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.
{"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":"2025-11-01","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}
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.
{"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":"2025-10-10","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}
Pub Date : 2025-10-08DOI: 10.1016/j.mcn.2025.104051
Lisa Nieland , Edwina Abou Haidar , David Rufino-Ramos , Shilpa Prabhakar , Youssef Samaha , Koen Breyne , Francis K. Fordjour , Saumya Das , Marike L.D. Broekman , Stephen Gould , Xandra O. Breakefield , Erik R. Abels
Astrocytes interact with neighboring cells by releasing extracellular vesicles (EVs). Tools to study astrocyte EV-mediated communication with other brain cells in vivo are essential. In this study, we crossed the Exomap1 transgenic mouse expressing Cre-activated human-specific CD81 (HsCD81) fused to the fluorescent protein mNeonGreen (HsCD81mNG), to a transgenic mouse expressing Cre under the astrocyte-expressing GFAP promoter resulting in Exomap1::Gfap-Cre mice, referred to here as AstroGreen. We characterized HsCD81mNG-expressing astrocytes and shedded EVs loaded with HsCD81mNG and Cre, both in vitro and in mouse brains. Using this model, we show that HsCD81mNG can be used to track EV content, production, and functional Cre transfer in vitro and in the brain, allowing evaluation of the interaction of astrocytes with neighboring cells mediated by EVs. We anticipate that this model will improve our understanding of astrocytes transferring EVs within their surroundings during normal physiological processes and in the context of neuropathological conditions.
{"title":"AstroGreen transgenic mouse illuminates the trafficking of astrocyte-derived extracellular vesicles","authors":"Lisa Nieland , Edwina Abou Haidar , David Rufino-Ramos , Shilpa Prabhakar , Youssef Samaha , Koen Breyne , Francis K. Fordjour , Saumya Das , Marike L.D. Broekman , Stephen Gould , Xandra O. Breakefield , Erik R. Abels","doi":"10.1016/j.mcn.2025.104051","DOIUrl":"10.1016/j.mcn.2025.104051","url":null,"abstract":"<div><div>Astrocytes interact with neighboring cells by releasing extracellular vesicles (EVs). Tools to study astrocyte EV-mediated communication with other brain cells <em>in vivo</em> are essential<em>.</em> In this study, we crossed the Exomap1 transgenic mouse expressing Cre-activated human-specific CD81 (HsCD81) fused to the fluorescent protein mNeonGreen (HsCD81mNG), to a transgenic mouse expressing Cre under the astrocyte-expressing GFAP promoter resulting in <em>Exomap1</em>::<em>Gfap-Cre</em> mice, referred to here as AstroGreen. We characterized HsCD81mNG-expressing astrocytes and shedded EVs loaded with HsCD81mNG and Cre, both <em>in vitro</em> and in mouse brains. Using this model, we show that HsCD81mNG can be used to track EV content, production, and functional Cre transfer <em>in vitro</em> and in the brain, allowing evaluation of the interaction of astrocytes with neighboring cells mediated by EVs. We anticipate that this model will improve our understanding of astrocytes transferring EVs within their surroundings during normal physiological processes and in the context of neuropathological conditions.</div></div>","PeriodicalId":18739,"journal":{"name":"Molecular and Cellular Neuroscience","volume":"135 ","pages":"Article 104051"},"PeriodicalIF":2.4,"publicationDate":"2025-10-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145275075","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}
Pub Date : 2025-09-25DOI: 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.
{"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":"2025-09-25","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}
Pub Date : 2025-09-23DOI: 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.
{"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":"2025-09-23","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}
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.
{"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":"2025-09-09","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}
Pub Date : 2025-09-05DOI: 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.
{"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":"2025-09-05","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}
Pub Date : 2025-09-04DOI: 10.1016/j.mcn.2025.104036
Priya Sharma , Mary Erazo Bastidas , Usman Ali , Shivadas Sivasubramaniam , Vadivel Parthsarathy
Emerging evidence indicates that apelin, an adipokine, plays a critical role in numerous biological functions and may hold potential for therapeutic applications; however, its efficacy is constrained by rapid plasma degradation. Thus, the search for novel apelin analogues with reduced susceptibility to plasma degradation is ongoing. We have previously shown novel modified apelin-13 analogues, providing exciting opportunities for potential therapeutic development against Alzheimer's disease. In this study we explored novel insights into the neuroprotective effects of stable fatty acid modified (Lys8GluPAL) apelin-13-amide and amidated apelin-13 amide in mitigating cellular damage in SH-SY5Y neuroblastoma cells exposed to palmitic acid (PA) and lipopolysaccharide-induced (LPS) stress. Both apelin-13 analogues were found to modulate ER stress response and reduce oxidative stress by suppressing PA- and LPS-induced ROS production (36 % and 42 % reductions in GSH/GSG (p < 0.005). The peptides attenuated apoptosis by reducing caspase 3/7 activity and restoring bcl2 expression (p < 0.05) in cells treated with PA and LPS. They also downregulated pro-apoptotic genes, protected neurites from stress-induced damage, and promoted neurite outgrowth. The observed protective effects could be due to activation of the AMPK pathway, a critical regulator of cellular energy homeostasis and survival. These findings provide insight into novel, enzymatically stable apelin-13 analogues and highlight their potential to be developed as therapeutic agents against neuroinflammation and neurodegenerative disease, including Alzheimer's disease.
{"title":"Stable apelin-13 analogues promote cell proliferation, differentiation and protect inflammation induced cell death","authors":"Priya Sharma , Mary Erazo Bastidas , Usman Ali , Shivadas Sivasubramaniam , Vadivel Parthsarathy","doi":"10.1016/j.mcn.2025.104036","DOIUrl":"10.1016/j.mcn.2025.104036","url":null,"abstract":"<div><div>Emerging evidence indicates that apelin, an adipokine, plays a critical role in numerous biological functions and may hold potential for therapeutic applications; however, its efficacy is constrained by rapid plasma degradation. Thus, the search for novel apelin analogues with reduced susceptibility to plasma degradation is ongoing. We have previously shown novel modified apelin-13 analogues, providing exciting opportunities for potential therapeutic development against Alzheimer's disease. In this study we explored novel insights into the neuroprotective effects of stable fatty acid modified (Lys8GluPAL) apelin-13-amide and amidated apelin-13 amide in mitigating cellular damage in SH-SY5Y neuroblastoma cells exposed to palmitic acid (PA) and lipopolysaccharide-induced (LPS) stress. Both apelin-13 analogues were found to modulate ER stress response and reduce oxidative stress by suppressing PA- and LPS-induced ROS production (36 % and 42 % reductions in GSH/GSG (<em>p</em> < 0.005). The peptides attenuated apoptosis by reducing caspase 3/7 activity and restoring bcl2 expression (<em>p</em> < 0.05) in cells treated with PA and LPS. They also downregulated pro-apoptotic genes, protected neurites from stress-induced damage, and promoted neurite outgrowth. The observed protective effects could be due to activation of the AMPK pathway, a critical regulator of cellular energy homeostasis and survival. These findings provide insight into novel, enzymatically stable apelin-13 analogues and highlight their potential to be developed as therapeutic agents against neuroinflammation and neurodegenerative disease, including Alzheimer's disease.</div></div>","PeriodicalId":18739,"journal":{"name":"Molecular and Cellular Neuroscience","volume":"135 ","pages":"Article 104036"},"PeriodicalIF":2.4,"publicationDate":"2025-09-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145008344","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}
Ischemic stroke (IS) reduces the blood flow to the brain regions that trigger oxidative stress-induced biochemical, behavioural, molecular, and cellular impairments. Current treatment strategies are limited due to their narrow therapeutic window as, there is an urgent need to identify alternative therapeutic strategies in clinical settings to promote beneficial outcomes in stroke patients. Current study, focused on the neuro-protective potential of Arbutin (AR) in ischemic brain injury via modulation in Nrf-2/HO-1/HIF-1α/TFAM pathway. MCAO surgery was performed for 90 min, followed by reperfusion on male wistar rats, and the drug was administered intra-peritoneally. Animals were then sacrificed to estimate infarct volume, brain edema, BBB permeability, oxidative stress, inflammation, mitochondrial dysfunction, gene expression along with behavioural and morphological studies at different time intervals, i.e., 24 h and 21 days post-stroke. The results revealed that AR treatment improved neurological functions by maintaining BBB integrity and reducing edema, infarct volume, oxidative stress, and neuro-inflammation. It also improved the mitochondrial functions by increasing the gene expression of HIF-1α and TFAM along with reducing caspase-3 activation and iNOS gene expression through enhancing Nrf-2/HO-1 expression that supports the antioxidant activity of AR. Further, strong binding affinity of AR with the Nrf2 as revealed by the docking studies, reinforces our finding especially given the lack of prior target specific investigations exploring the detailed patho-mechanism of IS. Overall, AR exerts neuro-protective effect by modulating the Nrf-2/HO-1/HIF-1/TFAM pathways leading to improved mitochondrial functions, enhanced neurological outcomes, and increased neuronal survival which underscore its potential to as a therapeutic candidate for the treatment of IS.
{"title":"Modulation of Nrf-2/HO-1/HIF-1α/TFAM pathways by Arbutin in rat model of cerebral ischemic stroke.","authors":"Pinki Balhara, Sunil Sharma, Neeru Vasudeva, Neelam Rani, Sapna Grewal, Deepak Deepak, Babu Lal Jangir","doi":"10.1016/j.mcn.2025.104034","DOIUrl":"10.1016/j.mcn.2025.104034","url":null,"abstract":"<p><p>Ischemic stroke (IS) reduces the blood flow to the brain regions that trigger oxidative stress-induced biochemical, behavioural, molecular, and cellular impairments. Current treatment strategies are limited due to their narrow therapeutic window as, there is an urgent need to identify alternative therapeutic strategies in clinical settings to promote beneficial outcomes in stroke patients. Current study, focused on the neuro-protective potential of Arbutin (AR) in ischemic brain injury via modulation in Nrf-2/HO-1/HIF-1α/TFAM pathway. MCAO surgery was performed for 90 min, followed by reperfusion on male wistar rats, and the drug was administered intra-peritoneally. Animals were then sacrificed to estimate infarct volume, brain edema, BBB permeability, oxidative stress, inflammation, mitochondrial dysfunction, gene expression along with behavioural and morphological studies at different time intervals, i.e., 24 h and 21 days post-stroke. The results revealed that AR treatment improved neurological functions by maintaining BBB integrity and reducing edema, infarct volume, oxidative stress, and neuro-inflammation. It also improved the mitochondrial functions by increasing the gene expression of HIF-1α and TFAM along with reducing caspase-3 activation and iNOS gene expression through enhancing Nrf-2/HO-1 expression that supports the antioxidant activity of AR. Further, strong binding affinity of AR with the Nrf2 as revealed by the docking studies, reinforces our finding especially given the lack of prior target specific investigations exploring the detailed patho-mechanism of IS. Overall, AR exerts neuro-protective effect by modulating the Nrf-2/HO-1/HIF-1/TFAM pathways leading to improved mitochondrial functions, enhanced neurological outcomes, and increased neuronal survival which underscore its potential to as a therapeutic candidate for the treatment of IS.</p>","PeriodicalId":18739,"journal":{"name":"Molecular and Cellular Neuroscience","volume":" ","pages":"104034"},"PeriodicalIF":2.4,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144789578","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}
Pub Date : 2025-09-01Epub Date: 2025-07-10DOI: 10.1016/j.mcn.2025.104030
Tae Jung Kim, Young-Ju Kim, Soo-Hyun Park, Youngjoon Kim, Sang-Bae Ko
Lobeglitazone, an oral antidiabetic medication, acts as a peroxisome proliferator-activated receptor γ (PPARγ) agonist and demonstrates neuroprotective effects. This study investigated beneficial effects and mechanisms of lobeglitazone treatment in an experimental intracerebral hemorrhage (ICH) rat model. ICH was induced in the left striatum of Sprague-Dawley rats by administration of 0.6 units of collagenase type IV. Rats with ICH were assigned randomly to three treatment groups: (1) control group, (2) lobeglitazone 2 mg/kg, and (3) lobeglitazone 4 mg/kg (N = 6, in each group). Medications were administered orally for 3 days following ICH. Outcomes were measured based on brain edema on the third day after ICH. Behavioral outcomes were evaluated on days 1, 3, 6, and 13 following ICH utilizing the modified neurological severity score (mNSS). On the third day after ICH, inflammatory cytokines were evaluated using western blotting, and inflammatory cells were examined through immunohistochemistry. Administration of lobeglitazone at a dosage of 4 mg/kg reduced brain edema significantly (15 %) in comparison to the control and 2 mg/kg (7 %) groups. Moreover, lobeglitazone administration at a dosage of 4 mg/kg suppressed infiltration of macrophages and neutrophils in perihematomal areas. Expression of several inflammatory cytokines, including interleukin-1 beta (IL-1b), extracellular signal-regulated kinase (ERK), and cyclooxygenase-2 (COX2) were also reduced. Regarding functional outcomes, a high dose of lobeglitazone (4 mg/kg) improved the mNSS significantly on days 3 and 13 after ICH. The results suggest that lobeglitazone, a PPARγ agonist, has potential neuroprotective effects on ICH by modulating brain edema and brain inflammation via IL-1β-ERK-COX-2 pathway inhibition.
{"title":"Neuroprotective effect of the peroxisome proliferator-activated receptor γ agonist lobeglitazone following intracerebral hemorrhage in rats.","authors":"Tae Jung Kim, Young-Ju Kim, Soo-Hyun Park, Youngjoon Kim, Sang-Bae Ko","doi":"10.1016/j.mcn.2025.104030","DOIUrl":"10.1016/j.mcn.2025.104030","url":null,"abstract":"<p><p>Lobeglitazone, an oral antidiabetic medication, acts as a peroxisome proliferator-activated receptor γ (PPARγ) agonist and demonstrates neuroprotective effects. This study investigated beneficial effects and mechanisms of lobeglitazone treatment in an experimental intracerebral hemorrhage (ICH) rat model. ICH was induced in the left striatum of Sprague-Dawley rats by administration of 0.6 units of collagenase type IV. Rats with ICH were assigned randomly to three treatment groups: (1) control group, (2) lobeglitazone 2 mg/kg, and (3) lobeglitazone 4 mg/kg (N = 6, in each group). Medications were administered orally for 3 days following ICH. Outcomes were measured based on brain edema on the third day after ICH. Behavioral outcomes were evaluated on days 1, 3, 6, and 13 following ICH utilizing the modified neurological severity score (mNSS). On the third day after ICH, inflammatory cytokines were evaluated using western blotting, and inflammatory cells were examined through immunohistochemistry. Administration of lobeglitazone at a dosage of 4 mg/kg reduced brain edema significantly (15 %) in comparison to the control and 2 mg/kg (7 %) groups. Moreover, lobeglitazone administration at a dosage of 4 mg/kg suppressed infiltration of macrophages and neutrophils in perihematomal areas. Expression of several inflammatory cytokines, including interleukin-1 beta (IL-1b), extracellular signal-regulated kinase (ERK), and cyclooxygenase-2 (COX2) were also reduced. Regarding functional outcomes, a high dose of lobeglitazone (4 mg/kg) improved the mNSS significantly on days 3 and 13 after ICH. The results suggest that lobeglitazone, a PPARγ agonist, has potential neuroprotective effects on ICH by modulating brain edema and brain inflammation via IL-1β-ERK-COX-2 pathway inhibition.</p>","PeriodicalId":18739,"journal":{"name":"Molecular and Cellular Neuroscience","volume":" ","pages":"104030"},"PeriodicalIF":2.4,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144619086","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}
扫码关注我们
求助内容：
应助结果提醒方式：
京公网安备 11010802042870号