Molecular and Cellular Neuroscience最新文献_第3页

Exosome-based therapeutic approach for spinal cord injury: A review 基于外泌体的脊髓损伤治疗方法综述。

IF 2.4 3区医学 Q3 NEUROSCIENCES

Molecular and Cellular Neuroscience

Pub Date : 2025-12-01 Epub Date: 2025-09-25 DOI: 10.1016/j.mcn.2025.104048

Shuai Bai , Rong Rong Qiang , Rui Yang Liu , De Jie Kang , Yan Ling Yang

Spinal cord injury (SCI) is a devastating neurological condition associated with high rates of disability and mortality, placing substantial burdens on patients, families, and healthcare systems. Current treatment strategies, including surgical decompression, pharmacological intervention, and rehabilitation, offer only limited functional recovery. Exosomes, extracellular vesicles with a double-membrane structure, range in diameter from 30 to 150 nm and play a key role in intercellular communication by transporting proteins, lipids, and nucleic acids. Recent studies have highlighted their potential as natural nanocarriers for the treatment of neurodegenerative disorders. Due to their low immunogenicity and multifunctional reparative properties, exosomes have shown considerable efficacy in promoting neurological recovery following SCI. They exert therapeutic effects through multiple mechanisms, including modulation of the inflammatory response, promoting axonal regeneration and angiogenesis, and inhibiting apoptosis. This review summarizes the pathophysiological mechanisms underlying SCI and elucidates the therapeutic roles of exosomes and exosomal microRNAs (exo-miR) in SCI repair. Furthermore, it discusses current challenges and prospects for the clinical translation of exosome-based therapies, aiming to provide valuable insights for future research and clinical applications.

脊髓损伤（SCI）是一种具有高致残率和高死亡率的破坏性神经系统疾病，给患者、家庭和医疗保健系统带来了沉重的负担。目前的治疗策略，包括手术减压、药物干预和康复，只能提供有限的功能恢复。外泌体是具有双膜结构的细胞外囊泡，直径从30到150 nm （nm）不等，通过运输蛋白质、脂质和核酸在细胞间通讯中起关键作用。最近的研究强调了它们作为治疗神经退行性疾病的天然纳米载体的潜力。由于其低免疫原性和多功能修复特性，外泌体在促进脊髓损伤后神经恢复方面显示出相当大的功效。它们通过多种机制发挥治疗作用，包括调节炎症反应、促进轴突再生和血管生成、抑制细胞凋亡。本文综述了脊髓损伤的病理生理机制，并阐明了外泌体和外泌体microRNAs （exo-miR）在脊髓损伤修复中的治疗作用。此外，本文还讨论了目前基于外泌体疗法的临床翻译面临的挑战和前景，旨在为未来的研究和临床应用提供有价值的见解。

{"title":"Exosome-based therapeutic approach for spinal cord injury: A review","authors":"Shuai Bai , Rong Rong Qiang , Rui Yang Liu , De Jie Kang , Yan Ling Yang","doi":"10.1016/j.mcn.2025.104048","DOIUrl":"10.1016/j.mcn.2025.104048","url":null,"abstract":"<div><div>Spinal cord injury (SCI) is a devastating neurological condition associated with high rates of disability and mortality, placing substantial burdens on patients, families, and healthcare systems. Current treatment strategies, including surgical decompression, pharmacological intervention, and rehabilitation, offer only limited functional recovery. Exosomes, extracellular vesicles with a double-membrane structure, range in diameter from 30 to 150 nm and play a key role in intercellular communication by transporting proteins, lipids, and nucleic acids. Recent studies have highlighted their potential as natural nanocarriers for the treatment of neurodegenerative disorders. Due to their low immunogenicity and multifunctional reparative properties, exosomes have shown considerable efficacy in promoting neurological recovery following SCI. They exert therapeutic effects through multiple mechanisms, including modulation of the inflammatory response, promoting axonal regeneration and angiogenesis, and inhibiting apoptosis. This review summarizes the pathophysiological mechanisms underlying SCI and elucidates the therapeutic roles of exosomes and exosomal microRNAs (<em>exo</em>-miR) in SCI repair. Furthermore, it discusses current challenges and prospects for the clinical translation of exosome-based therapies, aiming to provide valuable insights for future research and clinical applications.</div></div>","PeriodicalId":18739,"journal":{"name":"Molecular and Cellular Neuroscience","volume":"135 ","pages":"Article 104048"},"PeriodicalIF":2.4,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145182147","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"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

Agrimonolide exhibits anti-neuroinflammatory potential via TLR4-mediated pathways 农单内酯通过tlr4介导的途径显示出抗神经炎症的潜力。

IF 2.4 3区医学 Q3 NEUROSCIENCES

Molecular and Cellular Neuroscience

Pub Date : 2025-12-01 Epub Date: 2025-11-21 DOI: 10.1016/j.mcn.2025.104057

Weiling Li , Qian Peng , Ping Sun , Lingyi Xiang , Yangxin Qi , Xiansheng Ye , Yingying Shi , Song Hu , Haifeng Chen , Binlian Sun

Microglial and astrocytic activation is the main reason for the neuroinflammatory responses, which damages neurons resulting in neurological disorders. Currently, there are few drugs that directly target neuroinflammation in clinical practice, which highlights the urgent need for effective inhibitors. In this study, we identified agrimonolide, from a screen of 40 compounds, as an inhibitor of glia activation, and further confirmed its efficacy in vitro and in vivo. In cellular models, agrimonolide significantly reduced the expression levels of proinflammatory cytokines (IL-1β, IL-6 and TNFα) in LPS stimulated BV2 cells and primary astrocytes. Mechanistic investigation revealed that agrimonolide suppresses the activation of both NF-κB and MAPK signaling pathways, combined the molecular docking results, it is suggested that agrimonolide may have multiple targets. In ICR mice, our measurements showed that agrimonolide treatment decreased LPS-induced glial activation, as evidenced by the protein levels of IBA-1 and GFAP. Additionally, it significantly inhibited the activation of TLR4-mediated signaling pathways. Our findings suggest that agrimonolide suppresses neuroinflammatory responses by inhibiting microglial and astrocytic activation, providing insight into potential treatment strategies for neuroinflammation-related diseases.

小胶质细胞和星形胶质细胞的激活是神经炎症反应的主要原因，神经炎症反应损害神经元，导致神经系统疾病。目前，临床实践中直接针对神经炎症的药物很少，因此迫切需要有效的抑制剂。在本研究中，我们从40种化合物中筛选出了agrimonolide作为神经胶质细胞激活抑制剂，并进一步证实了其体外和体内的有效性。在细胞模型中，农素内酯显著降低LPS刺激的BV2小胶质细胞和原代星形胶质细胞中促炎因子（IL-1β、IL-6和TNFα）的表达水平。机制研究表明，农单内酯可抑制NF-κB和MAPK信号通路的激活，结合分子对接结果，提示农单内酯可能具有多靶点。在ICR小鼠中，我们的测量结果表明，农素内酯处理降低了lps诱导的胶质细胞激活，IBA-1和GFAP的蛋白水平证明了这一点。此外，它还能显著抑制tlr4介导的信号通路的激活。我们的研究结果表明，农单内酯通过抑制小胶质细胞和星形胶质细胞的激活来抑制神经炎症反应，为神经炎症相关疾病的潜在治疗策略提供了见解。

{"title":"Agrimonolide exhibits anti-neuroinflammatory potential via TLR4-mediated pathways","authors":"Weiling Li , Qian Peng , Ping Sun , Lingyi Xiang , Yangxin Qi , Xiansheng Ye , Yingying Shi , Song Hu , Haifeng Chen , Binlian Sun","doi":"10.1016/j.mcn.2025.104057","DOIUrl":"10.1016/j.mcn.2025.104057","url":null,"abstract":"<div><div>Microglial and astrocytic activation is the main reason for the neuroinflammatory responses, which damages neurons resulting in neurological disorders. Currently, there are few drugs that directly target neuroinflammation in clinical practice, which highlights the urgent need for effective inhibitors. In this study, we identified agrimonolide, from a screen of 40 compounds, as an inhibitor of glia activation, and further confirmed its efficacy in vitro and <em>in vivo</em>. In cellular models, agrimonolide significantly reduced the expression levels of proinflammatory cytokines (IL-1β, IL-6 and TNFα) in LPS stimulated BV2 cells and primary astrocytes. Mechanistic investigation revealed that agrimonolide suppresses the activation of both NF-κB and MAPK signaling pathways, combined the molecular docking results, it is suggested that agrimonolide may have multiple targets. In ICR mice, our measurements showed that agrimonolide treatment decreased LPS-induced glial activation, as evidenced by the protein levels of IBA-1 and GFAP. Additionally, it significantly inhibited the activation of TLR4-mediated signaling pathways. Our findings suggest that agrimonolide suppresses neuroinflammatory responses by inhibiting microglial and astrocytic activation, providing insight into potential treatment strategies for neuroinflammation-related diseases.</div></div>","PeriodicalId":18739,"journal":{"name":"Molecular and Cellular Neuroscience","volume":"135 ","pages":"Article 104057"},"PeriodicalIF":2.4,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145588231","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"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

The LINC00094/miR-19a-3p signalling regulates glycolysis and mediates cold induced traumatic brain injury LINC00094/miR-19a-3p信号调节糖酵解并介导冷诱导的创伤性脑损伤。

IF 2.4 3区医学 Q3 NEUROSCIENCES

Molecular and Cellular Neuroscience

Pub Date : 2025-12-01 Epub Date: 2025-10-10 DOI: 10.1016/j.mcn.2025.104050

Divya Mishra , Rashi Saxena , Deepak , Rekha Yadav , Durga Prasad Mishra

Cold induced traumatic brain injury (Ci-TBI), is a lethal and highly debilitating neurodegenerative condition with limited therapeutic options. Metabolic perturbations like deregulated glycolysis is perceived as a hallmark of TBIs including Ci-TBIs. Elucidation of the underlying mechanisms regulating Ci-TBI are essential devising effective therapeutic strategies. In the present study, induction of Ci-TBI in-vitro and in a mice model down regulated the long noncoding RNA LINC00094. Our mechanistic studies revealed that LINC00094 targeted and inhibited miR-19a-3p both in the neuronal culture based in vitro model of Ci-TBI vitro and a Ci-TBI mice model in vivo. The elevated expression of miR-19a-3p further targeted and inhibited the adiponectin receptor 2 (AdipoR2) and repressed glycolysis, glucose uptake and lactate production. Collectively, our results elucidated the molecular cascade and underscored the significance of the LINC00094/miR-19a-3p signalling in regulation of glycolysis mediating Ci-TBI. These novel findings indicate that LINC00094 and miR-19a-3p could be of prognostic and diagnostic value as potential biomarkers of Ci-TBI progression.

冷致创伤性脑损伤（Ci-TBI）是一种致命且高度衰弱的神经退行性疾病，治疗选择有限。代谢紊乱如糖酵解失调被认为是包括ci - tbi在内的tbi的标志。阐明调节Ci-TBI的潜在机制是制定有效治疗策略的必要条件。在本研究中，体外和小鼠模型诱导Ci-TBI下调长链非编码RNA LINC00094。我们的机制研究表明，LINC00094在体外培养的Ci-TBI模型和体内Ci-TBI小鼠模型中都能靶向并抑制miR-19a-3p。miR-19a-3p的表达升高进一步靶向并抑制脂联素受体2 (AdipoR2)，抑制糖酵解、葡萄糖摄取和乳酸生成。总的来说，我们的结果阐明了分子级联，并强调了LINC00094/miR-19a-3p信号传导在糖酵解介导的Ci-TBI调控中的重要性。这些新发现表明，LINC00094和miR-19a-3p可能作为Ci-TBI进展的潜在生物标志物具有预后和诊断价值。

{"title":"The LINC00094/miR-19a-3p signalling regulates glycolysis and mediates cold induced traumatic brain injury","authors":"Divya Mishra , Rashi Saxena , Deepak , Rekha Yadav , Durga Prasad Mishra","doi":"10.1016/j.mcn.2025.104050","DOIUrl":"10.1016/j.mcn.2025.104050","url":null,"abstract":"<div><div>Cold induced traumatic brain injury (Ci-TBI), is a lethal and highly debilitating neurodegenerative condition with limited therapeutic options. Metabolic perturbations like deregulated glycolysis is perceived as a hallmark of TBIs including Ci-TBIs. Elucidation of the underlying mechanisms regulating Ci-TBI are essential devising effective therapeutic strategies. In the present study, induction of Ci-TBI <em>in-vitro</em> and in a mice model down regulated the long noncoding RNA LINC00094. Our mechanistic studies revealed that LINC00094 targeted and inhibited miR-19a-3p both in the neuronal culture based <em>in vitro</em> model of Ci-TBI vitro and a Ci-TBI mice model <em>in vivo</em>. The elevated expression of miR-19a-3p further targeted and inhibited the adiponectin receptor 2 (AdipoR2) and repressed glycolysis, glucose uptake and lactate production. Collectively, our results elucidated the molecular cascade and underscored the significance of the LINC00094/miR-19a-3p signalling in regulation of glycolysis mediating Ci-TBI. These novel findings indicate that LINC00094 and miR-19a-3p could be of prognostic and diagnostic value as potential biomarkers of Ci-TBI progression.</div></div>","PeriodicalId":18739,"journal":{"name":"Molecular and Cellular Neuroscience","volume":"135 ","pages":"Article 104050"},"PeriodicalIF":2.4,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145275198","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"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

Chronic functional deficits following a single closed head injury in mice are prevented by minocycline and N-acetyl cysteine 二甲胺四环素和n -乙酰半胱氨酸可预防小鼠单一闭合性头部损伤后的慢性功能缺陷。

IF 2.4 3区医学 Q3 NEUROSCIENCES

Molecular and Cellular Neuroscience

Pub Date : 2025-12-01 Epub Date: 2025-09-23 DOI: 10.1016/j.mcn.2025.104049

Siobhán C. Lawless , Craig Kelley , Elena Nikulina , Ufaq Tahir , Ashmeet Kaur , Juan Marcos Alarcon , Peter J. Bergold

Traumatic brain injury (TBI) can produce chronic limb coordination and gait deficits that are associated with ongoing white matter damage. In rodent TBI models, chronic motor deficits may be obscured by aging or motor compensation. In addition, there are no treatments for TBI. The murine closed head injury (CHI) model produces diffuse, chronic white matter injury that may underlie chronic white matter dysfunction and motor deficits. Evoked compound action potentials (CAP) assess corpus callosum function from 3 to 180-days post injury (DPI). CHI acutely decreases total CAP amplitudes that recover by 90 DPI and increase further at 180 DPI. Total CAP amplitude changes are blocked by dosing of minocycline and N-acetylcysteine beginning 12 h post-injury (MN12). Injured or sham mice have similar times to traverse or number of foot faults on beam walk. DeepLabCut™ markerless limb tracking provides limb positions used to develop novel assays to assess beam walk and simple/complex wheel. Absition analysis integrates the duration and extent of foot faults during beam walk. Injured mice develop absition deficits at 90 DPI that worsen at 180 DPI suggesting a chronic and progressive decline. Chronic absition deficits are blocked by MN12 treatment. Speed typically assesses performance on simple/complex wheel. Novel limb coordination assays show that at 180 DPI, injured mice decrease coordination that significantly correlates with increased total CAP amplitude. MN12 alleviates chronic corpus callosum dysfunction and motor deficits suggesting a strong efficacy to treat TBI. DeepLabCut™ limb tracking reveals chronic deficits and motor compensation not seen with standard outcomes.

创伤性脑损伤（TBI）可产生慢性肢体协调和步态缺陷，这些缺陷与持续的白质损伤有关。在啮齿动物TBI模型中，慢性运动缺陷可能被衰老或运动补偿所掩盖。此外，TBI没有治疗方法。小鼠闭合性脑损伤（CHI）模型产生弥漫性慢性白质损伤，可能是慢性白质功能障碍和运动缺陷的基础。诱发复合动作电位（CAP）评估损伤后3 ~ 180天的胼胝体功能。CHI急剧降低总CAP振幅，在90 DPI时恢复，并在180 DPI时进一步增加。损伤后12 h （MN12）开始给药二甲胺四环素和n -乙酰半胱氨酸可阻断总CAP振幅变化。受伤小鼠和假小鼠在梁式行走中行走的时间和足部故障数量相似。DeepLabCut™无标记肢体跟踪提供肢体位置，用于开发新的分析方法来评估梁行走和简单/复杂车轮。姿态分析综合了梁行走过程中足部故障的持续时间和程度。受伤小鼠在90 DPI时出现定位缺陷，在180 DPI时恶化，表明慢性和进行性下降。MN12治疗可阻断慢性退位缺陷。速度通常评估简单/复杂车轮的性能。新的肢体协调实验表明，在180 DPI时，受伤小鼠的协调能力下降，与总CAP振幅增加显著相关。MN12可缓解慢性胼胝体功能障碍和运动缺陷，提示其对TBI有较强的治疗效果。DeepLabCut™肢体跟踪显示慢性缺陷和运动补偿未见标准结果。

{"title":"Chronic functional deficits following a single closed head injury in mice are prevented by minocycline and N-acetyl cysteine","authors":"Siobhán C. Lawless , Craig Kelley , Elena Nikulina , Ufaq Tahir , Ashmeet Kaur , Juan Marcos Alarcon , Peter J. Bergold","doi":"10.1016/j.mcn.2025.104049","DOIUrl":"10.1016/j.mcn.2025.104049","url":null,"abstract":"<div><div>Traumatic brain injury (TBI) can produce chronic limb coordination and gait deficits that are associated with ongoing white matter damage. In rodent TBI models, chronic motor deficits may be obscured by aging or motor compensation. In addition, there are no treatments for TBI. The murine closed head injury (CHI) model produces diffuse, chronic white matter injury that may underlie chronic white matter dysfunction and motor deficits. Evoked compound action potentials (CAP) assess corpus callosum function from 3 to 180-days post injury (DPI). CHI acutely decreases total CAP amplitudes that recover by 90 DPI and increase further at 180 DPI. Total CAP amplitude changes are blocked by dosing of minocycline and <em>N</em>-acetylcysteine beginning 12 h post-injury (MN12). Injured or sham mice have similar times to traverse or number of foot faults on beam walk. DeepLabCut™ markerless limb tracking provides limb positions used to develop novel assays to assess beam walk and simple/complex wheel. Absition analysis integrates the duration and extent of foot faults during beam walk. Injured mice develop absition deficits at 90 DPI that worsen at 180 DPI suggesting a chronic and progressive decline. Chronic absition deficits are blocked by MN12 treatment. Speed typically assesses performance on simple/complex wheel. Novel limb coordination assays show that at 180 DPI, injured mice decrease coordination that significantly correlates with increased total CAP amplitude. MN12 alleviates chronic corpus callosum dysfunction and motor deficits suggesting a strong efficacy to treat TBI. DeepLabCut™ limb tracking reveals chronic deficits and motor compensation not seen with standard outcomes.</div></div>","PeriodicalId":18739,"journal":{"name":"Molecular and Cellular Neuroscience","volume":"135 ","pages":"Article 104049"},"PeriodicalIF":2.4,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145150099","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"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

Glymphatic impairment in Moyamoya disease 烟雾病的淋巴损害。

IF 2.4 3区医学 Q3 NEUROSCIENCES

Molecular and Cellular Neuroscience

Pub Date : 2025-12-01 Epub Date: 2025-11-04 DOI: 10.1016/j.mcn.2025.104053

Yao Chen , Xichang Liu

Moyamoya disease (MMD) is a chronic disease characterized by the progressive narrowing of the terminal internal carotid artery, accompanied by abnormal angiogenesis at the base of the skull and defective formation of the vascular network, with a complex clinical picture and a risk of cognitive impairment and dementia in addition to ischemic and hemorrhagic events. The glymphatic system is a cerebrospinal fluid and interstitial fluid drainage pathway that acts throughout the brain to remove metabolic wastes from the brain parenchyma. Clinical studies have found that cognitive decline in patients with MMD is linked to metabolite accumulation and reduced diffusion tensor image analysis along the perivascular space (DTI-ALPS), highlighting the potential impact of glymphatic system impairment. This dysfunction may stem from a combination of chronic hypoperfusion, systemic microstructural damage and inflammatory response, and is an important link to further deterioration of vascular cognitive function. This article discusses the recent findings on glymphatic system disorders in MMD, with the objective of providing new approaches to the disease.

烟雾病（Moyamoya disease， MMD）是一种慢性疾病，以颈内动脉终末进行性狭窄为特征，伴有颅底血管生成异常和血管网络形成缺陷，临床表现复杂，除了缺血性和出血事件外，还存在认知障碍和痴呆的风险。淋巴系统是脑脊液和间质液的引流途径，作用于整个大脑，从脑实质中清除代谢废物。临床研究发现，烟雾病患者的认知能力下降与代谢物积累和沿血管周围间隙弥散张量图像分析（DTI-ALPS）减少有关，突出了淋巴系统损伤的潜在影响。这种功能障碍可能源于慢性灌注不足、全身微结构损伤和炎症反应的共同作用，是血管认知功能进一步恶化的重要环节。本文讨论了烟雾病中淋巴系统疾病的最新发现，目的是提供新的治疗方法。

引用次数: 0

Covalent inhibitors in Parkinson's disease: Molecular targeting strategies for neuroprotective intervention 帕金森病的共价抑制剂：神经保护干预的分子靶向策略。

IF 2.4 3区医学 Q3 NEUROSCIENCES

Molecular and Cellular Neuroscience

Pub Date : 2025-12-01 Epub Date: 2025-09-09 DOI: 10.1016/j.mcn.2025.104037

Devadharuna Mohan , Raghul Venkatesan , Amarjith Thiyyar Kandy , Santhoshkumar Muthu , Saravanan Jayaram , Rajinikanth Baskaran , Palanisamy Pethappachetty , Divakar Selvaraj

Parkinson's disease (PD) is a complex neurodegenerative disorder characterized by dopaminergic neuronal loss, protein aggregation, and neuroinflammation. Current symptomatic therapies have not demonstrated disease-modifying effects. Covalent inhibitors represent a promising multifactorial therapeutic approach due to their ability to form irreversible and specific bonds with target proteins. This narrative review incorporates recent experimental and computational findings on emerging covalent inhibitors that target key molecular mechanisms implicated in PD. This includes α-synuclein aggregation, LRRK2 kinase hyperactivity, monoamine oxidase B (MAO-B) dysfunction, glutathione S-transferase Pi 1 (GSTP1)-mediated oxidative stress, and modulation of the Nrf2 signaling pathway. We discuss structure-guided drug design strategies, warhead chemistry, and unique inhibition modalities that contribute to improved pharmacological profiles and neuroprotective potential. In addition to classical covalent inhibition, the review explores emerging targeted covalent degrader strategies that expand therapeutic possibilities by promoting selective protein degradation rather than mere functional suppression. Furthermore, recent preclinical advances and clinical translation challenges are evaluated, positioning covalent approaches as leading candidates for targeted and sustained PD interventions. Lastly, we address developmental obstacles, such as enhancing selectivity and blood-brain barrier penetration while minimizing off-target effects, highlighting the role of activity-based protein profiling, covalent PROTACs, and bifunctional covalent degraders as next-generation strategies to optimize therapeutic efficacy in PD treatment.

帕金森病（PD）是一种复杂的神经退行性疾病，以多巴胺能神经元丧失、蛋白质聚集和神经炎症为特征。目前的对症治疗尚未显示出改善疾病的效果。共价抑制剂由于其与靶蛋白形成不可逆和特异性键的能力，代表了一种有前途的多因子治疗方法。这篇叙述性的综述结合了最近的实验和计算发现，新出现的共价抑制剂的目标涉及PD的关键分子机制。这包括α-突触核蛋白聚集、LRRK2激酶高活性、单胺氧化酶B （MAO-B）功能障碍、谷胱甘肽s -转移酶Pi 1 （GSTP1）介导的氧化应激和Nrf2信号通路的调节。我们讨论了结构导向的药物设计策略，弹头化学和独特的抑制模式，有助于改善药理学概况和神经保护潜力。除了经典的共价抑制外，该综述还探讨了新兴的靶向共价降解策略，通过促进选择性蛋白质降解而不仅仅是功能抑制来扩大治疗可能性。此外，评估了最近的临床前进展和临床翻译挑战，将共价方法定位为靶向和持续PD干预的主要候选方法。最后，我们解决了发育障碍，如增强选择性和血脑屏障穿透，同时最大限度地减少脱靶效应，强调了基于活性的蛋白质谱分析，共价PROTACs和双功能共价降解物作为优化PD治疗效果的下一代策略的作用。

{"title":"Covalent inhibitors in Parkinson's disease: Molecular targeting strategies for neuroprotective intervention","authors":"Devadharuna Mohan , Raghul Venkatesan , Amarjith Thiyyar Kandy , Santhoshkumar Muthu , Saravanan Jayaram , Rajinikanth Baskaran , Palanisamy Pethappachetty , Divakar Selvaraj","doi":"10.1016/j.mcn.2025.104037","DOIUrl":"10.1016/j.mcn.2025.104037","url":null,"abstract":"<div><div>Parkinson's disease (PD) is a complex neurodegenerative disorder characterized by dopaminergic neuronal loss, protein aggregation, and neuroinflammation. Current symptomatic therapies have not demonstrated disease-modifying effects. Covalent inhibitors represent a promising multifactorial therapeutic approach due to their ability to form irreversible and specific bonds with target proteins. This narrative review incorporates recent experimental and computational findings on emerging covalent inhibitors that target key molecular mechanisms implicated in PD. This includes α-synuclein aggregation, LRRK2 kinase hyperactivity, monoamine oxidase B (MAO-B) dysfunction, glutathione S-transferase Pi 1 (GSTP1)-mediated oxidative stress, and modulation of the Nrf2 signaling pathway. We discuss structure-guided drug design strategies, warhead chemistry, and unique inhibition modalities that contribute to improved pharmacological profiles and neuroprotective potential. In addition to classical covalent inhibition, the review explores emerging targeted covalent degrader strategies that expand therapeutic possibilities by promoting selective protein degradation rather than mere functional suppression. Furthermore, recent preclinical advances and clinical translation challenges are evaluated, positioning covalent approaches as leading candidates for targeted and sustained PD interventions. Lastly, we address developmental obstacles, such as enhancing selectivity and blood-brain barrier penetration while minimizing off-target effects, highlighting the role of activity-based protein profiling, covalent PROTACs, and bifunctional covalent degraders as next-generation strategies to optimize therapeutic efficacy in PD treatment.</div></div>","PeriodicalId":18739,"journal":{"name":"Molecular and Cellular Neuroscience","volume":"135 ","pages":"Article 104037"},"PeriodicalIF":2.4,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145040897","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"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

Genetic modifiers of epilepsy: A narrative review 癫痫的遗传修饰因子：一个叙述性的回顾。

IF 2.4 3区医学 Q3 NEUROSCIENCES

Molecular and Cellular Neuroscience

Pub Date : 2025-12-01 Epub Date: 2025-09-05 DOI: 10.1016/j.mcn.2025.104038

Saliha Rizvi , Syed Tasleem Raza , Farzana Mahdi

Epilepsy is a neurological disorder that shows strong genetic control on the timing and onset of symptoms and drug response variability. Some epilepsy syndromes have clear monogenic mutations but genes with control on the phenotype and severity of the disorder and drug sensitivity are present in the whole genetic profile. Genetic modifiers are not the cause of epilepsy but control significant networks such as synaptic plasticity and ion channels and neurodevelopment and neuroinflammation and therefore the reason why two individuals with the same primary mutations have different clinical courses. The review comprehensively examines the genetics of epilepsy to outline standard and minority genetic determinants and to distinguish between single-genetic and poly-genetic causes. It examines genetic modifiers and the mechanism by which they act and the control they exert on drug resistance and seizure risk and development of epilepsy and cognitive and behavioral problems. Alongside it explains how GWAS data with the help of epigenetics to identify significant modifying genes with control on neurotransmission and the immune response and metabolic pathways and ion channel regulation such as SCN1A and KCNQ2. The major functional mechanisms of genetic modifiers and the control they exert on network excitability and the control on the blood-brain barrier and neurodevelopmental pathways has been emphasized and explained in specific sections. The final section in this overview discusses the future possibility with precision medicine through genetic modifier-directed treatments and new drug development strategies and will develop tailored epilepsy treatment strategies.

癫痫是一种神经系统疾病，对症状的时间和发作以及药物反应变异性有很强的遗传控制。一些癫痫综合征有明显的单基因突变，但控制表型、疾病严重程度和药物敏感性的基因存在于整个遗传谱中。遗传修饰因子不是癫痫的病因，但控制着突触可塑性、离子通道、神经发育和神经炎症等重要网络，因此，具有相同原发性突变的两个个体有不同的临床病程。这篇综述全面检查了癫痫的遗传学，概述了标准和少数遗传决定因素，并区分了单遗传和多遗传原因。它审查基因修饰物及其作用机制，以及它们对耐药性、癫痫发作风险和癫痫发展以及认知和行为问题的控制。此外，它还解释了GWAS数据如何在表观遗传学的帮助下识别具有控制神经传递和免疫反应以及代谢途径和离子通道调节的重要修饰基因，如SCN1A和KCNQ2。遗传修饰因子的主要功能机制及其对神经网络兴奋性、血脑屏障和神经发育途径的控制已在特定章节中得到强调和解释。本综述的最后一部分讨论了未来通过基因修饰导向治疗和新药开发策略的精准医学的可能性，并将制定量身定制的癫痫治疗策略。

{"title":"Genetic modifiers of epilepsy: A narrative review","authors":"Saliha Rizvi , Syed Tasleem Raza , Farzana Mahdi","doi":"10.1016/j.mcn.2025.104038","DOIUrl":"10.1016/j.mcn.2025.104038","url":null,"abstract":"<div><div>Epilepsy is a neurological disorder that shows strong genetic control on the timing and onset of symptoms and drug response variability. Some epilepsy syndromes have clear monogenic mutations but genes with control on the phenotype and severity of the disorder and drug sensitivity are present in the whole genetic profile. Genetic modifiers are not the cause of epilepsy but control significant networks such as synaptic plasticity and ion channels and neurodevelopment and neuroinflammation and therefore the reason why two individuals with the same primary mutations have different clinical courses. The review comprehensively examines the genetics of epilepsy to outline standard and minority genetic determinants and to distinguish between single-genetic and poly-genetic causes. It examines genetic modifiers and the mechanism by which they act and the control they exert on drug resistance and seizure risk and development of epilepsy and cognitive and behavioral problems. Alongside it explains how GWAS data with the help of epigenetics to identify significant modifying genes with control on neurotransmission and the immune response and metabolic pathways and ion channel regulation such as <em>SCN1A</em> and <em>KCNQ2</em>. The major functional mechanisms of genetic modifiers and the control they exert on network excitability and the control on the blood-brain barrier and neurodevelopmental pathways has been emphasized and explained in specific sections. The final section in this overview discusses the future possibility with precision medicine through genetic modifier-directed treatments and new drug development strategies and will develop tailored epilepsy treatment strategies.</div></div>","PeriodicalId":18739,"journal":{"name":"Molecular and Cellular Neuroscience","volume":"135 ","pages":"Article 104038"},"PeriodicalIF":2.4,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145015747","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"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

Bridging the gap in the management of Alzheimer's disease using fecal microbiota transplantation 利用粪便微生物群移植弥合阿尔茨海默病管理方面的差距。

IF 2.4 3区医学 Q3 NEUROSCIENCES

Molecular and Cellular Neuroscience

Pub Date : 2025-12-01 Epub Date: 2025-11-01 DOI: 10.1016/j.mcn.2025.104052

Bushra Bashir , Monica Gulati , Sukriti Vishwas , Md Sadique Hussain , Gaurav Gupta , Puneet Kumar , Poonam Negi , Neeraj Mittal , Kamal Dua , Sachin Kumar Singh

Alzheimer's disease (AD) is a neurodegenerative disease that greatly impairs the health status of human beings and creates significant burdens on individuals, families, and society. AD is characterized by the buildup of pathological proteins and glial cell dysregulated activity. Additional hallmark features include oxidative stress, neuroinflammation, impaired autophagy, cellular senescence, mitochondrial dysfunction, epigenetic alterations, reduced neurogenesis, increased blood-brain barrier permeability, and age-inappropriate intestinal dysbiosis. There is significant evidence that shows that microbiota in the gut affects the development and progression of AD. As a result, gut microbiota modulation has been identified as a new method of clinical management of AD, and more and more efforts have been devoted to identifying new methodologies for its prevention and treatment. This paper will discuss the role of gut microbiome in the etiopathogenesis of AD and consider the possibilities of fecal microbiota extract (FME) supplementation, commonly referred to as fecal microbiota transplantation (FMT). It is both a prophylactic and curative approach. The FMT therapy is grounded on the premise that anti-inflammatory effects, modifications of amyloid β, improved synaptic plasticity, short-chain fatty acids, and histone acetylation are the principles behind the enhancement of AD. The current review will present an overview of the linkage between FMT and AD as well. It further examines and evaluates the effects of FMT on aging-based mechanisms that support the development of AD. It also provides a broad description of the recent clinical and preclinical evidence on the application of FMT to AD.

阿尔茨海默病（Alzheimer's disease， AD）是一种严重损害人类健康的神经退行性疾病，给个人、家庭和社会造成了巨大的负担。AD的特点是病理蛋白的积累和神经胶质细胞活性失调。其他标志性特征包括氧化应激、神经炎症、自噬受损、细胞衰老、线粒体功能障碍、表观遗传改变、神经发生减少、血脑屏障通透性增加和与年龄不适应的肠道生态失调。有重要证据表明，肠道微生物群影响阿尔茨海默病的发生和进展。因此，调节肠道菌群已被确定为阿尔茨海默病临床管理的新方法，并且越来越多的人致力于寻找预防和治疗阿尔茨海默病的新方法。本文将讨论肠道微生物群在AD发病机制中的作用，并考虑补充粪便微生物群提取物（FME）的可能性，通常称为粪便微生物群移植（FMT）。它既是一种预防方法，也是一种治疗方法。FMT治疗的前提是抗炎作用、β淀粉样蛋白修饰、突触可塑性改善、短链脂肪酸和组蛋白乙酰化是阿尔茨海默病增强背后的原理。本综述也将概述FMT和AD之间的联系。它进一步检查和评估FMT对支持AD发展的基于衰老的机制的影响。它还提供了关于FMT应用于AD的近期临床和临床前证据的广泛描述。

{"title":"Bridging the gap in the management of Alzheimer's disease using fecal microbiota transplantation","authors":"Bushra Bashir , Monica Gulati , Sukriti Vishwas , Md Sadique Hussain , Gaurav Gupta , Puneet Kumar , Poonam Negi , Neeraj Mittal , Kamal Dua , Sachin Kumar Singh","doi":"10.1016/j.mcn.2025.104052","DOIUrl":"10.1016/j.mcn.2025.104052","url":null,"abstract":"<div><div>Alzheimer's disease (AD) is a neurodegenerative disease that greatly impairs the health status of human beings and creates significant burdens on individuals, families, and society. AD is characterized by the buildup of pathological proteins and glial cell dysregulated activity. Additional hallmark features include oxidative stress, neuroinflammation, impaired autophagy, cellular senescence, mitochondrial dysfunction, epigenetic alterations, reduced neurogenesis, increased blood-brain barrier permeability, and age-inappropriate intestinal dysbiosis. There is significant evidence that shows that microbiota in the gut affects the development and progression of AD. As a result, gut microbiota modulation has been identified as a new method of clinical management of AD, and more and more efforts have been devoted to identifying new methodologies for its prevention and treatment. This paper will discuss the role of gut microbiome in the etiopathogenesis of AD and consider the possibilities of fecal microbiota extract (FME) supplementation, commonly referred to as fecal microbiota transplantation (FMT). It is both a prophylactic and curative approach. The FMT therapy is grounded on the premise that anti-inflammatory effects, modifications of amyloid β, improved synaptic plasticity, short-chain fatty acids, and histone acetylation are the principles behind the enhancement of AD. The current review will present an overview of the linkage between FMT and AD as well. It further examines and evaluates the effects of FMT on aging-based mechanisms that support the development of AD. It also provides a broad description of the recent clinical and preclinical evidence on the application of FMT to AD.</div></div>","PeriodicalId":18739,"journal":{"name":"Molecular and Cellular Neuroscience","volume":"135 ","pages":"Article 104052"},"PeriodicalIF":2.4,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145431853","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"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

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 : 2025-09-01 Epub 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。

{"title":"Regulation of hippocampal excitatory synapse development by the adhesion G-protein coupled receptor brain-specific angiogenesis inhibitor 2 (BAI2/ADGRB2)","authors":"Christina M. Meyer, Olga Vafaeva, Henry Low, David J. Speca, Elva Díaz","doi":"10.1016/j.mcn.2025.104015","DOIUrl":"10.1016/j.mcn.2025.104015","url":null,"abstract":"<div><div>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.</div></div>","PeriodicalId":18739,"journal":{"name":"Molecular and Cellular Neuroscience","volume":"134 ","pages":"Article 104015"},"PeriodicalIF":2.6,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144199625","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"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

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 : 2025-09-01 Epub 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