Experimental Neurology最新文献_第9页

Serum/glucocorticoid regulated kinase 1 (SGK1) in neurological disorders: pain or gain 神经系统疾病中的血清/糖皮质激素调节激酶 1 (SGK1)：痛苦还是收获

IF 4.6 2区医学 Q1 NEUROSCIENCES

Experimental Neurology

Pub Date : 2024-09-24 DOI: 10.1016/j.expneurol.2024.114973

Peyton Grace Howard , Peibin Zou , Yulan Zhang , Fang Huang , Vesna Tesic , Celeste Yin-Chieh Wu , Reggie Hui-Chao Lee

Serum/Glucocorticoid Regulated Kinase 1 (SGK1), a serine/threonine kinase, is ubiquitous across a wide range of tissues, orchestrating numerous signaling pathways and associated with various human diseases. SGK1 has been extensively explored in diverse types of immune and inflammatory diseases, cardiovascular disorders, as well as cancer metastasis. These studies link SGK1 to cellular proliferation, survival, metabolism, membrane transport, and drug resistance. Recently, increasing research has focused on SGK1's role in neurological disorders, including a variety of neurodegenerative diseases (e.g., Alzheimer's disease, Huntington's disease and Parkinson's disease), brain injuries (e.g., cerebral ischemia and traumatic brain injury), psychiatric conditions (e.g., depression and drug addiction). SGK1 is emerging as an increasingly compelling therapeutic target across the spectrum of neurological disorders, supported by the availability of several effective agents. However, the conclusions of many studies observing the prevalence and function of SGK1 in neurological disorders are contradictory, necessitating a review of the SGK1 research within neurological disorders. Herein, we review recent literature on SGK1's primary functions within the nervous system and its impacts within different neurological disorders. We summarize significant findings, identify research gaps, and outline possible future research directions based on the current understanding of SGK1 to help further progress the understanding and treatment of neurological disorders.

血清/糖皮质激素调节激酶 1（SGK1）是一种丝氨酸/苏氨酸激酶，广泛存在于各种组织中，协调着众多信号通路，并与各种人类疾病相关。人们对 SGK1 在各种类型的免疫和炎症疾病、心血管疾病以及癌症转移中的作用进行了广泛的研究。这些研究将 SGK1 与细胞增殖、存活、新陈代谢、膜转运和耐药性联系在一起。最近，越来越多的研究集中于 SGK1 在神经系统疾病中的作用，包括各种神经退行性疾病（如阿尔茨海默病、亨廷顿病和帕金森病）、脑损伤（如脑缺血和脑外伤）、精神疾病（如抑郁症和药物成瘾）。在多种有效药物的支持下，SGK1 逐渐成为神经系统疾病中越来越引人注目的治疗靶点。然而，许多观察 SGK1 在神经系统疾病中的患病率和功能的研究结论相互矛盾，因此有必要对神经系统疾病中的 SGK1 研究进行回顾。在此，我们回顾了有关 SGK1 在神经系统中的主要功能及其对不同神经系统疾病的影响的最新文献。我们总结了重要发现，找出了研究空白，并根据目前对 SGK1 的理解概述了未来可能的研究方向，以帮助进一步加深对神经系统疾病的理解和治疗。

{"title":"Serum/glucocorticoid regulated kinase 1 (SGK1) in neurological disorders: pain or gain","authors":"Peyton Grace Howard , Peibin Zou , Yulan Zhang , Fang Huang , Vesna Tesic , Celeste Yin-Chieh Wu , Reggie Hui-Chao Lee","doi":"10.1016/j.expneurol.2024.114973","DOIUrl":"10.1016/j.expneurol.2024.114973","url":null,"abstract":"<div><div>Serum/Glucocorticoid Regulated Kinase 1 (SGK1), a serine/threonine kinase, is ubiquitous across a wide range of tissues, orchestrating numerous signaling pathways and associated with various human diseases. SGK1 has been extensively explored in diverse types of immune and inflammatory diseases, cardiovascular disorders, as well as cancer metastasis. These studies link SGK1 to cellular proliferation, survival, metabolism, membrane transport, and drug resistance. Recently, increasing research has focused on SGK1's role in neurological disorders, including a variety of neurodegenerative diseases (e.g., Alzheimer's disease, Huntington's disease and Parkinson's disease), brain injuries (e.g., cerebral ischemia and traumatic brain injury), psychiatric conditions (e.g., depression and drug addiction). SGK1 is emerging as an increasingly compelling therapeutic target across the spectrum of neurological disorders, supported by the availability of several effective agents. However, the conclusions of many studies observing the prevalence and function of SGK1 in neurological disorders are contradictory, necessitating a review of the SGK1 research within neurological disorders. Herein, we review recent literature on SGK1's primary functions within the nervous system and its impacts within different neurological disorders. We summarize significant findings, identify research gaps, and outline possible future research directions based on the current understanding of SGK1 to help further progress the understanding and treatment of neurological disorders.</div></div>","PeriodicalId":12246,"journal":{"name":"Experimental Neurology","volume":"382 ","pages":"Article 114973"},"PeriodicalIF":4.6,"publicationDate":"2024-09-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142328157","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"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

Identification of key regulatory genes involved in myelination after spinal cord injury by GSEA analysis 通过 GSEA 分析鉴定脊髓损伤后髓鞘形成过程中的关键调控基因

IF 4.6 2区医学 Q1 NEUROSCIENCES

Experimental Neurology

Pub Date : 2024-09-24 DOI: 10.1016/j.expneurol.2024.114966

Yehua Lv , Lingyun Ji , Hui Dai, Shanru Qiu, Yu Wang, Cheng Teng, Bin Yu, Daguo Mi, Chun Yao

Multilayer dense myelin tissue provides insulating space and nutritional support for axons in healthy spinal cord tissue. Oligodendrocyte precursor cells (OPCs) are the main glial cells that complement myelin loss in the central nervous system and play an important role in the repair of spinal cord injury (SCI). However, the regulation of axonal remyelination after SCI is still insufficient. In this study, we focused on the changes in genes related to myelin repair after rat hemisection SCI by gene set enrichment analysis (GSEA). Key genes proteolipid protein 1 (Plp1), hexosaminidase subunit alpha (Hexa), and hexosaminidase subunit beta (Hexb) during remyelination after SCI were found. Through quantitative real-time polymerase chain reaction (qPCR) experiments, we confirmed that within 28 days after rat hemisection SCI, the mRNA expression of gene Plp1 gradually decreased, while the expressions of gene Hexa and Hexb gradually increased, which was consistent with RNA sequencing results. In vitro, we performed EdU proliferation assays on OPC cell line OLN-93 and primary rat OPCs. We found that interference of Plp1 promoted OPC proliferation, while interference of Hexa and Hexb inhibited OPC proliferation. In addition, we performed in vitro differentiation experiments on primary rat OPCs. By measuring myelin sheath branch outgrowth and the fluorescence intensity of the mature myelin sheath marker myelin basic protein (MBP), we found that interference of Hexa or Hexb promoted OPC differentiation and maturation, but interference of Plp1 inhibited this process. Finally, we injected Hexb siRNA in vivo and found that interfering Hexb could improve motor movements and myelin regeneration after SCI in rats. Our results provide new target genes that can selectively regulate the proliferation and differentiation of endogenous OPCs, providing new ideas for promoting remyelination and functional recovery after SCI.

在健康的脊髓组织中，多层致密的髓鞘组织为轴突提供绝缘空间和营养支持。少突胶质细胞前体细胞（OPCs）是补充中枢神经系统髓鞘损失的主要胶质细胞，在脊髓损伤（SCI）的修复中发挥着重要作用。然而，目前对 SCI 后轴突再髓鞘化的调控仍不充分。本研究通过基因组富集分析（GSEA），重点研究了大鼠半切脊髓损伤后髓鞘修复相关基因的变化。研究发现了髓鞘损伤后再髓鞘化过程中的关键基因蛋白脂质蛋白1（Plp1）、己糖胺酸酶亚基α（Hexa）和己糖胺酸酶亚基β（Hexb）。通过实时定量聚合酶链式反应（qPCR）实验，我们证实了在大鼠断肢后28天内，基因Plp1的mRNA表达量逐渐减少，而基因Hexa和Hexb的表达量逐渐增加，这与RNA测序结果一致。在体外，我们对 OPC 细胞系 OLN-93 和原代大鼠 OPC 进行了 EdU 增殖实验。我们发现，干扰 Plp1 会促进 OPC 增殖，而干扰 Hexa 和 Hexb 则会抑制 OPC 增殖。此外，我们还对原代大鼠 OPC 进行了体外分化实验。通过测量髓鞘分支的生长和成熟髓鞘标志物髓鞘碱性蛋白（MBP）的荧光强度，我们发现干扰Hexa或Hexb会促进OPC的分化和成熟，而干扰Plp1则会抑制这一过程。最后，我们在体内注射了Hexb siRNA，发现干扰Hexb可以改善大鼠的运动能力和脊髓损伤后的髓鞘再生。我们的研究结果提供了可选择性调控内源性OPC增殖和分化的新靶基因，为促进损伤后髓鞘再形成和功能恢复提供了新思路。

{"title":"Identification of key regulatory genes involved in myelination after spinal cord injury by GSEA analysis","authors":"Yehua Lv , Lingyun Ji , Hui Dai, Shanru Qiu, Yu Wang, Cheng Teng, Bin Yu, Daguo Mi, Chun Yao","doi":"10.1016/j.expneurol.2024.114966","DOIUrl":"10.1016/j.expneurol.2024.114966","url":null,"abstract":"<div><div>Multilayer dense myelin tissue provides insulating space and nutritional support for axons in healthy spinal cord tissue. Oligodendrocyte precursor cells (OPCs) are the main glial cells that complement myelin loss in the central nervous system and play an important role in the repair of spinal cord injury (SCI). However, the regulation of axonal remyelination after SCI is still insufficient. In this study, we focused on the changes in genes related to myelin repair after rat hemisection SCI by gene set enrichment analysis (GSEA). Key genes proteolipid protein 1 (Plp1), hexosaminidase subunit alpha (Hexa), and hexosaminidase subunit beta (Hexb) during remyelination after SCI were found. Through quantitative real-time polymerase chain reaction (qPCR) experiments, we confirmed that within 28 days after rat hemisection SCI, the mRNA expression of gene Plp1 gradually decreased, while the expressions of gene Hexa and Hexb gradually increased, which was consistent with RNA sequencing results. In vitro, we performed EdU proliferation assays on OPC cell line OLN-93 and primary rat OPCs. We found that interference of Plp1 promoted OPC proliferation, while interference of Hexa and Hexb inhibited OPC proliferation. In addition, we performed in vitro differentiation experiments on primary rat OPCs. By measuring myelin sheath branch outgrowth and the fluorescence intensity of the mature myelin sheath marker myelin basic protein (MBP), we found that interference of Hexa or Hexb promoted OPC differentiation and maturation, but interference of Plp1 inhibited this process. Finally, we injected Hexb siRNA in vivo and found that interfering Hexb could improve motor movements and myelin regeneration after SCI in rats. Our results provide new target genes that can selectively regulate the proliferation and differentiation of endogenous OPCs, providing new ideas for promoting remyelination and functional recovery after SCI.</div></div>","PeriodicalId":12246,"journal":{"name":"Experimental Neurology","volume":"382 ","pages":"Article 114966"},"PeriodicalIF":4.6,"publicationDate":"2024-09-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142328156","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"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

TGN-020 ameliorates motor dysfunction post-spinal cord injury via enhancing astrocyte autophagy and mitigating inflammation by activating AQP4/PPAR-γ/mTOR pathway TGN-020通过激活AQP4/PPAR-γ/mTOR通路，增强星形胶质细胞自噬和减轻炎症，从而改善脊髓损伤后的运动功能障碍。

IF 4.6 2区医学 Q1 NEUROSCIENCES

Experimental Neurology

Pub Date : 2024-09-24 DOI: 10.1016/j.expneurol.2024.114975

Jundong Kong , Qiangqiang Zhang , Haohong Zheng , Diandong Tang , Li Fang , Shuaihao An , Jian Li , Zhongkai Fan

Spinal Cord Injury (SCI) is a severe condition that often leads to substantial neurological impairments. This study aimed to explore the role of Aquaporin-4 (AQP4) in regulating astrocyte autophagy and neuroinflammation post-SCI, as well as to evaluate the therapeutic potential of AQP4 inhibition using the specific inhibitor TGN-020. Using Western blot, CCK8 assays, immunofluorescence staining, histopathological assessments, and behavioral analyses, we investigated the effects of TGN-020 on SCI-induced alterations in autophagy, neuroinflammation, astrocyte proliferation, neuronal damage, and motor function recovery in both rat and astrocyte models. Our findings indicate that TGN-020 significantly enhances astrocyte autophagy, reduces neuroinflammation, thereby leading to mitigated astrocyte activation by suppressing AQP4 expression. These beneficial effects are associated with the activation of the peroxisome proliferator-activated receptor-γ/mammalian target of rapamycin (PPAR-γ/mTOR) signaling pathway. Notably, the introduction of the PPAR-γ specific inhibitor GW9662 abrogated the positive regulatory effects of TGN-020 on SCI-induced autophagy and neuroinflammation. Collectively, our in vivo and in vitro experiments demonstrate that TGN-020, by down-regulating AQP4, activates the PPAR-γ/mTOR pathway, ameliorates astrocyte autophagy, diminishes neuroinflammation, and ultimately enhances motor function recovery.

脊髓损伤（SCI）是一种严重的疾病，通常会导致严重的神经损伤。本研究旨在探索Aquaporin-4（AQP4）在调节SCI后星形胶质细胞自噬和神经炎症中的作用，并评估使用特异性抑制剂TGN-020抑制AQP4的治疗潜力。利用 Western 印迹、CCK8 检测、免疫荧光染色、组织病理学评估和行为分析，我们研究了 TGN-020 对 SCI 诱导的大鼠和星形胶质细胞模型中自噬、神经炎症、星形胶质细胞增殖、神经元损伤和运动功能恢复变化的影响。我们的研究结果表明，TGN-020 能显著提高星形胶质细胞的自噬能力，减少神经炎症，从而通过抑制 AQP4 的表达减轻星形胶质细胞的激活。这些有益作用与过氧化物酶体增殖激活受体-γ/哺乳动物雷帕霉素靶标（PPAR-γ/mTOR）信号通路的激活有关。值得注意的是，引入 PPAR-γ 特异性抑制剂 GW9662 会减弱 TGN-020 对 SCI 诱导的自噬和神经炎症的正向调节作用。总之，我们的体内和体外实验证明，TGN-020 通过下调 AQP4 激活了 PPAR-γ/mTOR 通路，改善了星形胶质细胞的自噬，减轻了神经炎症，并最终促进了运动功能的恢复。

{"title":"TGN-020 ameliorates motor dysfunction post-spinal cord injury via enhancing astrocyte autophagy and mitigating inflammation by activating AQP4/PPAR-γ/mTOR pathway","authors":"Jundong Kong , Qiangqiang Zhang , Haohong Zheng , Diandong Tang , Li Fang , Shuaihao An , Jian Li , Zhongkai Fan","doi":"10.1016/j.expneurol.2024.114975","DOIUrl":"10.1016/j.expneurol.2024.114975","url":null,"abstract":"<div><div>Spinal Cord Injury (SCI) is a severe condition that often leads to substantial neurological impairments. This study aimed to explore the role of Aquaporin-4 (AQP4) in regulating astrocyte autophagy and neuroinflammation post-SCI, as well as to evaluate the therapeutic potential of AQP4 inhibition using the specific inhibitor TGN-020. Using Western blot, CCK8 assays, immunofluorescence staining, histopathological assessments, and behavioral analyses, we investigated the effects of TGN-020 on SCI-induced alterations in autophagy, neuroinflammation, astrocyte proliferation, neuronal damage, and motor function recovery in both rat and astrocyte models. Our findings indicate that TGN-020 significantly enhances astrocyte autophagy, reduces neuroinflammation, thereby leading to mitigated astrocyte activation by suppressing AQP4 expression. These beneficial effects are associated with the activation of the peroxisome proliferator-activated receptor-γ/mammalian target of rapamycin (PPAR-γ/mTOR) signaling pathway. Notably, the introduction of the PPAR-γ specific inhibitor GW9662 abrogated the positive regulatory effects of TGN-020 on SCI-induced autophagy and neuroinflammation. Collectively, our in vivo and in vitro experiments demonstrate that TGN-020, by down-regulating AQP4, activates the PPAR-γ/mTOR pathway, ameliorates astrocyte autophagy, diminishes neuroinflammation, and ultimately enhances motor function recovery.</div></div>","PeriodicalId":12246,"journal":{"name":"Experimental Neurology","volume":"382 ","pages":"Article 114975"},"PeriodicalIF":4.6,"publicationDate":"2024-09-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142344429","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"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

Common and divergent pathways in early stages of glutamate and tau-mediated toxicities in neurodegeneration 神经退行性疾病中谷氨酸和 tau 介导的毒性早期阶段的共同和不同途径。

IF 4.6 2区医学 Q1 NEUROSCIENCES

Experimental Neurology

Pub Date : 2024-09-24 DOI: 10.1016/j.expneurol.2024.114967

Anjalika Chongtham , Abhijeet Sharma , Banshi Nath , Kaitlin Murtha , Kirill Gorbachev , Aarthi Ramakrishnan , Eric F. Schmidt , Li Shen , Ana C. Pereira

It has been shown that excitotoxicity and tau-mediated toxicities are major contributing factors to neuronal death in Alzheimer's disease (AD). The excitatory amino acid transporter 2 (EAAT2 or GLT-1), the major glutamate transporter in the brain that regulates glutamate levels synaptically and extrasynaptically, has been shown to be deficient in AD brains, leading to excitotoxicity and subsequent cell death. Similarly, buildup of neurofibrillary tangles, which consist of hyperphosphorylated tau protein, correlates with cognitive decline and neuronal atrophy in AD. However, common genes and pathways that are critical in the aforementioned toxicities have not been well elucidated. To investigate the impact of glutamate dyshomeostasis and tau accumulation on translational profiles of affected hippocampal neurons, we used mouse models of excitotoxicity and tau–mediated toxicities (GLT-1^−/− and P301S, respectively) in conjunction with BAC-TRAP technology. Our data show that GLT-1 deficiency in CA3 pyramidal neurons leads to translational signatures characterized by dysregulation of pathways associated with synaptic plasticity and neuronal survival, while the P301S mutation induces changes in endocytic pathways and mitochondrial dysfunction. Finally, the commonly dysregulated pathways include impaired ion homeostasis and metabolic pathways. These common pathways may shed light on potential therapeutic targets for ameliorating glutamate and tau-mediated toxicities in AD.

研究表明，兴奋性毒性和 tau 介导的毒性是导致阿尔茨海默病（AD）神经元死亡的主要因素。兴奋性氨基酸转运体 2（EAAT2 或 GLT-1）是大脑中调节突触内和突触外谷氨酸水平的主要谷氨酸转运体。同样，神经纤维缠结（由过度磷酸化的 tau 蛋白组成）的形成也与认知能力下降和神经元萎缩有关。然而，对上述毒性起关键作用的共同基因和途径尚未得到很好的阐明。为了研究谷氨酸失衡和 tau 积累对受影响的海马神经元翻译谱的影响，我们使用小鼠兴奋毒性模型和 tau 介导的毒性模型（分别为 GLT-1-/ 和 P301S），并结合 BAC-TRAP 技术。我们的数据显示，CA3 锥体神经元中 GLT-1 的缺乏会导致与突触可塑性和神经元存活相关的通路失调的翻译特征，而 P301S 突变会诱导内细胞通路的变化和线粒体功能障碍。最后，常见的失调途径包括离子平衡受损和代谢途径。这些常见途径可能为改善谷氨酸和tau介导的AD毒性提供了潜在的治疗靶点。

{"title":"Common and divergent pathways in early stages of glutamate and tau-mediated toxicities in neurodegeneration","authors":"Anjalika Chongtham , Abhijeet Sharma , Banshi Nath , Kaitlin Murtha , Kirill Gorbachev , Aarthi Ramakrishnan , Eric F. Schmidt , Li Shen , Ana C. Pereira","doi":"10.1016/j.expneurol.2024.114967","DOIUrl":"10.1016/j.expneurol.2024.114967","url":null,"abstract":"<div><div>It has been shown that excitotoxicity and tau-mediated toxicities are major contributing factors to neuronal death in Alzheimer's disease (AD). The excitatory amino acid transporter 2 (EAAT2 or <em>GLT-1</em>), the major glutamate transporter in the brain that regulates glutamate levels synaptically and extrasynaptically, has been shown to be deficient in AD brains, leading to excitotoxicity and subsequent cell death. Similarly, buildup of neurofibrillary tangles, which consist of hyperphosphorylated tau protein, correlates with cognitive decline and neuronal atrophy in AD. However, common genes and pathways that are critical in the aforementioned toxicities have not been well elucidated. To investigate the impact of glutamate dyshomeostasis and tau accumulation on translational profiles of affected hippocampal neurons, we used mouse models of excitotoxicity and tau–mediated toxicities (<em>GLT-1</em><sup>−/−</sup> and P301S, respectively) in conjunction with BAC-TRAP technology. Our data show that GLT-1 deficiency in CA3 pyramidal neurons leads to translational signatures characterized by dysregulation of pathways associated with synaptic plasticity and neuronal survival, while the P301S mutation induces changes in endocytic pathways and mitochondrial dysfunction. Finally, the commonly dysregulated pathways include impaired ion homeostasis and metabolic pathways. These common pathways may shed light on potential therapeutic targets for ameliorating glutamate and tau-mediated toxicities in AD.</div></div>","PeriodicalId":12246,"journal":{"name":"Experimental Neurology","volume":"382 ","pages":"Article 114967"},"PeriodicalIF":4.6,"publicationDate":"2024-09-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142344419","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"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

Pathogenic SHQ1 variants result in disruptions to neuronal development and the dopaminergic pathway 致病性 SHQ1 变异会导致神经元发育和多巴胺能通路中断。

IF 4.6 2区医学 Q1 NEUROSCIENCES

Experimental Neurology

Pub Date : 2024-09-24 DOI: 10.1016/j.expneurol.2024.114968

Chien-Hui Chang , Lee-Chin Wong , Chia-Wei Huang , Yue-Ru Li , Chainne-Wen Yang , Jin-Wu Tsai , Wang-Tso Lee

Background

Compound heterozygous variants of SHQ1, an assembly factor of H/ACA ribonucleoproteins (RNPs) involved in critical biological pathways, have been identified in patients with developmental delay, dystonia, epilepsy, and microcephaly. We investigated the role of SHQ1 in brain development and movement disorders.

Methods

SHQ1 expression was knocked down using short-hairpin RNA (shRNA) to investigate its effects on neurons. Shq1 shRNA and cDNA of WT and mutant SHQ1 were also introduced into neural progenitors in the embryonic mouse cortex through in utero electroporation. Co-immunoprecipitation was performed to investigate the interaction between SHQ1 and DKC1, a core protein of H/ACA RNPs.

Results

We found that SHQ1 was highly expressed in the developing mouse cortex. SHQ1 knockdown impaired the migration and neurite morphology of cortical neurons during brain development. Additionally, SHQ1 knockdown impaired neurite growth and sensitivity to glutamate toxicity in vitro. There was also increased dopaminergic function upon SHQ1 knockdown, which may underlie the increased glutamate toxicity of the cells. Most SHQ1 variants attenuated their binding ability toward DKC1, implying SHQ1 variants may influence brain development by disrupting the assembly and biogenesis of H/ACA RNPs.

Conclusions

SHQ1 plays an essential role in brain development and dopaminergic function by upregulating dopaminergic pathways and regulating the behaviors of neural progenitors and their neuronal progeny, potentially leading to dystonia and developmental delay in patients. Our study provides insights into the functions of SHQ1 in neuronal development and dopaminergic function, providing a possible pathogenic mechanism for H/ACA RNPs-related disorders.

背景：在发育迟缓、肌张力障碍、癫痫和小头畸形患者中发现了SHQ1的复合杂合变异体，SHQ1是H/ACA核糖核蛋白（RNPs）的组装因子，参与重要的生物通路。我们研究了 SHQ1 在大脑发育和运动障碍中的作用：方法：使用短发夹RNA（shRNA）敲除SHQ1的表达，研究其对神经元的影响。通过宫内电穿孔将 Shq1 shRNA 和 WT 及突变体 SHQ1 的 cDNA 导入胚胎小鼠皮层的神经祖细胞。通过共免疫沉淀研究了SHQ1与H/ACA RNPs的核心蛋白DKC1之间的相互作用：结果：我们发现SHQ1在发育中的小鼠皮层中高表达。结果：我们发现 SHQ1 在发育中的小鼠大脑皮层中高表达，敲除 SHQ1 会影响大脑皮层神经元的迁移和神经元形态。此外，SHQ1基因敲除还损害了神经元的生长和体外对谷氨酸毒性的敏感性。SHQ1敲除后多巴胺能功能也会增强，这可能是细胞谷氨酸毒性增强的原因。大多数SHQ1变体削弱了它们与DKC1的结合能力，这意味着SHQ1变体可能会通过破坏H/ACA RNPs的组装和生物生成来影响大脑发育：结论：SHQ1通过上调多巴胺能通路和调节神经祖细胞及其神经元后代的行为，在大脑发育和多巴胺能功能中发挥着重要作用，可能导致患者肌张力障碍和发育迟缓。我们的研究深入揭示了 SHQ1 在神经元发育和多巴胺能功能中的作用，为 H/ACA RNPs 相关疾病提供了一种可能的致病机制。

{"title":"Pathogenic SHQ1 variants result in disruptions to neuronal development and the dopaminergic pathway","authors":"Chien-Hui Chang , Lee-Chin Wong , Chia-Wei Huang , Yue-Ru Li , Chainne-Wen Yang , Jin-Wu Tsai , Wang-Tso Lee","doi":"10.1016/j.expneurol.2024.114968","DOIUrl":"10.1016/j.expneurol.2024.114968","url":null,"abstract":"<div><h3>Background</h3><div>Compound heterozygous variants of <em>SHQ1</em>, an assembly factor of H/ACA ribonucleoproteins (RNPs) involved in critical biological pathways, have been identified in patients with developmental delay, dystonia, epilepsy, and microcephaly. We investigated the role of SHQ1 in brain development and movement disorders.</div></div><div><h3>Methods</h3><div><em>SHQ1</em> expression was knocked down using short-hairpin RNA (shRNA) to investigate its effects on neurons. <em>Shq1</em> shRNA and cDNA of WT and mutant <em>SHQ1</em> were also introduced into neural progenitors in the embryonic mouse cortex through <em>in utero</em> electroporation. Co-immunoprecipitation was performed to investigate the interaction between SHQ1 and DKC1, a core protein of H/ACA RNPs.</div></div><div><h3>Results</h3><div>We found that SHQ1 was highly expressed in the developing mouse cortex. <em>SHQ1</em> knockdown impaired the migration and neurite morphology of cortical neurons during brain development. Additionally, <em>SHQ1</em> knockdown impaired neurite growth and sensitivity to glutamate toxicity <em>in vitro</em>. There was also increased dopaminergic function upon <em>SHQ1</em> knockdown, which may underlie the increased glutamate toxicity of the cells. Most SHQ1 variants attenuated their binding ability toward DKC1, implying <em>SHQ1</em> variants may influence brain development by disrupting the assembly and biogenesis of H/ACA RNPs.</div></div><div><h3>Conclusions</h3><div>SHQ1 plays an essential role in brain development and dopaminergic function by upregulating dopaminergic pathways and regulating the behaviors of neural progenitors and their neuronal progeny, potentially leading to dystonia and developmental delay in patients. Our study provides insights into the functions of SHQ1 in neuronal development and dopaminergic function, providing a possible pathogenic mechanism for H/ACA RNPs-related disorders.</div></div>","PeriodicalId":12246,"journal":{"name":"Experimental Neurology","volume":"382 ","pages":"Article 114968"},"PeriodicalIF":4.6,"publicationDate":"2024-09-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142344421","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Transfer RNAs and transfer RNA-derived small RNAs in cerebrovascular diseases 脑血管疾病中的转运核糖核酸和转运核糖核酸衍生小核糖核酸。

IF 4.6 2区医学 Q1 NEUROSCIENCES

Experimental Neurology

Pub Date : 2024-09-24 DOI: 10.1016/j.expneurol.2024.114971

Jiajie Yuan , Zibin Song , Jun Liu , Khalil Ur Rahman , Qixiong Zhou , Guangjie Liu , Yifeng Deng , Haotian Wen , Xiaonan Fan , Nanqi Fang , Zhaojun Zhou , Qiancheng Song , Guozhong Zhang , Peng Li , Ye Song

This article explores the important functions of transfer RNA and - transfer RNA derived small RNAs (tsRNAs) in cellular processes and disease pathogenesis, with a particular emphasis on their involvement in cerebrovascular disorders. It discusses the biogenesis and structure of tsRNAs, including types such as tRNA halves and tRNA-derived fragments, and their functional significance in gene regulation, stress response, and cell signaling pathways. The importance of tsRNAs in neurodegenerative diseases, cancer, and cardiovascular diseases has already been highlighted, while their role in cerebrovascular diseases is in early phase of exploration. This paper presents the latest advancements in the field of tsRNAs in cerebrovascular conditions, such as ischemic stroke, intracerebral hemorrhage, and moyamoya disease. Furthermore, revealing the aptitude of tsRNAs as biomarkers for the prediction of cerebrovascular diseases and as targets for therapeutic intervention. It provides insights into the role of tsRNAs in these conditions and proposes directions for future research.

本文探讨了转运核糖核酸和转运核糖核酸衍生的小核糖核酸（tsRNA）在细胞过程和疾病发病机制中的重要功能，特别强调了它们在脑血管疾病中的参与。该书讨论了 tsRNA 的生物发生和结构，包括 tRNA 半体和 tRNA 衍生片段等类型，以及它们在基因调控、应激反应和细胞信号通路中的功能意义。tsRNA在神经退行性疾病、癌症和心血管疾病中的重要性已经得到强调，而它们在脑血管疾病中的作用还处于早期探索阶段。本文介绍了 tsRNAs 在缺血性中风、脑内出血和 moyamoya 病等脑血管疾病中的最新研究进展。此外，还揭示了 tsRNA 作为预测脑血管疾病的生物标志物和治疗干预靶点的能力。该研究深入探讨了 tsRNAs 在这些疾病中的作用，并提出了未来的研究方向。

{"title":"Transfer RNAs and transfer RNA-derived small RNAs in cerebrovascular diseases","authors":"Jiajie Yuan , Zibin Song , Jun Liu , Khalil Ur Rahman , Qixiong Zhou , Guangjie Liu , Yifeng Deng , Haotian Wen , Xiaonan Fan , Nanqi Fang , Zhaojun Zhou , Qiancheng Song , Guozhong Zhang , Peng Li , Ye Song","doi":"10.1016/j.expneurol.2024.114971","DOIUrl":"10.1016/j.expneurol.2024.114971","url":null,"abstract":"<div><div>This article explores the important functions of transfer RNA and - transfer RNA derived small RNAs (tsRNAs) in cellular processes and disease pathogenesis, with a particular emphasis on their involvement in cerebrovascular disorders. It discusses the biogenesis and structure of tsRNAs, including types such as tRNA halves and tRNA-derived fragments, and their functional significance in gene regulation, stress response, and cell signaling pathways. The importance of tsRNAs in neurodegenerative diseases, cancer, and cardiovascular diseases has already been highlighted, while their role in cerebrovascular diseases is in early phase of exploration. This paper presents the latest advancements in the field of tsRNAs in cerebrovascular conditions, such as ischemic stroke, intracerebral hemorrhage, and moyamoya disease. Furthermore, revealing the aptitude of tsRNAs as biomarkers for the prediction of cerebrovascular diseases and as targets for therapeutic intervention. It provides insights into the role of tsRNAs in these conditions and proposes directions for future research.</div></div>","PeriodicalId":12246,"journal":{"name":"Experimental Neurology","volume":"382 ","pages":"Article 114971"},"PeriodicalIF":4.6,"publicationDate":"2024-09-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142344431","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"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

Integrative transcriptomic analysis reveals Cd72 as a novel pro-inflammatory factor in microglia following experimental ischemic stroke 整合转录组分析发现 Cd72 是实验性缺血性中风后小胶质细胞中的新型促炎因子。

IF 4.6 2区医学 Q1 NEUROSCIENCES

Experimental Neurology

Pub Date : 2024-09-24 DOI: 10.1016/j.expneurol.2024.114974

Haojie Ding , Xuan Shi , Junwei Ma , Chang Cao , Yangyang Liu , Jinxin Lu , Lei Bai , Xiang Li Jr , Haiying Li

Ischemic stroke remains a leading cause of global mortality and disability, with neuroinflammation playing a critical role in determining patient outcomes. Microglia, the brain's resident immune cells, can both exacerbate neuroinflammation and neuronal damage by releasing neurotoxic mediators and engaging in excessive phagocytosis, while also aiding recovery through the production of anti-inflammatory cytokines and debris clearance. However, the molecular mechanisms governing microglial activation and polarization after ischemic stroke are not well elucidated. In this study, we combined integrative transcriptomic analyses with experimental validation in a murine model of middle cerebral artery occlusion/reperfusion (MCAO/R) to explore microglial heterogeneity and identify key regulatory factors in ischemic stroke. Bioinformatics analysis identified Cd72 as a novel pro-inflammatory modulator within ischemia-associated microglial phenotypes. We observed significant upregulation of Cd72 in microglia following MCAO/R, and selective knockdown of Cd72 using CX3CR1^Cre/ERT2 mice and Cre recombinase-dependent adeno-associated virus reduced MCAO/R-induced infarct volume, neuronal apoptosis, and neurological deficits. Furthermore, Cd72 expression in microglia was positively correlated with pro-inflammatory pathways and cytokines, including TNF-α, IL-1β, and IL-6. Knockdown of Cd72 significantly reduced these pro-inflammatory factors, highlighting its potential as a therapeutic target for mitigating inflammation in ischemic stroke. In conclusion, this study identifies Cd72 as a critical pro-inflammatory regulator in microglia following ischemic stroke, with its knockdown effectively reducing neuroinflammation and associated brain injury, highlighting Cd72 as a promising therapeutic target.

缺血性中风仍然是导致全球死亡和残疾的主要原因，而神经炎症在决定患者预后方面起着至关重要的作用。小胶质细胞是大脑的常驻免疫细胞，既能通过释放神经毒性介质和过度吞噬作用加剧神经炎症和神经元损伤，也能通过产生抗炎细胞因子和清除碎片帮助恢复。然而，缺血性中风后小胶质细胞活化和极化的分子机制尚未得到很好的阐明。在这项研究中，我们在大脑中动脉闭塞/再灌注（MCAO/R）的小鼠模型中结合了综合转录组分析和实验验证，以探索小胶质细胞的异质性并确定缺血性中风的关键调控因子。生物信息学分析发现，Cd72 是缺血相关小胶质细胞表型中的一种新型促炎调节因子。我们观察到 MCAO/R 后小胶质细胞中 Cd72 的明显上调，使用 CX3CR1Cre/ERT2 小鼠和 Cre 重组酶依赖性腺相关病毒选择性敲除 Cd72 可减少 MCAO/R 诱导的梗死体积、神经元凋亡和神经功能缺损。此外，Cd72在小胶质细胞中的表达与促炎途径和细胞因子（包括TNF-α、IL-1β和IL-6）呈正相关。敲除 Cd72 能明显降低这些促炎因子，突出了其作为减轻缺血性中风炎症的治疗靶点的潜力。总之，本研究发现 Cd72 是缺血性中风后小胶质细胞中的一个关键促炎调节因子，敲除 Cd72 能有效减轻神经炎症和相关脑损伤，从而凸显了 Cd72 作为治疗靶点的潜力。

{"title":"Integrative transcriptomic analysis reveals Cd72 as a novel pro-inflammatory factor in microglia following experimental ischemic stroke","authors":"Haojie Ding , Xuan Shi , Junwei Ma , Chang Cao , Yangyang Liu , Jinxin Lu , Lei Bai , Xiang Li Jr , Haiying Li","doi":"10.1016/j.expneurol.2024.114974","DOIUrl":"10.1016/j.expneurol.2024.114974","url":null,"abstract":"<div><div>Ischemic stroke remains a leading cause of global mortality and disability, with neuroinflammation playing a critical role in determining patient outcomes. Microglia, the brain's resident immune cells, can both exacerbate neuroinflammation and neuronal damage by releasing neurotoxic mediators and engaging in excessive phagocytosis, while also aiding recovery through the production of anti-inflammatory cytokines and debris clearance. However, the molecular mechanisms governing microglial activation and polarization after ischemic stroke are not well elucidated. In this study, we combined integrative transcriptomic analyses with experimental validation in a murine model of middle cerebral artery occlusion/reperfusion (MCAO/R) to explore microglial heterogeneity and identify key regulatory factors in ischemic stroke. Bioinformatics analysis identified Cd72 as a novel pro-inflammatory modulator within ischemia-associated microglial phenotypes. We observed significant upregulation of Cd72 in microglia following MCAO/R, and selective knockdown of Cd72 using CX3CR1<sup>Cre/ERT2</sup> mice and Cre recombinase-dependent adeno-associated virus reduced MCAO/R-induced infarct volume, neuronal apoptosis, and neurological deficits. Furthermore, Cd72 expression in microglia was positively correlated with pro-inflammatory pathways and cytokines, including TNF-α, IL-1β, and IL-6. Knockdown of Cd72 significantly reduced these pro-inflammatory factors, highlighting its potential as a therapeutic target for mitigating inflammation in ischemic stroke. In conclusion, this study identifies Cd72 as a critical pro-inflammatory regulator in microglia following ischemic stroke, with its knockdown effectively reducing neuroinflammation and associated brain injury, highlighting Cd72 as a promising therapeutic target.</div></div>","PeriodicalId":12246,"journal":{"name":"Experimental Neurology","volume":"382 ","pages":"Article 114974"},"PeriodicalIF":4.6,"publicationDate":"2024-09-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142344423","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"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

Sleep dysfunction and gut dysbiosis related amino acids metabolism disorders in cynomolgus monkeys after middle cerebral artery occlusion 大脑中动脉闭塞后猴的睡眠功能障碍和肠道菌群失调导致的氨基酸代谢紊乱

IF 4.6 2区医学 Q1 NEUROSCIENCES

Experimental Neurology

Pub Date : 2024-09-24 DOI: 10.1016/j.expneurol.2024.114970

Jiahui Liang , Zhiyi Xiong , Qingfeng Lei , Zimu Jiang , Jiating Wei , Fubing Ouyang , Yicong Chen , Jinsheng Zeng

Introduction

This study aimed to explore the characteristics of post-stroke sleep dysfunction and verify their association with gut dysbiosis and the related amino acid metabolism disorders. This was achieved by using fecal microbiota transplantation (FMT) in a non-human primate stroke model.

Methods

Twenty adult male cynomolgus monkeys were divided into the sham (n = 4), middle cerebral artery occlusion (MCAO, n = 5), MCAO + FMT (n = 3), and donor (n = 8) groups. The MCAO+FMT group received FMT at post-MCAO week 4. Sleep parameters, gut microbiota, gamma-aminobutyric acid (GABA), and glutamine (Gln) in the cerebrospinal fluid (CSF) were measured at baseline and postoperative weeks 4, 8, and 12.

Results

At postoperative weeks 4, 8, and 12, the MCAO group showed decreased sleep efficiency, measured as the percentage of sleep during the whole night (82.3 ± 3.2 % vs 91.3 ± 2.5 %, 79.0 ± 3.75 % vs 90.8 ± 3.2 %, and 69.5 ± 4.8 % vs 90.5 ± 2.7 %; all P < 0.05), lower relative abundance of Lactobacillus (all P < 0.05), and reduced GABA concentrations in the CSF (317.3 ± 30.6 nmol/L vs 437.7 ± 25.6 nmol/L, 303.1 ± 48.9 nmol/L vs 4 40.9 ± 37.8 nmol/L, and 337.9 ± 49.4 nmol/L vs 457.4 ± 39.2 nmol/L; all P < 0.05) compared with the sham group. Sleep efficiency at post-FMT weeks 4 and 8 (84.7 ± 1.1 % vs 79.0 ± 3.75 %, and 84.1 ± 2.0 % vs 69.5 ± 4.8 %; both P < 0.05) and GABA concentration in the CSF at post-FMT week 4 (403.1 ± 25.4 nmol/L vs 303.1 ± 48.9 nmol/L, P < 0.05) was higher in the MCAO+FMT group than in the MCAO group.

Conclusions

Post-stroke sleep dysfunction in monkeys is characterized by impaired sleep coherence, associated with decreased levels of probiotics such as Lactobacillus, GABA, and Gln in the CSF and can be ameliorated using FMT.

简介本研究旨在探索中风后睡眠功能障碍的特征，并验证其与肠道菌群失调及相关氨基酸代谢紊乱的关系。方法：在非人灵长类中风模型中使用粪便微生物群移植（FMT）：方法：20 只成年雄性眼镜猴被分为假组（n = 4）、大脑中动脉闭塞组（MCAO，n = 5）、MCAO + FMT 组（n = 3）和供体组（n = 8）。MCAO+FMT组在MCAO后第4周接受FMT治疗。在基线和术后第 4、8 和 12 周测量睡眠参数、肠道微生物群、γ-氨基丁酸（GABA）和脑脊液（CSF）中的谷氨酰胺（Gln）：结果：在术后第 4、8 和 12 周，MCAO 组的睡眠效率下降，以整夜睡眠的百分比来衡量（82.3 ± 3.2 % vs 91.3 ± 2.5 %、79.0 ± 3.75 % vs 90.8 ± 3.2 % 和 69.5 ± 4.8 % vs 90.5 ± 2.7 %；均为 P 结论：MCAO 组的睡眠效率高于 MCAO 组（P<0.05）：中风后猴子睡眠功能障碍的特点是睡眠连贯性受损，与脑脊液中益生菌（如乳酸杆菌、GABA和Gln）水平下降有关，可通过FMT改善。

{"title":"Sleep dysfunction and gut dysbiosis related amino acids metabolism disorders in cynomolgus monkeys after middle cerebral artery occlusion","authors":"Jiahui Liang , Zhiyi Xiong , Qingfeng Lei , Zimu Jiang , Jiating Wei , Fubing Ouyang , Yicong Chen , Jinsheng Zeng","doi":"10.1016/j.expneurol.2024.114970","DOIUrl":"10.1016/j.expneurol.2024.114970","url":null,"abstract":"<div><h3>Introduction</h3><div>This study aimed to explore the characteristics of post-stroke sleep dysfunction and verify their association with gut dysbiosis and the related amino acid metabolism disorders. This was achieved by using fecal microbiota transplantation (FMT) in a non-human primate stroke model.</div></div><div><h3>Methods</h3><div>Twenty adult male cynomolgus monkeys were divided into the sham (<em>n</em> = 4), middle cerebral artery occlusion (MCAO, <em>n</em> = 5), MCAO + FMT (<em>n</em> = 3), and donor (<em>n</em> = 8) groups. The MCAO+FMT group received FMT at post-MCAO week 4. Sleep parameters, gut microbiota, gamma-aminobutyric acid (GABA), and glutamine (Gln) in the cerebrospinal fluid (CSF) were measured at baseline and postoperative weeks 4, 8, and 12.</div></div><div><h3>Results</h3><div>At postoperative weeks 4, 8, and 12, the MCAO group showed decreased sleep efficiency, measured as the percentage of sleep during the whole night (82.3 ± 3.2 % vs 91.3 ± 2.5 %, 79.0 ± 3.75 % vs 90.8 ± 3.2 %, and 69.5 ± 4.8 % vs 90.5 ± 2.7 %; all <em>P</em> < 0.05), lower relative abundance of <em>Lactobacillus</em> (all <em>P</em> < 0.05), and reduced GABA concentrations in the CSF (317.3 ± 30.6 nmol/L vs 437.7 ± 25.6 nmol/L, 303.1 ± 48.9 nmol/L vs 4 40.9 ± 37.8 nmol/L, and 337.9 ± 49.4 nmol/L vs 457.4 ± 39.2 nmol/L; all <em>P</em> < 0.05) compared with the sham group. Sleep efficiency at post-FMT weeks 4 and 8 (84.7 ± 1.1 % vs 79.0 ± 3.75 %, and 84.1 ± 2.0 % vs 69.5 ± 4.8 %; both <em>P</em> < 0.05) and GABA concentration in the CSF at post-FMT week 4 (403.1 ± 25.4 nmol/L vs 303.1 ± 48.9 nmol/L, <em>P</em> < 0.05) was higher in the MCAO+FMT group than in the MCAO group.</div></div><div><h3>Conclusions</h3><div>Post-stroke sleep dysfunction in monkeys is characterized by impaired sleep coherence, associated with decreased levels of probiotics such as <em>Lactobacillus,</em> GABA, and Gln in the CSF and can be ameliorated using FMT.</div></div>","PeriodicalId":12246,"journal":{"name":"Experimental Neurology","volume":"382 ","pages":"Article 114970"},"PeriodicalIF":4.6,"publicationDate":"2024-09-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142344424","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"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

Transcranial direct current stimulation as a potential remyelinating therapy: Visual evoked potentials recovery in cuprizone demyelination 经颅直流电刺激作为一种潜在的脱髓鞘疗法：铜绿素脱髓鞘的视觉诱发电位恢复。

IF 4.6 2区医学 Q1 NEUROSCIENCES

Experimental Neurology

Pub Date : 2024-09-24 DOI: 10.1016/j.expneurol.2024.114972

Elena Rossi , Silvia Marenna , Valerio Castoldi , Giancarlo Comi , Letizia Leocani

Aims

Non-invasive neuromodulation by transcranial direct current stimulation (tDCS), owing to its reported beneficial effects on neuronal plasticity, has been proposed as a treatment to promote functional recovery in several neurological conditions, including demyelinating diseases like multiple sclerosis. Less information is available on the effects of tDCS in major pathological mechanisms of multiple sclerosis, such as demyelination and inflammation. To learn more about the latter effects, we applied multi-session anodal tDCS in mice exposed to long-term cuprizone (CPZ) diet, known to induce chronic demyelination.

Methods

Visual evoked potentials (VEP) and motor performance (beam test) were employed for longitudinal monitoring of visual and motor pathways in 28 mice undergoing CPZ diet, compared with 12 control (H) mice. After randomization, anodal tDCS was applied for 5 days in awake, freely-moving surviving animals: 12 CPZ-anodal, 10 CPZ-sham, 5H-anodal, 5 h-sham. At the end of the experiment, histological analysis was performed on the optic nerves and corpus callosum for myelin, axons and microglia/macrophages.

Key findings

CPZ diet was associated with significantly delayed VEPs starting at 4 weeks compared with their baseline, significant compared with controls at 8 weeks. After 5-day tDCS, VEPs latency significantly recovered in the active group compared with the sham group. Similar findings were observed in the time to cross on the beam test Optic nerve histology revealed higher myelin content and lower microglia/macrophage counts in the CPZ-Anodal group compared with CPZ-Sham.

Significance

Multiple sessions of anodal transcranial direct current stimulation (tDCS) in freely moving mice induced recovery of visual nervous conduction and significant beneficial effects in myelin content and inflammatory cells in the cuprizone model of demyelination. Altogether, these promising findings prompt further exploration of tDCS as a potential therapeutic approach for remyelination.

目的：据报道，经颅直流电刺激（tDCS）对神经元的可塑性具有有益的影响，因此已被提议作为促进多种神经系统疾病（包括多发性硬化症等脱髓鞘疾病）功能恢复的一种治疗方法。有关 tDCS 对多发性硬化症主要病理机制（如脱髓鞘和炎症）的影响的信息较少。为了更多地了解后者的影响，我们在长期食用铜松（CPZ）的小鼠身上应用了多节阳极tDCS，众所周知，铜松会诱发慢性脱髓鞘：方法：采用视觉诱发电位（VEP）和运动表现（光束测试）对28只接受CPZ饮食的小鼠和12只对照组（H）小鼠的视觉和运动通路进行纵向监测。随机分组后，对清醒、自由活动的存活小鼠进行为期 5 天的阳极 tDCS 治疗：12 只 CPZ-anodal、10 只 CPZ-sham、5 只 H-anodal、5 只 h-sham。实验结束后，对视神经和胼胝体的髓鞘、轴突和小胶质细胞/巨噬细胞进行组织学分析：主要发现：与基线相比，CPZ 饮食会导致 4 周开始的 VEPs 明显延迟，与对照组相比，8 周开始的 VEPs 明显延迟。经过 5 天的 tDCS 后，活性组的 VEPs 潜伏期比假组有明显恢复。在光束交叉时间测试中也观察到了类似的结果。视神经组织学显示，CPZ-Anodal 组与 CPZ-Sham 组相比，髓鞘含量更高，小胶质细胞/巨噬细胞数量更少：对自由活动的小鼠进行多次阳极经颅直流电刺激（tDCS）可恢复视觉神经传导，并对铜绿素脱髓鞘模型中的髓鞘含量和炎性细胞产生显著的有益影响。总之，这些令人鼓舞的发现促使人们进一步探索将 tDCS 作为髓鞘再形成的潜在治疗方法。

{"title":"Transcranial direct current stimulation as a potential remyelinating therapy: Visual evoked potentials recovery in cuprizone demyelination","authors":"Elena Rossi , Silvia Marenna , Valerio Castoldi , Giancarlo Comi , Letizia Leocani","doi":"10.1016/j.expneurol.2024.114972","DOIUrl":"10.1016/j.expneurol.2024.114972","url":null,"abstract":"<div><h3>Aims</h3><div>Non-invasive neuromodulation by transcranial direct current stimulation (tDCS), owing to its reported beneficial effects on neuronal plasticity, has been proposed as a treatment to promote functional recovery in several neurological conditions, including demyelinating diseases like multiple sclerosis. Less information is available on the effects of tDCS in major pathological mechanisms of multiple sclerosis, such as demyelination and inflammation. To learn more about the latter effects, we applied multi-session anodal tDCS in mice exposed to long-term cuprizone (CPZ) diet, known to induce chronic demyelination.</div></div><div><h3>Methods</h3><div>Visual evoked potentials (VEP) and motor performance (beam test) were employed for longitudinal monitoring of visual and motor pathways in 28 mice undergoing CPZ diet, compared with 12 control (H) mice. After randomization, anodal tDCS was applied for 5 days in awake, freely-moving surviving animals: 12 CPZ-anodal, 10 CPZ-sham, 5H-anodal, 5 h-sham. At the end of the experiment, histological analysis was performed on the optic nerves and corpus callosum for myelin, axons and microglia/macrophages.</div></div><div><h3>Key findings</h3><div>CPZ diet was associated with significantly delayed VEPs starting at 4 weeks compared with their baseline, significant compared with controls at 8 weeks. After 5-day tDCS, VEPs latency significantly recovered in the active group compared with the sham group. Similar findings were observed in the time to cross on the beam test Optic nerve histology revealed higher myelin content and lower microglia/macrophage counts in the CPZ-Anodal group compared with CPZ-Sham.</div></div><div><h3>Significance</h3><div>Multiple sessions of anodal transcranial direct current stimulation (tDCS) in freely moving mice induced recovery of visual nervous conduction and significant beneficial effects in myelin content and inflammatory cells in the cuprizone model of demyelination. Altogether, these promising findings prompt further exploration of tDCS as a potential therapeutic approach for remyelination.</div></div>","PeriodicalId":12246,"journal":{"name":"Experimental Neurology","volume":"382 ","pages":"Article 114972"},"PeriodicalIF":4.6,"publicationDate":"2024-09-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142344422","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"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

Extract from Nasco pomace loaded in nutriosomes exerts anti-inflammatory effects in the MPTP mouse model of Parkinson's disease 在帕金森病 MPTP 小鼠模型中，营养体中含有的纳斯科果渣提取物具有抗炎作用。

IF 4.6 2区医学 Q1 NEUROSCIENCES

Experimental Neurology

Pub Date : 2024-09-18 DOI: 10.1016/j.expneurol.2024.114958

Pathik Parekh , Marcello Serra , Mohamad Allaw , Matteo Perra , Annalisa Pinna , Maria Manconi , Micaela Morelli

Neuroinflammation has recently emerged as a key event in Parkinson's disease (PD) pathophysiology and as a potential target for disease-modifying therapies. Plant-derived extracts, rich in bioactive phytochemicals with antioxidant properties, have shown potential in this regard. Yet their clinical utility is hampered by poor systemic availability and rapid metabolism. Recently, our group demonstrated that intragastric delivery of Nasco pomace extract via nutriosomes (NN), a novel nanoliposome formulation, contrasts the degeneration of nigrostriatal dopaminergic neurons in a subacute 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) mouse model of PD. In the present study, we investigated the impact of intragastric NN treatment on the reactivity of glial cells in the substantia nigra pars compacta (SNc) and caudate-putamen (CPu) of MPTP-treated mice. To this scope, in mice exposed to MPTP (20 mg/kg/day, × 4 days), we conducted immunohistochemistry analyses of glial fibrillary acidic protein (GFAP) and ionized calcium-binding adapter molecule 1 (IBA1) to assess the responsiveness of astrocytes and microglial cells, respectively. Additionally, we studied the co-localization of the pro-inflammatory interleukin (IL)-1β and tumor necrosis factor (TNF)-α with IBA1 to obtain insights into microglial phenotype. Immunohistochemical results showed that NN administration significantly mitigated astrogliosis and microgliosis in the CPu and SNc of mice receiving subacute MPTP treatment, with region-specific variations in anti-inflammatory efficacy. Remarkably, the CPu showed a heightened response to NN treatment, including a pronounced decrease in microglial IL-1β and TNF-α production. Altogether, these findings underscore the anti-inflammatory effects of NN treatment and provide a potential mechanism underlying the neuroprotective effects previously observed in a subacute MPTP mouse model of PD.

最近，神经炎症已成为帕金森病（PD）病理生理学中的一个关键事件，并成为改变疾病疗法的一个潜在靶点。植物提取物富含具有抗氧化特性的生物活性植物化学物质，在这方面已显示出潜力。然而，这些提取物在临床上的应用却受到了全身可用性差和新陈代谢快的阻碍。最近，我们的研究小组证实，通过一种新型纳米脂质体制剂--营养体（NN）--胃内输送纳斯科果渣提取物，可在亚急性 1-甲基-4-苯基-1,2,3,6-四氢吡啶（MPTP）脑损伤小鼠模型中逆转黑质多巴胺能神经元的退化。在本研究中，我们探讨了胃内 NN 治疗对 MPTP 治疗小鼠黑质（SNc）和尾状核（CPu）神经胶质细胞反应性的影响。为此，我们对暴露于 MPTP（20 毫克/千克/天，×4 天）的小鼠进行了神经胶质纤维酸性蛋白（GFAP）和电离钙结合适配器分子 1（IBA1）的免疫组化分析，以分别评估星形胶质细胞和微胶质细胞的反应性。此外，我们还研究了促炎性白细胞介素（IL）-1β和肿瘤坏死因子（TNF）-α与IBA1的共定位，以深入了解小胶质细胞的表型。免疫组化结果表明，给予 NN 能显著缓解亚急性 MPTP 治疗小鼠 CPu 和 SNc 中的星形胶质细胞和小胶质细胞病变，抗炎效果因区域而异。值得注意的是，CPu 对 NN 治疗的反应更加强烈，包括小胶质细胞 IL-1β 和 TNF-α 的产生明显减少。总之，这些发现强调了 NN 治疗的抗炎作用，并为之前在亚急性 MPTP PD 小鼠模型中观察到的神经保护作用提供了潜在机制。

{"title":"Extract from Nasco pomace loaded in nutriosomes exerts anti-inflammatory effects in the MPTP mouse model of Parkinson's disease","authors":"Pathik Parekh , Marcello Serra , Mohamad Allaw , Matteo Perra , Annalisa Pinna , Maria Manconi , Micaela Morelli","doi":"10.1016/j.expneurol.2024.114958","DOIUrl":"10.1016/j.expneurol.2024.114958","url":null,"abstract":"<div><div>Neuroinflammation has recently emerged as a key event in Parkinson's disease (PD) pathophysiology and as a potential target for disease-modifying therapies. Plant-derived extracts, rich in bioactive phytochemicals with antioxidant properties, have shown potential in this regard. Yet their clinical utility is hampered by poor systemic availability and rapid metabolism. Recently, our group demonstrated that intragastric delivery of Nasco pomace extract via nutriosomes (NN), a novel nanoliposome formulation, contrasts the degeneration of nigrostriatal dopaminergic neurons in a subacute 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) mouse model of PD. In the present study, we investigated the impact of intragastric NN treatment on the reactivity of glial cells in the substantia nigra pars compacta (SNc) and caudate-putamen (CPu) of MPTP-treated mice. To this scope, in mice exposed to MPTP (20 mg/kg/day, × 4 days), we conducted immunohistochemistry analyses of glial fibrillary acidic protein (GFAP) and ionized calcium-binding adapter molecule 1 (IBA1) to assess the responsiveness of astrocytes and microglial cells, respectively. Additionally, we studied the co-localization of the pro-inflammatory interleukin (IL)-1β and tumor necrosis factor (TNF)-α with IBA1 to obtain insights into microglial phenotype. Immunohistochemical results showed that NN administration significantly mitigated astrogliosis and microgliosis in the CPu and SNc of mice receiving subacute MPTP treatment, with region-specific variations in anti-inflammatory efficacy. Remarkably, the CPu showed a heightened response to NN treatment, including a pronounced decrease in microglial IL-1β and TNF-α production. Altogether, these findings underscore the anti-inflammatory effects of NN treatment and provide a potential mechanism underlying the neuroprotective effects previously observed in a subacute MPTP mouse model of PD.</div></div>","PeriodicalId":12246,"journal":{"name":"Experimental Neurology","volume":"382 ","pages":"Article 114958"},"PeriodicalIF":4.6,"publicationDate":"2024-09-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S001448862400284X/pdfft?md5=5df3210bf129aa24e796a3ecdd73e7f8&pid=1-s2.0-S001448862400284X-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142282666","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0