Pub Date : 2024-10-01DOI: 10.1016/j.neurot.2024.e00425
Sidhanth Chandra , Robert Vassar
Alzheimer's disease (AD) is the most common neurodegenerative disorder and is the most common cause of dementia. AD is characterized pathologically by proteinaceous aggregates composed of amyloid beta (Aβ) and tau as well as progressive neurodegeneration. Concurrently with the buildup of protein aggregates, a strong neuroinflammatory response, in the form of reactive astrocytosis and microgliosis, occurs in the AD brain. It has recently been shown that the gut microbiome (GMB), composed of trillions of bacteria in the human intestine, can regulate both reactive astrocytosis and microgliosis in the context of both amyloidosis and tauopathy. Many studies have implicated microglia in these processes. However, growing evidence suggests that interactions between the GMB and astrocytes have a much larger role than previously thought. In this review, we summarize evidence regarding the gut microbiome in the control of reactive astrocytosis in AD.
阿尔茨海默病（AD）是最常见的神经退行性疾病，也是导致痴呆症的最常见原因。阿尔茨海默病的病理特征是由淀粉样 beta（Aβ）和 tau 组成的蛋白聚集体以及进行性神经变性。在蛋白聚集体堆积的同时，AD 大脑中还会出现强烈的神经炎症反应，表现为反应性星形胶质细胞增多和小胶质细胞增多。最近的研究表明，由人体肠道中数万亿细菌组成的肠道微生物组（GMB）可在淀粉样变性和牛磺酸病的背景下调节反应性星形胶质细胞增多症和小胶质细胞增多症。许多研究都认为小胶质细胞与这些过程有关。然而，越来越多的证据表明，GMB 与星形胶质细胞之间的相互作用所起的作用要比以前认为的大得多。在这篇综述中，我们总结了有关肠道微生物组控制 AD 中反应性星形胶质细胞增多的证据。
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Pub Date : 2024-10-01DOI: 10.1016/j.neurot.2024.e00478
Ali Keshavarzian, Sangram S. Sisodia
{"title":"Gut microbiota dysbiosis and neurologic diseases: New Horizon with potential diagnostic and therapeutic impact","authors":"Ali Keshavarzian, Sangram S. Sisodia","doi":"10.1016/j.neurot.2024.e00478","DOIUrl":"10.1016/j.neurot.2024.e00478","url":null,"abstract":"","PeriodicalId":19159,"journal":{"name":"Neurotherapeutics","volume":"21 6","pages":"Article e00478"},"PeriodicalIF":5.6,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142564807","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}
Pub Date : 2024-10-01DOI: 10.1016/j.neurot.2024.e00461
Rakesh B. Patel, Anil K. Chauhan
{"title":"Cerebroprotective action of butylphthalide in acute ischemic stroke: Potential role of Nrf2/HO-1 signaling pathway","authors":"Rakesh B. Patel, Anil K. Chauhan","doi":"10.1016/j.neurot.2024.e00461","DOIUrl":"10.1016/j.neurot.2024.e00461","url":null,"abstract":"","PeriodicalId":19159,"journal":{"name":"Neurotherapeutics","volume":"21 6","pages":"Article e00461"},"PeriodicalIF":5.6,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142365919","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}
Pub Date : 2024-10-01DOI: 10.1016/j.neurot.2024.e00423
Yiyang Zhu, Wade K. Self, David M. Holtzman
Tauopathies constitute a group of neurodegenerative diseases characterized by abnormal aggregation of the protein tau, progressive neuronal and synaptic loss, and eventual cognitive and motor impairment. In this review, we will highlight the latest efforts investigating the intricate interplay between the gut microbiome and tauopathies. We discuss the physiological interactions between the microbiome and the brain as well as clinical and experimental evidence that suggests that the presence of tauopathy alters the composition of gut microbiota. We explore both animal and human studies that define causative relationships between the gut microbiome and tauopathy by directly manipulating or transferring gut microbiota. This review highlights future directions into identifying and mechanistically elucidating microbial species causally linked to tauopathies, with an ultimate goal of devising therapeutic targets towards the gut microbiome to treat tauopathies.
tau病是一组神经退行性疾病，其特征是蛋白质tau的异常聚集、神经元和突触的进行性丧失以及最终的认知和运动障碍。在本综述中，我们将重点介绍研究肠道微生物组与 tau 病之间错综复杂的相互作用的最新进展。我们将讨论微生物群与大脑之间的生理相互作用，以及表明陶陶病的存在会改变肠道微生物群组成的临床和实验证据。我们探讨了通过直接操纵或转移肠道微生物群来确定肠道微生物群与牛脑病之间因果关系的动物和人体研究。本综述强调了确定和从机理上阐明与陶陶病有因果关系的微生物物种的未来方向，其最终目标是设计出针对肠道微生物组的治疗靶点来治疗陶陶病。
{"title":"An emerging role for the gut microbiome in tauopathy","authors":"Yiyang Zhu, Wade K. Self, David M. Holtzman","doi":"10.1016/j.neurot.2024.e00423","DOIUrl":"10.1016/j.neurot.2024.e00423","url":null,"abstract":"<div><div>Tauopathies constitute a group of neurodegenerative diseases characterized by abnormal aggregation of the protein tau, progressive neuronal and synaptic loss, and eventual cognitive and motor impairment. In this review, we will highlight the latest efforts investigating the intricate interplay between the gut microbiome and tauopathies. We discuss the physiological interactions between the microbiome and the brain as well as clinical and experimental evidence that suggests that the presence of tauopathy alters the composition of gut microbiota. We explore both animal and human studies that define causative relationships between the gut microbiome and tauopathy by directly manipulating or transferring gut microbiota. This review highlights future directions into identifying and mechanistically elucidating microbial species causally linked to tauopathies, with an ultimate goal of devising therapeutic targets towards the gut microbiome to treat tauopathies.</div></div>","PeriodicalId":19159,"journal":{"name":"Neurotherapeutics","volume":"21 6","pages":"Article e00423"},"PeriodicalIF":5.6,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141534917","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}
Pub Date : 2024-10-01DOI: 10.1016/j.neurot.2024.e00471
Bowen Chang , Zhi Geng , Jiaming Mei , Zhengyu Wang , Peng Chen , Yuge Jiang , Chaoshi Niu
Parkinson's Disease (PD) is a progressive neurodegenerative disorder with substantial impact on patients' quality of life. Subthalamic nucleus deep brain stimulation (STN-DBS) is an effective treatment for advanced PD, but patient responses vary, necessitating predictive models for personalized care. Recent advancements in medical imaging and machine learning offer opportunities to enhance predictive accuracy, particularly through deep learning and multi-instance learning (MIL) techniques. This retrospective study included 127 PD patients undergoing STN-DBS. Medical records and imaging data were collected, and patients were categorized based on treatment outcomes. Advanced segmentation models were trained for automated region of interest (ROI) delineation. A novel 2.5D deep learning approach incorporating multi-slice representation was developed to extract detailed ROI features. Multi-instance learning fusion techniques integrated predictions across multiple slices, combining radiomics and deep learning features to enhance model performance. Various machine learning algorithms were evaluated, and model robustness was assessed using cross-validation and hyperparameter optimization. The MIL model achieved an area under the curve (AUC) of 0.846 for predicting STN-DBS outcomes, surpassing the radiomics model's AUC of 0.825. Integration of MIL and radiomics features in the DLRad model further improved discriminative ability to an AUC of 0.871. Calibration tests showed good model reliability, and decision curve analysis demonstrated clinical utility, affirming the model's predictive advantage. This study demonstrates the efficacy of integrating MIL, radiomics, and deep learning techniques to predict STN-DBS outcomes in PD patients. The multimodal fusion approach enhances predictive accuracy, supporting personalized treatment planning and advancing patient care.
帕金森病（PD）是一种进行性神经退行性疾病，对患者的生活质量有很大影响。丘脑下核深部脑刺激（STN-DBS）是治疗晚期帕金森病的有效方法，但患者的反应各不相同，因此需要建立个性化护理的预测模型。医学成像和机器学习的最新进展为提高预测准确性提供了机会，特别是通过深度学习和多实例学习（MIL）技术。这项回顾性研究纳入了 127 名接受 STN-DBS 治疗的帕金森病患者。研究收集了病历和成像数据，并根据治疗结果对患者进行了分类。对高级分割模型进行了训练，以实现感兴趣区（ROI）的自动划分。开发了一种结合多切片表示的新型 2.5D 深度学习方法，以提取详细的 ROI 特征。多实例学习融合技术整合了多个切片的预测，结合了放射组学和深度学习特征，以提高模型性能。对各种机器学习算法进行了评估，并使用交叉验证和超参数优化对模型的稳健性进行了评估。MIL模型预测STN-DBS结果的曲线下面积（AUC）达到了0.846，超过了放射组学模型0.825的AUC。在 DLRad 模型中整合 MIL 和放射组学特征进一步提高了判别能力，AUC 达到 0.871。校准测试表明该模型具有良好的可靠性，决策曲线分析表明该模型具有临床实用性，从而肯定了该模型的预测优势。这项研究证明了整合 MIL、放射组学和深度学习技术来预测 STN-DBS 在帕金森病患者中的疗效。多模态融合方法提高了预测的准确性，支持个性化治疗规划，促进了患者护理。
{"title":"Application of multimodal deep learning and multi-instance learning fusion techniques in predicting STN-DBS outcomes for Parkinson's disease patients","authors":"Bowen Chang , Zhi Geng , Jiaming Mei , Zhengyu Wang , Peng Chen , Yuge Jiang , Chaoshi Niu","doi":"10.1016/j.neurot.2024.e00471","DOIUrl":"10.1016/j.neurot.2024.e00471","url":null,"abstract":"<div><div>Parkinson's Disease (PD) is a progressive neurodegenerative disorder with substantial impact on patients' quality of life. Subthalamic nucleus deep brain stimulation (STN-DBS) is an effective treatment for advanced PD, but patient responses vary, necessitating predictive models for personalized care. Recent advancements in medical imaging and machine learning offer opportunities to enhance predictive accuracy, particularly through deep learning and multi-instance learning (MIL) techniques. This retrospective study included 127 PD patients undergoing STN-DBS. Medical records and imaging data were collected, and patients were categorized based on treatment outcomes. Advanced segmentation models were trained for automated region of interest (ROI) delineation. A novel 2.5D deep learning approach incorporating multi-slice representation was developed to extract detailed ROI features. Multi-instance learning fusion techniques integrated predictions across multiple slices, combining radiomics and deep learning features to enhance model performance. Various machine learning algorithms were evaluated, and model robustness was assessed using cross-validation and hyperparameter optimization. The MIL model achieved an area under the curve (AUC) of 0.846 for predicting STN-DBS outcomes, surpassing the radiomics model's AUC of 0.825. Integration of MIL and radiomics features in the DLRad model further improved discriminative ability to an AUC of 0.871. Calibration tests showed good model reliability, and decision curve analysis demonstrated clinical utility, affirming the model's predictive advantage. This study demonstrates the efficacy of integrating MIL, radiomics, and deep learning techniques to predict STN-DBS outcomes in PD patients. The multimodal fusion approach enhances predictive accuracy, supporting personalized treatment planning and advancing patient care.</div></div>","PeriodicalId":19159,"journal":{"name":"Neurotherapeutics","volume":"21 6","pages":"Article e00471"},"PeriodicalIF":5.6,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142470919","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}
Pub Date : 2024-09-01DOI: 10.1016/j.neurot.2024.e00446
Matthieu Colpaert , Pankaj K. Singh , Katherine J. Donohue , Natacha T. Pires , David D. Fuller , Manuela Corti , Barry J. Byrne , Ramon C. Sun , Craig W. Vander Kooi , Matthew S. Gentry
Glycogen storage diseases (GSDs) comprise a group of inherited metabolic disorders characterized by defects in glycogen metabolism, leading to abnormal glycogen accumulation in multiple tissues, most notably affecting the liver, skeletal muscle, and heart. Recent findings have uncovered the importance of glycogen metabolism in the brain, sustaining a myriad of physiological functions and linking its perturbation to central nervous system (CNS) pathology. This link resulted in classification of neurological-GSDs (n-GSDs), a group of diseases with shared deficits in neurological glycogen metabolism. The n-GSD patients exhibit a spectrum of clinical presentations with common etiology while requiring tailored therapeutic approaches from the traditional GSDs. Recent research has elucidated the genetic and biochemical mechanisms and pathophysiological basis underlying different n-GSDs. Further, the last decade has witnessed some promising developments in novel therapeutic approaches, including enzyme replacement therapy (ERT), substrate reduction therapy (SRT), small molecule drugs, and gene therapy targeting key aspects of glycogen metabolism in specific n-GSDs. This preclinical progress has generated noticeable success in potentially modifying disease course and improving clinical outcomes in patients. Herein, we provide an overview of current perspectives on n-GSDs, emphasizing recent advances in understanding their molecular basis, therapeutic developments, underscore key challenges and the need to deepen our understanding of n-GSDs pathogenesis to develop better therapeutic strategies that could offer improved treatment and sustainable benefits to the patients.
{"title":"Neurological glycogen storage diseases and emerging therapeutics","authors":"Matthieu Colpaert , Pankaj K. Singh , Katherine J. Donohue , Natacha T. Pires , David D. Fuller , Manuela Corti , Barry J. Byrne , Ramon C. Sun , Craig W. Vander Kooi , Matthew S. Gentry","doi":"10.1016/j.neurot.2024.e00446","DOIUrl":"10.1016/j.neurot.2024.e00446","url":null,"abstract":"<div><div>Glycogen storage diseases (GSDs) comprise a group of inherited metabolic disorders characterized by defects in glycogen metabolism, leading to abnormal glycogen accumulation in multiple tissues, most notably affecting the liver, skeletal muscle, and heart. Recent findings have uncovered the importance of glycogen metabolism in the brain, sustaining a myriad of physiological functions and linking its perturbation to central nervous system (CNS) pathology. This link resulted in classification of neurological-GSDs (n-GSDs), a group of diseases with shared deficits in neurological glycogen metabolism. The n-GSD patients exhibit a spectrum of clinical presentations with common etiology while requiring tailored therapeutic approaches from the traditional GSDs. Recent research has elucidated the genetic and biochemical mechanisms and pathophysiological basis underlying different n-GSDs. Further, the last decade has witnessed some promising developments in novel therapeutic approaches, including enzyme replacement therapy (ERT), substrate reduction therapy (SRT), small molecule drugs, and gene therapy targeting key aspects of glycogen metabolism in specific n-GSDs. This preclinical progress has generated noticeable success in potentially modifying disease course and improving clinical outcomes in patients. Herein, we provide an overview of current perspectives on n-GSDs, emphasizing recent advances in understanding their molecular basis, therapeutic developments, underscore key challenges and the need to deepen our understanding of n-GSDs pathogenesis to develop better therapeutic strategies that could offer improved treatment and sustainable benefits to the patients.</div></div>","PeriodicalId":19159,"journal":{"name":"Neurotherapeutics","volume":"21 5","pages":"Article e00446"},"PeriodicalIF":5.6,"publicationDate":"2024-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142292176","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}
Pub Date : 2024-09-01DOI: 10.1016/j.neurot.2024.e00387
The precise oxygen content thresholds of ischemic deep parenchymal (OCIDP) and that in cortical microcirculation (OCCM), which leads to ischemic penumbra converting into the infarcted core, remain uncertain. This study employed an invasive fiber-optic oxygen meter and a newly developed oxygen-responsive probe called RuA3-Cy5-rtPA (RC-rtPA) based on recombinant tissue-type plasminogen activator (rtPA) to examine the oxygen content thresholds. A mouse model of middle cerebral artery occlusion was generated and animals were randomly divided into a sham, 24-h reperfusion after 3-h ischemia (IR 3-h), and IR 6-h groups, all of which were sacrificed following reperfusion. Stroke severity was evaluated based on the infarction area, neurological symptoms, microcirculation perfusion, and microemboli in microcirculation. OCIDP was characterized based on its extent and distribution, whereas OCCM was measured using RC-rtPA. During ischemia, stroke severity escalation manifested as increasing infarction area, severe neurologic symptoms, and poorer microcirculation perfusion with more microthrombi depositions. OCIDP presented rapid decline following artery occlusion along with a gradual increase in the hypoxic area. Within 3 h following ischemia induction, the ischemic tissue that experienced hypoxia could be rescued, and this reversibility would disappear after 6 h. Within 6 h, OCCM continued to decrease. A significant decrease in oxygen content in cortical venules and cortical parenchyma was observed. These findings assist in establishing the extent of the ischemic penumbra at the microcirculation level and offer a foundation for assessing the ischemic penumbra that could respond positively to reperfusion therapy beyond the typical time window.
{"title":"The relationship between ischemic penumbra progression and the oxygen content of cortex microcirculation in acute ischemic stroke","authors":"","doi":"10.1016/j.neurot.2024.e00387","DOIUrl":"10.1016/j.neurot.2024.e00387","url":null,"abstract":"<div><div>The precise oxygen content thresholds of ischemic deep parenchymal (OCIDP) and that in cortical microcirculation (OCCM), which leads to ischemic penumbra converting into the infarcted core, remain uncertain. This study employed an invasive fiber-optic oxygen meter and a newly developed oxygen-responsive probe called RuA<sub>3</sub>-Cy5-rtPA (RC-rtPA) based on recombinant tissue-type plasminogen activator (rtPA) to examine the oxygen content thresholds. A mouse model of middle cerebral artery occlusion was generated and animals were randomly divided into a sham, 24-h reperfusion after 3-h ischemia (IR 3-h), and IR 6-h groups, all of which were sacrificed following reperfusion. Stroke severity was evaluated based on the infarction area, neurological symptoms, microcirculation perfusion, and microemboli in microcirculation. OCIDP was characterized based on its extent and distribution, whereas OCCM was measured using RC-rtPA. During ischemia, stroke severity escalation manifested as increasing infarction area, severe neurologic symptoms, and poorer microcirculation perfusion with more microthrombi depositions. OCIDP presented rapid decline following artery occlusion along with a gradual increase in the hypoxic area. Within 3 h following ischemia induction, the ischemic tissue that experienced hypoxia could be rescued, and this reversibility would disappear after 6 h. Within 6 h, OCCM continued to decrease. A significant decrease in oxygen content in cortical venules and cortical parenchyma was observed. These findings assist in establishing the extent of the ischemic penumbra at the microcirculation level and offer a foundation for assessing the ischemic penumbra that could respond positively to reperfusion therapy beyond the typical time window.</div></div>","PeriodicalId":19159,"journal":{"name":"Neurotherapeutics","volume":"21 5","pages":"Article e00387"},"PeriodicalIF":5.6,"publicationDate":"2024-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141450998","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}
Pub Date : 2024-09-01DOI: 10.1016/j.neurot.2024.e00388
Protein misfolding and mislocalization are common to both familial and sporadic forms of amyotrophic lateral sclerosis (ALS). Maintaining proteostasis through induction of heat shock proteins (HSP) to increase chaperoning capacity is a rational therapeutic strategy in the treatment of ALS. However, the threshold for upregulating stress-inducible HSPs remains high in neurons, presenting a therapeutic obstacle. This study used mouse models expressing the ALS variants FUSR521G or SOD1G93A to follow up on previous work in cultured motor neurons showing varied effects of the HSP co-inducer, arimoclomol, and class I histone deacetylase (HDAC) inhibitors on HSP expression depending on the ALS variant being expressed. As in cultured neurons, neither expression of the transgene nor drug treatments induced expression of HSPs in cortex, spinal cord or muscle of FUSR521G mice, indicating suppression of the heat shock response. Nonetheless, arimoclomol, and RGFP963, restored performance on cognitive tests and improved cortical dendritic spine densities. In SOD1G93A mice, multiple HSPs were upregulated in hindlimb skeletal muscle, but not in lumbar spinal cord with the exception of HSPB1 associated with astrocytosis. Drug treatments improved contractile force but reduced the increase in HSPs in muscle rather than facilitating their expression. The data point to mechanisms other than amplification of the heat shock response underlying recovery of cognitive function in ALS-FUS mice by arimoclomol and class I HDAC inhibition and suggest potential benefits in counteracting cognitive impairment in ALS, frontotemporal dementia and related disorders.
蛋白质错误折叠和错误定位是家族性和散发性肌萎缩性脊髓侧索硬化症（ALS）的共同特征。通过诱导热休克蛋白（HSP）以提高伴侣能力来维持蛋白稳态是治疗渐冻人症的一种合理治疗策略。然而，神经元上调应激诱导型 HSP 的阈值仍然很高，这给治疗带来了障碍。本研究使用表达 ALS 变异体 FUSR521G 或 SOD1G93A 的小鼠模型，以跟进之前在培养运动神经元中进行的研究，这些研究显示 HSP 协同诱导剂阿瑞莫司醇和 I 类组蛋白去乙酰化酶（HDAC）抑制剂对 HSP 表达的不同影响取决于所表达的 ALS 变异体。与培养神经元一样，转基因的表达或药物处理都不会诱导 FUSR521G 小鼠皮质、脊髓或肌肉中 HSP 的表达，这表明热休克反应受到了抑制。然而，阿瑞莫司洛尔和 RGFP963 能恢复认知测试的表现，并改善皮质树突棘密度。在 SOD1G93A 小鼠中，多种 HSPs 在后肢骨骼肌中上调，但在腰椎脊髓中没有上调，只有与星形细胞增多有关的 HSPB1 除外。药物治疗可提高收缩力，但会降低肌肉中 HSPs 的增加，而不是促进其表达。这些数据表明，通过阿瑞莫司洛尔和 I 类 HDAC 抑制剂，ALS-FUS 小鼠认知功能的恢复除了热休克反应的扩大之外，还有其他机制。
{"title":"Reversal of cognitive deficits in FUSR521G amyotrophic lateral sclerosis mice by arimoclomol and a class I histone deacetylase inhibitor independent of heat shock protein induction","authors":"","doi":"10.1016/j.neurot.2024.e00388","DOIUrl":"10.1016/j.neurot.2024.e00388","url":null,"abstract":"<div><div>Protein misfolding and mislocalization are common to both familial and sporadic forms of amyotrophic lateral sclerosis (ALS). Maintaining proteostasis through induction of heat shock proteins (HSP) to increase chaperoning capacity is a rational therapeutic strategy in the treatment of ALS. However, the threshold for upregulating stress-inducible HSPs remains high in neurons, presenting a therapeutic obstacle. This study used mouse models expressing the ALS variants FUS<sup>R521G</sup> or SOD1<sup>G93A</sup> to follow up on previous work in cultured motor neurons showing varied effects of the HSP co-inducer, arimoclomol, and class I histone deacetylase (HDAC) inhibitors on HSP expression depending on the ALS variant being expressed. As in cultured neurons, neither expression of the transgene nor drug treatments induced expression of HSPs in cortex, spinal cord or muscle of FUS<sup>R521G</sup> mice, indicating suppression of the heat shock response. Nonetheless, arimoclomol, and RGFP963, restored performance on cognitive tests and improved cortical dendritic spine densities. In SOD1<sup>G93A</sup> mice, multiple HSPs were upregulated in hindlimb skeletal muscle, but not in lumbar spinal cord with the exception of HSPB1 associated with astrocytosis. Drug treatments improved contractile force but reduced the increase in HSPs in muscle rather than facilitating their expression. The data point to mechanisms other than amplification of the heat shock response underlying recovery of cognitive function in ALS-FUS mice by arimoclomol and class I HDAC inhibition and suggest potential benefits in counteracting cognitive impairment in ALS, frontotemporal dementia and related disorders.</div></div>","PeriodicalId":19159,"journal":{"name":"Neurotherapeutics","volume":"21 5","pages":"Article e00388"},"PeriodicalIF":5.6,"publicationDate":"2024-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141555285","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}
Pub Date : 2024-09-01DOI: 10.1016/j.neurot.2024.e00424
Yanhui Duan , Chenyuan Ye , Jingyi Liao , Xin Xie
The myelin sheath plays crucial roles in brain development and neuronal functions. In the central nervous system, myelin is generated by oligodendrocytes, that differentiate from oligodendrocyte progenitor cells (OPC). In demyelinating diseases, the differentiation capacity of OPC is impaired and remyelination is dampened. Boosting remyelination by promoting OPC differentiation is a novel strategy for the treatment of demyelinating diseases. The opioid system, which consists of four receptors and their ligands, has been implicated in OPC differentiation and myelin formation. However, the exact roles of each opioid receptor and the relevant pharmacological molecules in OPC differentiation and myelin formation remain elusive. In the present study, specific agonists and antagonists of each opioid receptor were used to explore the function of opioid receptors in OPC differentiation. Nociceptin/orphanin FQ receptor (NOPR) specific antagonist LY2940094 was found to stimulate OPC differentiation and myelination in both in vitro and in vivo models. Unexpectedly, other NOPR ligands did not affect OPC differentiation, and NOPR knockdown did not mimic or impede the effect of LY2940094. LY2940094 was found to modulate the expression of the oligodendrocytes differentiation-associated transcription factors ID4 and Myrf, although the exact mechanism remains unclear. Since LY2940094 has been tested clinically to treat depression and alcohol dependency and has displayed an acceptable safety profile, it may provide an alternative approach to treat demyelinating diseases.
{"title":"LY2940094, an NOPR antagonist, promotes oligodendrocyte generation and myelin recovery in an NOPR independent manner","authors":"Yanhui Duan , Chenyuan Ye , Jingyi Liao , Xin Xie","doi":"10.1016/j.neurot.2024.e00424","DOIUrl":"10.1016/j.neurot.2024.e00424","url":null,"abstract":"<div><div>The myelin sheath plays crucial roles in brain development and neuronal functions. In the central nervous system, myelin is generated by oligodendrocytes, that differentiate from oligodendrocyte progenitor cells (OPC). In demyelinating diseases, the differentiation capacity of OPC is impaired and remyelination is dampened. Boosting remyelination by promoting OPC differentiation is a novel strategy for the treatment of demyelinating diseases. The opioid system, which consists of four receptors and their ligands, has been implicated in OPC differentiation and myelin formation. However, the exact roles of each opioid receptor and the relevant pharmacological molecules in OPC differentiation and myelin formation remain elusive. In the present study, specific agonists and antagonists of each opioid receptor were used to explore the function of opioid receptors in OPC differentiation. Nociceptin/orphanin FQ receptor (NOPR) specific antagonist LY2940094 was found to stimulate OPC differentiation and myelination in both in vitro and in vivo models. Unexpectedly, other NOPR ligands did not affect OPC differentiation, and NOPR knockdown did not mimic or impede the effect of LY2940094. LY2940094 was found to modulate the expression of the oligodendrocytes differentiation-associated transcription factors ID4 and Myrf, although the exact mechanism remains unclear. Since LY2940094 has been tested clinically to treat depression and alcohol dependency and has displayed an acceptable safety profile, it may provide an alternative approach to treat demyelinating diseases.</div></div>","PeriodicalId":19159,"journal":{"name":"Neurotherapeutics","volume":"21 5","pages":"Article e00424"},"PeriodicalIF":5.6,"publicationDate":"2024-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141616890","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}
Pub Date : 2024-09-01DOI: 10.1016/j.neurot.2024.100438
Zahra Moussavi , Maria Uehara , Grant Rutherford , Brian Lithgow , Colleen Millikin , Xikui Wang , Chandan Saha , Behzad Mansouri , Craig Omelan , Lesley Fellows , Paul B. Fitzgerald , Lisa Koski
{"title":"Corrigendum to “Repetitive transcranial magnetic stimulation as a treatment for Alzheimer's disease: A randomized placebo-controlled double-blind clinical trial” [Neurotherapeutics 21 (3) (2024) e00331]","authors":"Zahra Moussavi , Maria Uehara , Grant Rutherford , Brian Lithgow , Colleen Millikin , Xikui Wang , Chandan Saha , Behzad Mansouri , Craig Omelan , Lesley Fellows , Paul B. Fitzgerald , Lisa Koski","doi":"10.1016/j.neurot.2024.100438","DOIUrl":"10.1016/j.neurot.2024.100438","url":null,"abstract":"","PeriodicalId":19159,"journal":{"name":"Neurotherapeutics","volume":"21 5","pages":"Article 100438"},"PeriodicalIF":5.6,"publicationDate":"2024-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142109951","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}
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