receptor genes, including Npy and its family receptors, Penk, Pomc, and Tac1, and the peroxisome pathway included Mvk and Dao and the Hmgc family of genes. The effect of morphine treatment in males was detected in the enrichment of the interleukin-17 and T cell receptor signaling pathways. These results offer further evidence that chronic morphine exposure evokes distinct molecular mechanism disruption in females and males, highlighting the need for sex-dependent molecular target therapies.

突触可塑性是一种公认的大脑对环境信号的神经适应。此外，女性和男性对阿片类药物反应的神经元可塑性存在差异。然而，下丘脑对阿片类药物的反应是部分特征，下丘脑是一个包含两性二态核的结构。进一步表征基因网络的性别依赖性失调，在相对于对照组暴露于吗啡的雌性和雄性猪的下丘脑转录组中进行了分析。在923个差异表达基因中（经fdr调整的p值）

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引用次数: 0

A potential role for NADPH oxidase (NOX1/2) in mutant huntingtin-induced anomalous neurite outgrowth NADPH氧化酶（NOX1/2）在突变型亨廷顿蛋白诱导的异常神经突生长中的潜在作用。

IF 2.6 3区医学 Q3 NEUROSCIENCES

Molecular and Cellular Neuroscience

Pub Date : 2025-05-22 DOI: 10.1016/j.mcn.2025.104012

Luisana Duque Villegas , Alberte Vad Mathiesen , Izabela Rasmussen , Maria von Broich , Filippa Liliendahl Qvist , Niels Skotte , Costanza Ferrari Bardile , Esben Budtz-Jørgensen , Kristine Freude , Benjamin Schmid , Mahmoud A. Pouladi , Anne Nørremølle , Frederik Vilhardt

Neurite growth is regulated by NADPH Oxidase (NOX1 and 2) and in this study, we investigate whether neuritic abnormalities observed in stem cell models of Huntington's disease relates to altered NOX function during NGF-driven differentiation of PC12 neuronal cells. NOX1 and 2 were contained in separate vesicular compartments, and by overexpression inhibited or promoted neurite extension, respectively. Expression of mutant Htt (mHtt; exon 1 fragment) accelerated neuronal induction causing longer neurites in the first phase of differentiation, but fewer and shorter mature neurites. Htt/mHtt increased NOX2 protein levels but did not change global oxidant production; However, Htt/mHtt prominently redistributed NOX activity to neurites. Oxidant production was concentrated in intraluminal vesicles in multivesicular bodies, and mHtt specifically increased secretion of NOX1 in exosomes, which demonstrated oxidant production capacity, while rerouting NOX2 to lysosomal degradation. Knockdown of TSG101, required for intraluminal vesicle formation, increased cellular levels of NOX2/p22phox and neurite growth.

Our study provides new insights on the disposition of NOX enzymes in nerve cells, indicating that deficient neurites in HD may be a correlate of altered trafficking, distribution, and activity of NOX.

神经突的生长受NADPH氧化酶（NOX1和2）的调节，在本研究中，我们研究了亨廷顿病干细胞模型中观察到的神经突异常是否与ngf驱动的PC12神经元细胞分化过程中NOX功能的改变有关。NOX1和no2分别包含在不同的囊室中，通过过表达分别抑制或促进神经突的延伸。突变体Htt的表达(mHtt；外显子1片段)加速了神经元的诱导，导致分化第一阶段的神经突变长，而成熟阶段的神经突变少、变短。Htt/mHtt增加了NOX2蛋白水平，但没有改变整体氧化剂的产生；然而，Htt/mHtt显著地将NOX活性重新分配给神经突。氧化剂的产生集中在多泡体的腔内囊泡中，而mHtt特异性地增加了外泌体中NOX1的分泌，这表明了氧化生产能力，同时将NOX2转向溶酶体降解。敲低腔内囊泡形成所需的TSG101，增加细胞中NOX2/p22phox水平和神经突生长。我们的研究为神经细胞中氮氧化物酶的配置提供了新的见解，表明HD患者的神经突缺陷可能与氮氧化物运输、分布和活性的改变有关。

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引用次数: 0

The role of alarmins in neuroinflammation following spinal cord injury: A systematic review of the literature 警报在脊髓损伤后神经炎症中的作用：文献的系统回顾

IF 2.6 3区医学 Q3 NEUROSCIENCES

Molecular and Cellular Neuroscience

Pub Date : 2025-05-17 DOI: 10.1016/j.mcn.2025.104011

Christian Rajkovic , Donald MacElroy , Eris Spirollari , Sima Vazquez , Galadu Subah , Julianna Lazzari , Sabrina L. Zeller , John V. Wainwright , Meena Jhanwar-Uniyal , Merritt D. Kinon

Background

Alarmins, or damage-associated molecular patterns (DAMPs), are a diverse class of molecules essential for cellular homeostasis; however, their activation following traumatic cell necrosis contributes to neuroinflammation leading to neurologic deficits. This review aims to highlight the current preclinical alarmin studies and define their neuroprotective role in the treatment of SCI.

Methods

A systematic review was performed to evaluate studies investigating alarmin-mediated immune and neuroinflammatory responses following SCI in animal models. Primary outcomes investigated included immunostaining of cell lines, quantification of alarmin, cytokine, and inflammatory mediators, myelin staining, and animal function scores.

Results

IL-1α, HMGB1, S100A1, MIF, D-DT, IL-33, heme, cell-free DNA, and extracellular nucleotides were found to act as alarmins in animal models of SCI. The expression of these molecules in neurons and neuroglia at the SCI lesion site increased levels of TNF-α, IL-1β, and iNOS, contributing to neuroinflammation. Induction of the neurotoxic phenotypes of macrophages, microglia, and astrocytes by IL-1α, HMGB1, and IL-33 promoted cell death and reduction in oligodendrocyte number. Inhibitors of alarmin-signaling pathways, such as toll-like receptors (TLRs), IL-1R1, RAGE, ST2, and mTOR improved neurological function, as shown by enhanced postoperative locomotion.

Conclusions

Elevated alarmin expression and activity at the SCI site contribute to functional deficits by augmenting neuroinflammation, cell death, and cytotoxic neuroglia. Targeting alarmin-mediated signaling pathways represents a promising therapeutic approach in SCI treatment.

损伤相关分子模式（DAMPs）是一类对细胞稳态至关重要的分子。然而，它们在创伤性细胞坏死后的激活会导致神经炎症，导致神经功能缺陷。本文综述了目前的临床前警报素研究，并明确了它们在脊髓损伤治疗中的神经保护作用。方法对动物模型脊髓损伤后报警蛋白介导的免疫和神经炎症反应进行系统评价。研究的主要结果包括细胞系的免疫染色、警报素、细胞因子和炎症介质的定量、髓磷脂染色和动物功能评分。结果sil -1α、HMGB1、S100A1、MIF、D-DT、IL-33、血红素、游离DNA和胞外核苷酸在脊髓损伤动物模型中起报警作用。这些分子在脊髓损伤部位的神经元和神经胶质中的表达增加了TNF-α、IL-1β和iNOS的水平，从而导致神经炎症。IL-1α、HMGB1和IL-33诱导巨噬细胞、小胶质细胞和星形胶质细胞的神经毒性表型可促进细胞死亡和少突胶质细胞数量减少。报警信号通路的抑制剂，如toll样受体（TLRs）、IL-1R1、RAGE、ST2和mTOR，可改善神经功能，如术后运动增强。结论脊髓损伤部位报警蛋白表达和活性的升高通过增加神经炎症、细胞死亡和细胞毒性神经胶质细胞而导致功能缺陷。靶向报警介导的信号通路在脊髓损伤治疗中是一种很有前途的治疗方法。

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引用次数: 0

Striatal damage may underlie motor learning impairment following experimental mild traumatic brain injury in mice 纹状体损伤可能是小鼠实验性轻度创伤性脑损伤后运动学习障碍的基础

IF 2.6 3区医学 Q3 NEUROSCIENCES

Molecular and Cellular Neuroscience

Pub Date : 2025-05-14 DOI: 10.1016/j.mcn.2025.104013

Caroline Amaral Machado , Bruna da Silva Oliveira , Heliana de Barros Fernandes , Ricardo Tadeu de Carvalho , Emanuele Tadeu Pozzolin , Lucas Miranda Kangussu , Brener Cunha Carvalho , Antônio Lúcio Teixeira , Aline Silva de Miranda

The Renin-Angiotensin system (RAS) has receptors in key brain areas, including the striatum, and has been implicated in traumatic brain injury (TBI) outcomes through involvement in inflammation and oxidative stress. To date, whether striatal RAS dysregulation alongside inflammatory response and oxidative stress underlie mild TBI-related motor coordination and learning impairments remain to be explored. Herein, we employed a weight drop model to induce mild TBI (mTBI) in mice and investigate striatal damage at 72 h after the trauma. mTBI mice displayed significant decrease in the motor learning index and increase in the latency to fall in the rotarod compared with sham controls. In parallel, mTBI-mice had increased expression of RAS classical arm components AT1 and AT2 receptors along with a decrease in RAS counter-regulatory component Mas receptor in the ipsilateral striatum. The neurotrophic factor GDNF increased and the chemokine CX3CL1 decreased in the ipsilateral striatum while TNF-α enhanced in the contralateral striatum at 72 h after mTBI. Higher lipid peroxidation (TBARS) levels were found in both ipsilateral and contralateral striatum of mTBI mice compared with sham mice. We provided original evidence that changes in RAS, inflammatory, neurotrophic and oxidative stress responses in the striatum may contribute to motor dysfunction following acute mTBI.

肾素-血管紧张素系统（RAS）在包括纹状体在内的关键脑区都有受体，并且通过参与炎症和氧化应激与创伤性脑损伤（TBI）的结果有关。到目前为止，纹状体RAS失调是否与炎症反应和氧化应激一起成为轻度创伤性脑损伤相关运动协调和学习障碍的基础仍有待探索。在此，我们采用体重下降模型诱导小鼠轻度TBI (mTBI)，并在创伤后72 h观察纹状体损伤。与假对照组相比，mTBI小鼠的运动学习指数明显下降，旋转体的跌倒潜伏期明显增加。同时，mtbi小鼠在同侧纹状体中RAS经典臂组分AT1和AT2受体的表达增加，RAS反调控组分Mas受体的表达减少。mTBI后72h，同侧纹状体神经营养因子GDNF升高，趋化因子CX3CL1降低，对侧纹状体TNF-α升高。与假手术小鼠相比，mTBI小鼠的同侧纹状体和对侧纹状体均发现较高的脂质过氧化（TBARS）水平。我们提供的原始证据表明，纹状体中RAS、炎症、神经营养和氧化应激反应的变化可能导致急性mTBI后的运动功能障碍。

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引用次数: 0

RNA-based therapies for neurodegenerative disease: Targeting molecular mechanisms for disease modification 基于rna的神经退行性疾病治疗：靶向疾病修饰的分子机制

IF 2.6 3区医学 Q3 NEUROSCIENCES

Molecular and Cellular Neuroscience

Pub Date : 2025-05-06 DOI: 10.1016/j.mcn.2025.104010

Vishal Bhati, Sonima Prasad, Atul Kabra

Neurodegenerative diseases such as Alzheimer's disease (AD), Parkinson's disease (PD), and Huntington's disease (HD) are characterized by progressive neuronal damage, protein aggregation, and chronic inflammation, leading to cognitive and motor impairments. Despite symptomatic relief from current therapies, disease-modifying treatments targeting the core molecular mechanism are still lacking. RNA-based therapies offer a promising approach to treating neurodegenerative disease by targeting molecular mechanisms such as gene expression, protein synthesis, and neuroinflammation. Therapeutic strategies include Long non-coding RNA (lncRNA), Antisense oligonucleotides (ASOs), RNA interference (RNAi), small interfering RNA (siRNA) and short hairpin RNA (shRNA), messenger RNA (mRNA) therapies, and microRNA (miRNA)-based interventions. These therapies aim to decrease toxic protein accumulation, restore deficient proteins, and modulate inflammatory responses in conditions like AD, PD, and HD. Unlike conventional treatments that primarily manage symptoms, RNA-based therapies have the potential to modify disease progression by addressing its root causes. This review aims to provide a comprehensive overview of current RNA-based therapeutic strategies for neurodegenerative diseases, discussing their mechanism of action, preclinical and clinical advancement. It further explores innovative solutions, including nanocarrier-mediated delivery, chemical modifications to enhance RNA stability, and personalized medicine approaches guided by genetic profiling that are being developed to overcome these barriers. This review also underscores the therapeutic opportunities and current limitations of RNA-based interventions, highlighting their potential to transform the future of neurodegenerative disease management.

神经退行性疾病，如阿尔茨海默病（AD）、帕金森病（PD）和亨廷顿病（HD），其特征是进行性神经元损伤、蛋白质聚集和慢性炎症，导致认知和运动障碍。尽管目前的治疗方法可以缓解症状，但针对核心分子机制的疾病修饰治疗仍然缺乏。基于rna的疗法通过靶向分子机制，如基因表达、蛋白质合成和神经炎症，为治疗神经退行性疾病提供了一种很有前途的方法。治疗策略包括长非编码RNA （lncRNA）、反义寡核苷酸（ASOs）、RNA干扰（RNAi）、小干扰RNA （siRNA）和短发夹RNA （shRNA）、信使RNA （mRNA）治疗和基于microRNA （miRNA）的干预。这些疗法旨在减少有毒蛋白的积累，恢复缺陷蛋白，并调节AD、PD和HD等疾病的炎症反应。与主要控制症状的传统疗法不同，基于rna的疗法有可能通过解决其根本原因来改变疾病的进展。本文综述了目前基于rna的神经退行性疾病的治疗策略，讨论了它们的作用机制、临床前和临床进展。它进一步探索了创新的解决方案，包括纳米载体介导的递送，化学修饰以增强RNA稳定性，以及正在开发的以遗传谱为指导的个性化医疗方法，以克服这些障碍。这篇综述还强调了基于rna的干预的治疗机会和当前的局限性，强调了它们改变神经退行性疾病管理未来的潜力。

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引用次数: 0

One nanoparticle delivers two different neuroprotective amino acids into ischemic brain and protects against neuronal death in rat cerebral ischemia injury 一个纳米颗粒将两种不同的神经保护氨基酸输送到缺血脑内，对大鼠脑缺血损伤的神经元死亡具有保护作用。

IF 2.6 3区医学 Q3 NEUROSCIENCES

Molecular and Cellular Neuroscience

Pub Date : 2025-04-05 DOI: 10.1016/j.mcn.2025.104009

Jingchen Gao, Xiyuran Wang, Qi Wan

Previous studies have proven that glycine and proline are neuroprotective but have very low permeability through the blood-brain barrier (BBB), which is a major barrier to the application of these neuroprotective amino acids in the therapy of brain injury. In this study, we aimed to develop a therapeutic strategy by which one chitosan nanoparticle could deliver two different neuroprotective amino acids, glycine and proline, into the rat ischemic brain to confer neuroprotection in a rat model of cerebral ischemia-reperfusion (I/R) injury. Using the ion cross-linking method, we developed a preparation in which one chitosan nanoparticle was simultaneously loaded with glycine and proline (AA-NPs). We evaluated the therapeutic potential of AA-NPs in both cell and animal models of cerebral ischemic stroke. We found that the levels of glycine and proline were decreased in the brain tissues of I/R rats. AA-NPs delivered both glycine and proline into the ischemic brain and reduced ischemic neuronal death in both in vitro and in vivo. These results indicated that the dual delivery of glycine and proline via AA-NPs mediated neuroprotective effects, as evidenced by the reduction of neuronal death in both cellular and animal models of ischemic stroke. AA-NPs provide an efficient and potential delivery strategy by which multiple neuroprotective amino acids can be transported into the ischemic brain simultaneously for the treatment of ischemic stroke.

以往的研究证明，甘氨酸和脯氨酸具有神经保护作用，但其通过血脑屏障（BBB）的渗透性很低，这是这些神经保护氨基酸应用于脑损伤治疗的主要障碍。在这项研究中，我们旨在开发一种治疗策略，通过一种壳聚糖纳米颗粒将两种不同的神经保护氨基酸，甘氨酸和脯氨酸输送到大鼠缺血脑中，以赋予大鼠脑缺血再灌注（I/R）损伤模型的神经保护作用。采用离子交联的方法，制备了甘氨酸和脯氨酸（AA-NPs）同时负载的壳聚糖纳米颗粒。我们在脑缺血性中风的细胞和动物模型中评估了AA-NPs的治疗潜力。我们发现I/R大鼠脑组织中甘氨酸和脯氨酸水平降低。AA-NPs在体外和体内均可将甘氨酸和脯氨酸输送到缺血性脑中，并减少缺血性神经元死亡。这些结果表明，甘氨酸和脯氨酸通过AA-NPs的双重递送介导的神经保护作用，可以通过减少缺血性卒中细胞和动物模型中的神经元死亡得到证明。AA-NPs提供了一种高效和潜在的递送策略，通过这种策略，多种神经保护氨基酸可以同时运输到缺血性脑，用于治疗缺血性脑卒中。

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引用次数: 0

Estradiol activates the CaMKKβ/AMPK pathway to enhance neurite outgrowth in cultured adult sensory neurons 雌二醇激活CaMKKβ/AMPK通路，促进培养的成人感觉神经元的神经突生长。

IF 2.6 3区医学 Q3 NEUROSCIENCES

Molecular and Cellular Neuroscience

Pub Date : 2025-03-29 DOI: 10.1016/j.mcn.2025.104008

Pranav Mishra , Benedict C. Albensi , Paul Fernyhough

Adult rat dorsal root ganglion (DRG) sensory neurons express estrogen receptors (ERs) α and β. Estrogen regulates multiple aspects of the nervous system including development, survival, and axonal outgrowth of DRG neurons. While previous studies have established estrogen's neuroprotective role in these neurons, the specific ER subtypes and downstream signaling pathways mediating these effects remain poorly defined. The objective of our study was to investigate the effects of 17 beta-estradiol (E2) on mitochondrial function and axonal regeneration of cultured DRG neurons and explore the pathways by which E2 acts. We observed that E2 treatment upregulated the levels of phosphorylated AMP-activated protein kinase (AMPK). E2 also increased the levels of peroxisome proliferator-activated receptor-γ coactivator-1α (PGC-1α) and activating transcription factor 3 (ATF3), which are proteins involved in mitochondrial biogenesis and axonal regeneration. The Seahorse assay showed that E2 elevated basal respiration in cultured DRG neurons. Additionally, E2 treatment for 24 h significantly increased total neurite outgrowth of DRG neurons. Pharmacological inhibition of AMPK using Compound C inhibited E2-mediated increases in ATF3 expression and neurite outgrowth. The Ca²⁺/calmodulin-dependent protein kinase kinase β (CaMKKβ) inhibitor STO-609 blocked E2-mediated AMPK activation. Furthermore, we assessed whether these effects were mediated by ERα or ERβ by using the ERα selective agonist propyl pyrazole triol (PPT) and ERβ selective agonist diarylpropionitrile (DPN). PPT upregulated phosphorylated AMPK levels and increased total neurite outgrowth, whereas DPN was ineffective. The results demonstrate that E2 acts through ERα to promote neurite outgrowth via a pathway involving activation of CaMKKβ/AMPK in adult DRG neurons. Our findings identify ERα-mediated AMPK activation as a therapeutic target for enhancing neuronal regeneration and mitochondrial function in neurodegenerative disorders.

成年大鼠背根神经节感觉神经元表达雌激素受体α和β。雌激素调节神经系统的多个方面，包括DRG神经元的发育、存活和轴突生长。虽然先前的研究已经确定了雌激素在这些神经元中的神经保护作用，但介导这些作用的特定ER亚型和下游信号通路仍然不清楚。本研究旨在探讨17 β -雌二醇（E2）对培养DRG神经元线粒体功能和轴突再生的影响，并探讨E2的作用途径。我们观察到E2处理上调了磷酸化amp活化蛋白激酶（AMPK）的水平。E2还增加了过氧化物酶体增殖物激活受体-γ共激活因子-1α (PGC-1α)和激活转录因子3 （ATF3）的水平，这是参与线粒体生物发生和轴突再生的蛋白质。海马实验显示E2可提高培养DRG神经元的基础呼吸。此外，E2处理24 h显著增加DRG神经元的总神经突生长。化合物C对AMPK的药理抑制抑制e2介导的ATF3表达和神经突生长的增加。Ca2+/钙调素依赖性蛋白激酶激酶β (CaMKKβ)抑制剂STO-609阻断e2介导的AMPK激活。此外，我们使用ERα选择性激动剂丙基吡唑三醇（PPT）和ERβ选择性激动剂二烷基丙腈（DPN）来评估这些作用是由ERα还是ERβ介导的。PPT上调磷酸化AMPK水平，增加神经突总生长，而DPN无效。结果表明，E2通过ERα通过激活成人DRG神经元的CaMKKβ/AMPK通路促进神经突生长。我们的研究结果确定了er α介导的AMPK激活作为神经退行性疾病中增强神经元再生和线粒体功能的治疗靶点。

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