Controlling and mitigating the burden and impact of neurodegenerative diseases has three major components.The first is prevention,for instance,aiming at risk factors and comorbidities that increase the incidence of ac...Controlling and mitigating the burden and impact of neurodegenerative diseases has three major components.The first is prevention,for instance,aiming at risk factors and comorbidities that increase the incidence of acute or chronic neurodegenerative diseases.This requires a detailed understanding of the prevalence of these factors as well as their pathomechanistical impact on neurodegenerative diseases,plus of efficient ways to control them.It also requires knowledge about potential protective factors.The second component is active medical treatment of a manifesting neurodegenerative conditions by either targeting its cause or at least its most disabling symptoms.This component is addressed by most therapeutic research activities.The third component focuses on long-term outcome.It requires a better mechanistic understanding of neurodegeneration sequelae as well as of the brain's unique capacity to respond to pathological challenges,for instance,by synaptic and circuit plasticity.Whereas previous issues of Neuroprotection often focused on the second component,the recent one will put more emphasis on the first and third component.It will deal with both central nervous system(CNS)disorders caused by acute neurodegeneration,such as ischemic stroke,as well as less acute diseases,including Alzheimer's(AD)and Parkinson's disease(PD).展开更多
Investigating causes of and treatments for neurological diseases originally focused almost exclusively on the central nervous system(CNS).However,a more holistic understanding of neurological diseases emerged in recen...Investigating causes of and treatments for neurological diseases originally focused almost exclusively on the central nervous system(CNS).However,a more holistic understanding of neurological diseases emerged in recent years.Contemporary research increasingly considers organs,organ systems,and pathobiological processes outside the CNS as well as their contribution to the course of neurological diseases.Prominent examples are the systemic immunological responses after ischemic,hemorrhagic,or traumatic brain injury1 as well as the gut–brain axis modulating numerous CNS conditions.2,3 Focusing on the interactions between central and peripheral pathobiological processes may result in a considerable increase of experimental strategy complexity and the necessity for additional research efforts.展开更多
Major depressive disorder(MDD)is a complex psychiatric condition increasingly linked to chronic neuroinflammation,particularly in the context of aging,stress,and systemic comorbidities.While microglia have traditional...Major depressive disorder(MDD)is a complex psychiatric condition increasingly linked to chronic neuroinflammation,particularly in the context of aging,stress,and systemic comorbidities.While microglia have traditionally been the focus of neuroimmune studies,growing evidence highlights astrocytes as central regulators in the pathogenesis of MDD.This review synthesizes current findings on the multifaceted roles of astrocytes in neuroplasticity,neurotransmission,metabolic support,and blood‐brain barrier regulation.It explores how astrocyte reactivity and the release of pro‐inflammatory cytokines are often triggered by psychosocial stress,aging,and peripheral immune activation and contribute to synaptic dysfunction and cognitive impairment.The review also examines the bidirectional crosstalk between astrocytes and microglia,astrocytic calcium signaling,epigenetic modulation via histone lactylation,and metabolic pathways involving lactate.Special attention is given to the region‐specific and phenotypedependent responses of astrocytes,as well as their influence on the onset and maintenance of depressive symptoms.Additionally,therapeutic strategies targeting astrocyte‐mediated pathways,including anti‐inflammatory agents,metabolic modulators,repetitive transcranial magnetic stimulation,and inflammasome inhibitors,are discussed.Finally,methodological challenges and future research directions are outlined,emphasizing the need for precision medicine approaches in developing astrocyte‐targeted interventions for MDD.展开更多
Background:Despite the World Health Organization's prioritization of familial hypercholesterolemia(FH),its global diagnostic rate remains critically low,leading to inadequate treatment and control,thereby increasi...Background:Despite the World Health Organization's prioritization of familial hypercholesterolemia(FH),its global diagnostic rate remains critically low,leading to inadequate treatment and control,thereby increasing the risk of atherosclerotic cardiovascular disease.This study aimed to investigate the comorbidity burden of FH in China and analyze the differences between familial and general hypercholesterolemia(HC)populations.Methods:Using a national medical insurance database from 2013 to 2017 including 13,976 patients with FH and 13,976 matched control patients with HC,we utilized case-control methods to compare the composition ratio,comorbidity rates,medical expenses,and healthcare burden of patients with FH to those of control patients.Results:The FH population had a higher comorbidity rate of more than one cardiometabolic disease(83.7%[11,697/13,976])compared to the HC group(70.3%[9279/13,976];χ2=250.45,p<0.0001).The rates of coronary heart disease,hypertension,stroke,and diabetes were higher in patients with FH(39.2%[5475/13,976],71.0%[9925/13,976],14.2%[1982/13,976],and 31.2%[4363/13,976],respectively)compared to those in the HC group(30.4%[4255/13,976],61.4%[8587/13,976],11.5%[1601/13,976],and 28.1%[3923/13,976],respectively;all p<0.0001).In the 40−49 age group,patients with FH had a significantly higher average number of comorbidities compared to control patients with HC(1.2 vs.0.9;t=15.67,p<0.0001).Notably,the comorbidity count in patients with FH aged 40−49 years even exceeded that in patients with HC aged 50−59 years.Furthermore,the annual per capita medical cost for patients with FH was significantly higher at 5045.5 Chinese yuan(CNY)compared to 4184.7 CNY for patients with HC(t=12.54,p<0.0001).Conclusion:With a large number of patients with dyslipidemia,the type and number of comorbidities significantly impact the healthcare burden.FH presents with earlier onset,more comorbidities,and heavier cardiovascularrelated medical burdens than HC.Early identification,intervention,and comprehensive management of comorbidities in the FH population are crucial for neuroprotection and prevention of atherosclerotic cardiovascular disease.展开更多
Central nervous system(CNS)disorders are usually characterized by a complex pathophysiology.The last issue of Neuroprotection featured reviews and research articles looking at peripheral factors such as the gut microb...Central nervous system(CNS)disorders are usually characterized by a complex pathophysiology.The last issue of Neuroprotection featured reviews and research articles looking at peripheral factors such as the gut microbiome1,2 or a history of pre‐eclampsia3 and their impact on CNS conditions.Articles presented in the current issue of Neuroprotection will shift the focus back to the CNS but will continue to provide insights from recent research that help to better understand the pathophysiological complexity of CNS conditions.展开更多
Highlights Fatiguing syndromes affect millions of patients in the United States and globally,but are grossly underserved in the clinic and in the contemplative design of basic research.
Most conditions of the central nervous system(CNS)and the peripheral nervous system are not stand-alone disorders but are modulated and influenced by other pathobiological processes.For instance,the impact of frequent...Most conditions of the central nervous system(CNS)and the peripheral nervous system are not stand-alone disorders but are modulated and influenced by other pathobiological processes.For instance,the impact of frequent comorbidities such as hypertension1 or dyslipidemia2 as factors contributing to and aggravating CNS diseases has been much better understood in recent years.Another prominent disease-modifying factor is the gut microbiome which can exert both protective and detrimental effects on the nervous system in health and disease.3 An even better understanding of these factors will contribute to the development of individualized treatment approaches,a major research objective in the era of precision medicine.4 The current issue of Neuroprotection presents articles focusing on diseasemodifying factors or novel treatment approaches for a broad spectrum of conditions.展开更多
The human brain functions as a highly integrated system.Interconnected cellular and molecular networks within this system process sensory information,cognitive functions,and motor responses.The brain also exhibits a r...The human brain functions as a highly integrated system.Interconnected cellular and molecular networks within this system process sensory information,cognitive functions,and motor responses.The brain also exhibits a remarkable potential for plasticity-driven adaptive learning and memory.Importantly,neuroplasticity serves as a key mechanism of neuroprotection while also enabling the brain to compensate for injury through adaptive structural remodeling.Understanding the brain as a dynamic system requires examining how its components interact to produce adaptive physiological responses and complex behaviors,such as social interactions.Key molecules,such as brain-derived neurotrophic factor(BDNF)and oxytocin(OT),play pivotal roles in maintaining the brain's dynamic complexity and integrative functioning.In this review,we introduce the concept of“neurosocial plasticity”,which refers to the brain's ability to adapt both neural circuitry and social behavior through the dynamic interaction between BDNF and OT.This concept highlights how BDNF–OT interactions may support both neural plasticity and the capacity for adaptive social functioning.We then explore how their co-localization,co-expression,and co-regulation may regulate neural and social plasticity,ultimately shaping the brain's adaptability and the development of social behaviors across various contexts.展开更多
Adaptive plasticity,the brain's ability to reorganize and form new neural connections after injury,is crucial for recovery following acquired brain injury(ABI).This process involves axonal sprouting,dendritic remo...Adaptive plasticity,the brain's ability to reorganize and form new neural connections after injury,is crucial for recovery following acquired brain injury(ABI).This process involves axonal sprouting,dendritic remodeling,and neurogenesis,which restore neural connections and compensate for lost functions.While neuroinflammation and reactive astrocytes aid tissue repair,optimizing these responses to minimize secondary damage remains a challenge.Brain‐derived neurotrophic factor(BDNF)plays a vital role in neurogenesis and dendritic growth,positioning it as a potential therapeutic target for brain repair.Rehabilitation strategies that stimulate these adaptive changes can enhance neuroplasticity and functional recovery.The complexity of ABI recovery is influenced by factors such as injury severity,age,and genetic and epigenetic factors,which regulate neuronal repair and synaptic plasticity.Maladaptive plasticity refers to compensatory mechanisms that initially aid recovery but ultimately become harmful.Severe injuries like traumatic brain injury(TBI)and stroke can trigger adaptive responses,such as axonal sprouting,but excessive reliance on these processes may become maladaptive.In contrast,mild TBIs offer greater recovery potential.Age‐related differences in plasticity complicate recovery,with younger individuals exhibiting greater plasticity and older adults experiencing reduced plasticity and increased likelihood of maladaptive changes.Genetic factors,such as BDNF gene polymorphisms and DNA methylation,influence recovery outcomes.Neuroinflammation plays a dual role:acute inflammation supports recovery,while chronic inflammation can exacerbate damage.Precision medicine,tailored to an individual's genetic and epigenetic profile,offers promising strategies to optimize recovery.Growth factors like BDNF and insulin‐like growth factor 1(IGF‐1)are essential for neurogenesis,synaptic plasticity,and neural network reorganization,supporting both structural and functional recovery.However,maladaptive plasticity must be managed carefully for effective recovery.Targeted rehabilitation therapies,along with pharmacological agents and neuromodulation techniques,offer insights into personalized treatment strategies to enhance adaptive plasticity and optimize ABI recovery outcomes.This review explores the mechanisms of adaptive plasticity following ABI and discusses therapeutic interventions to support and optimize recovery,offering promising avenues for improving patient outcomes.展开更多
Chronic neuroinflammation and protein aggregation are the fundamental events mainly responsible for the progression of neurodegenerative diseases(NDs).Potential neurotoxic changes in the intra-and extracellular enviro...Chronic neuroinflammation and protein aggregation are the fundamental events mainly responsible for the progression of neurodegenerative diseases(NDs).Potential neurotoxic changes in the intra-and extracellular environment are typical hallmarks of many NDs.Treatment of ND is challenging,as the symptoms in these patients arises when a significant numbers of neurons have already been destroyed.Heat shock proteins(HSPs)can bind to recipient cells that are susceptible to stress,such as neurons,in the extracellular environment,therefore enhancing stress resistance.Among all,HSP60,HSP70,and HSP90 are highly conserved molecular chaperones involved in protein folding and assembly,maintaining cellular homeostasis in the central nervous system.Notably,α-synuclein accumulation is a major pathophysiology in Parkinson's disease,where HSP90 modulates the assembly ofα-synuclein in vesicles to prevent its accumulation.Moreover,HSP90 regulates the activity of the glycogen synthase kinase-3βprotein,which is crucial in diabetes mellitus-associated neurocognitive disorder.Therefore,understanding the molecular mechanism by which HSPs facilitate protein aggregation and respond to inflammatory stimuli,including metabolic disease such as diabetes,is essential for understanding the significance of HSPs in NDs.This review emphasizes the role of various HSPs in the progression of NDs such as Alzheimer's,Parkinson's,multiple sclerosis,and Huntington's disease,including diabetes,which is one of the major risk factors for neurodegeneration.展开更多
Stroke,a leading cause of mortality and morbidity worldwide,is a complex cerebrovascular disease.Stroke risk factors are diverse,encompassing age,sex,and ethnicity.Comorbid conditions,including hypertension,hyperglyce...Stroke,a leading cause of mortality and morbidity worldwide,is a complex cerebrovascular disease.Stroke risk factors are diverse,encompassing age,sex,and ethnicity.Comorbid conditions,including hypertension,hyperglycemia,hyperlipidemia,and atrial fibrillation,exacerbate stroke outcomes,contributing to the overall stroke burden within populations.In addition to these factors,lifestyle-related diseases can impact individuals across all age groups,and often include as comorbidities linked to stroke.Socioeconomic conditions,healthcare access,and the quality of clinical data significantly influence the prevalence of comorbidities.Asia,the largest continent and home to 60%of the world's population,includes many developing nations undergoing diverse economic transitions.In Southeast Asian countries,stroke prevalence is high,imposing a substantial burden on healthcare systems and economies.Research disparities in stroke are often attributed to insufficient demographic data on comorbidities.Hence,the review discusses all previously published results of hospital-based studies and data from national registries.It has been noticed that due to insufficient documentation on stroke-related comorbidities in various developing countries of Southeast Asia,stroke management becomes difficult.Therefore,this review aims to discuss the association between various comorbidities and stroke,with special emphasis on the incidence and prevalence of stroke burden in Southeast Asian countries.展开更多
Background Alzheimer's disease(AD)is a neurodegenerative disorder that affects the central nervous system.Silent information regulator sirtuin 1(SIRT1)may deacetylate and suppress forkhead box O(FOXO)activities to...Background Alzheimer's disease(AD)is a neurodegenerative disorder that affects the central nervous system.Silent information regulator sirtuin 1(SIRT1)may deacetylate and suppress forkhead box O(FOXO)activities to promote neuronal survival.FOXO1 is involved in the regulation of metabolism,senescence,stress response,and apoptosis.Moreover,endoplasmic reticulum stress(ERS)mediates cell apoptosis.Therefore,this study aimed to determine whether the downregulation of SIRT1 expression exacerbates cognitive dysfunction by activating FOXO1 acetylation and promoting ERS-mediated apoptosis in amyloid precursor protein/presenilin 1(APP/PS1)transgenic mice.MethodsWe used APP/PS1 transgenic mice to construct an in vivo AD model.Additionally,we usedβ-amyloid(Aβ)-incubated HT22 cells and primary neurons(PNs)for in vitro analyses.Cognitive function was assessed using novel object recognition,the Morris water maze,and fear conditioning.Discrepancies between wild-type(WT)and APP/PS1 transgenic mice were evaluated using an unpaired t test.In addition,one-way analysis of variance was conducted for behavioral assessments and other tests involving four distinct groups,followed by a Tukey's honestly significant difference test for post hoc pairwise comparisons.ResultsThe expression of SIRT1 was downregulated(in animal experiments,WT mice vs.APP/PS1 mice,n=3,p=0.002;in cell experiments,HT22 cells vs.HT22 cells+Aβ_(1−42),n=3,p=0.001;primary neurons vs.primary neurons+Aβ_(1−42),n=3,p<0.001),whereas FOXO1 acetylation was upregulated both in vivo and in vitro(in animal experiments,WT mice vs.APP/PS1 mice,n=3,p<0.001;in cell experiments,HT22 cells vs.HT22 cells+Aβ_(1−42),n=3,p=0.004;primary neurons vs.primary neurons+Aβ_(1−42),n=3,p<0.001),leading to cognitive dysfunction,Aβplaque deposition,and neuronal apoptosis.Quercetin,a SIRT1 agonist,reversed these changes(For SIRT1,APP/PS1 mice vs.Quercetin-treated APP/PS1 mice,n=3,p=0.014;HT22 cells+Aβ_(1−42)vs.HT22 cells+Aβ_(1−42)+Quercetin,n=3,p=0.003;primary neurons+Aβ_(1−42)vs.primary neurons+Aβ1−42+Quercetin,n=3,p=0.014.For ac-FOXO1,APP/PS1 mice vs.Quercetin-treated APP/PS1 mice,n=3,p<0.001;HT22 cells+Aβ_(1−42)vs.HT22 cells+Aβ_(1−42)+Quercetin,n=3,p=0.023;primary neurons+Aβ_(1−42)vs.primary neurons+Aβ_(1−42)+Quercetin,n=3,p=0.003).However,the FOXO1 antagonist AS1842856 invalidated the positive effects of quercetin in APP/PS1 transgenic mice(ac-FOXO1:Quercetin-treated APP/PS1 mice vs.AS1842856-treated APP/PS1 mice,n=3,p<0.001).Quercetin counteracted FOXO1 acetylation and ERS-mediated apoptosis.In contrast,AS1842856 promoted these processes in vivo and in vitro.Conclusion Our findings demonstrate that the downregulation of SIRT1 expression exacerbates cognitive dysfunction by activating FOXO1 acetylation and promoting ERS-mediated apoptosis.展开更多
Background:Aging affects almost all aspects of central nervous system(CNS)function,including the blood–brain barrier(BBB).Here,we use cell culture models to ask whether senescence,a cellular feature of aging,alters t...Background:Aging affects almost all aspects of central nervous system(CNS)function,including the blood–brain barrier(BBB).Here,we use cell culture models to ask whether senescence,a cellular feature of aging,alters the BBB by modifying interactions between astrocytes and brain endothelial cells.Methods:Human astrocyte and Human brain microvascular endothelial cells were subcultured and maintained for cells at low and high passages,then confirmed with senescence‐associatedβ‐galactosidase staining and gene expression of cyclin‐dependent kinase inhibitor 2A(Cdkn2a).After coculturing with astrocyte,the Alexa Fluor 488‐labeled bovine serum albumin(Alexa 488‐BSA)was used as a tracer to measure the permeability of brain endothelial cells;the expression of related proteins was measured by quantitative real‐time polymerase chain reaction.Reducing the angiotensinogen(AGT)by small interfering RNA(siRNA)in senescent astrocyte to test the effect of angiotensin signals on endothelial permeability.Results:Young astrocytes(cumulative population doublings[CPD]≤4)modified the expression of barrier genes and decreased brain endothelial permeability in coculture,whereas aged senescent astrocytes(CPD≥9)had no effects(45.5%±18.0%vs.122.8%±28.6%,p=0.0016).Angiotensin is known to alter the BBB.Its precursor,AGT,is highly expressed in astrocytes in the brain.Therefore,we asked whether angiotensin signaling may mediate the loss of endothelial barrier‐promoting properties in senescent astrocytes.Both protein and messenger RNA(mRNA)levels of AGT were increased in high‐passage senescent astrocytes.Reducing AGT levels through siRNA restored the endothelial barrier‐promoting effects of high‐passage senescent astrocytes(F(2,15)=6.508,p=0.0092).By contrast,brain endothelial cells at different passages did not change the expression of AGT in astrocytes.Conclusion:Taken together,these findings suggest that increased angiotensin signaling from astrocytes to brain endothelium may partly mediate the decrease of BBB function in the aging CNS.展开更多
Pediatric neurological disorders comprise diverse conditions that impair nervous system function in children and contribute substantially to global disease burden.Stem cell therapy has become a promising treatment in ...Pediatric neurological disorders comprise diverse conditions that impair nervous system function in children and contribute substantially to global disease burden.Stem cell therapy has become a promising treatment in neurology due to the cells'ability to self-renew,ensuring a continuous supply of cells.Cells are harvested from various origins,notably embryonic tissues and adult sources such as bone marrow,adipose tissue,and umbilical cord.Therapeutic effects arise from cell or enzyme replacement,trophic support,immunomodulation,and paracrine actions of the secretome.This review summarizes clinical applications of stem cell therapies across pediatric neurological diseases—including autism spectrum disorder,cerebral palsy,traumatic brain and spinal cord injury,epilepsy,neuromuscular disorders,and lysosomal storage diseases—and appraises evidence from preliminary descriptive studies that update the field and reveal methodological limitations.Reported therapeutic effect differs markedly by cell type,disease biology,timing of intervention,dose,and delivery method,producing inconsistent clinical results.Positive functional or developmental improvements have been documented in selected reports,but safety concerns,heterogeneity in study design,short follow-up,and variable potency assays limit conclusions.Because stem cell populations share phenotypic features but vary in therapeutic capacity,a universal,onesize-fits-all strategy is unlikely to succeed.Critical gaps remain regarding long-term safety,durability,standardized manufacturing,and optimal clinical endpoints.Continued rigorous translational research,standardized clinical trials,and expanded long-term surveillance are essential to optimize these therapies and improve outcomes for affected children and to ensure equitable access for diverse pediatric populations worldwide and sustainable implementation.展开更多
Background:Multiple sclerosis(MS)is a chronic demyelinating disease characterized by autoimmune attacks on myelin sheaths.Its deleterious effects may be reversed by remyelination,a process that restores the integrity ...Background:Multiple sclerosis(MS)is a chronic demyelinating disease characterized by autoimmune attacks on myelin sheaths.Its deleterious effects may be reversed by remyelination,a process that restores the integrity of myelin sheaths and,consequently,neuronal function.However,the functional implications of demyelination and remyelination in MS,as well as the potential impact of therapeutic interventions,remain incompletely understood.We used noninvasive longitudinal resting-state functional magnetic resonance imaging in a cuprizone murine model of demyelination to investigate these unsolved questions.Methods:Three groups of(n=6)animals were studied.A control group was fed with standard food for 5 weeks while two treatment groups(cuprizone and clemastine)suffered progressive demyelination by feeding them with 2%cuprizone.At Week 5(W5),all animals returned to the standard diet and studied for another 5-week period to compare controls vs spontaneous(cuprizone group)vs clemastine-aided(clemastine group)remyelination group.Group clemastine was treated with this antihistaminic(oral gavage)during the remyelination period(Weeks 5–10).Anatomical magnetic resonance imaging(T2w-MRI)and resting state functional MRI(rs-FMRI)studies were conducted on weeks W0,W2,W5(maximal demyelination)W7 and W10(remyelination).MRI images were processed with the FMRIB Software Library,involving seed-free functional imaging and seed-based correlation.This study uses the t-test and the D'Agostino–Pearson normality test to make an assessment.Results:The principal findings of our research include:(1)cuprizone-treated animals suffer an initial phase of elevated connectivity at Week 2 with respect to controls,transitioning to reduced connectivity at Week 5;(2)different temporal trajectories across brain regions,reflecting varying susceptibility to demyelination;(3)while spontaneous remyelination normalizes connectivity in most networks at Week 10(5 weeks after ceasing cuprizone intoxication),the thalamocortical axis exhibits lasting disruption even 6 months after normalization of diet;and(4)on the contrary,clemastine-aided remyelination re-establishes normal thalamocortical connectivity at 6 months after demyelination.Conclusion:This approach provides insights into the dynamic processes of demyelination and remyelination,informing the development of more effective interventions for MS.展开更多
Recent evidence suggests a more important role of the gut microbiota in neurodegenerative diseases (NDDs) given its relationship through the microbiota-gut-brain as an active communication system aiding in maintaining...Recent evidence suggests a more important role of the gut microbiota in neurodegenerative diseases (NDDs) given its relationship through the microbiota-gut-brain as an active communication system aiding in maintaining homeostasis between the brain and the gut. This review focuses on how modulation of gut microbiota can serves as a therapeutic strategy for NDDs, emphasizing the neuroprotective effects of probiotics. Probiotics are live microorganisms that confer health benefits, and their interaction with gut-microbiota influences neurogenesis, neurotransmitter regulation, and neuroinflammation. Recent advancements, including germ-free animal models, fecal microbiota transplantation (FMT), and diverse probiotic strains, have revealed the underlying mechanisms linking gut health to brain function. Notably, several Lactobacillus and Bifidobacterium species have been shown to exert neuroprotective effects via the upregulation of neurotrophic factors such as brain-derived neurotrophic factor and enhancing mitochondrial function through reducing the impacts of oxidative stress. Interestingly, FMT has exhibited a degree of success in overcoming cognitive impairment and motor deficits in preclinical studies and clinical trials. However, further research is warranted to explore its therapeutic potential in humans. Overall, this review highlights the significant role of gut microbiota in NDDs and advocates for gut-targeted interventions as innovative approaches to mitigate these diseases.展开更多
BackgroundPre-eclampsia(PE)is a serious hypertensive disorder of pregnancy with lifelong deleterious effects including an increased risk of stroke postpartum(PP).In the present study,we aimed to determine whether prev...BackgroundPre-eclampsia(PE)is a serious hypertensive disorder of pregnancy with lifelong deleterious effects including an increased risk of stroke postpartum(PP).In the present study,we aimed to determine whether previous PE exacerbates ischemic injury during PP and investigate the underlying mechanisms.MethodsFemale Sprague-Dawley rats were studied at 4–9 months PP after either a normal pregnancy postpartum(NormP-PP,n=7)or experimental PE(ePE)induced using a high-cholesterol diet(ePE-PP,n=9).The animals underwent transient middle cerebral artery occlusion for 2 h with 1 h of reperfusion.Dual-site laser Doppler flowmetry was used to measure cerebral blood flow changes in the middle cerebral artery and collateral territories.Ischemic injury was measured using 2,3,5-triphenyl tetrazolium chloride staining.Circulating 8-isoprostane,3-nitrotyrosine,and oxidized low-density lipoprotein levels were measured using enzyme-linked immunosorbent assays.In separate groups of animals,NormP-PP(n=10)and ePE-PP(n=9)at 3–4 months PP,isolated pial collateral vessels,leptomeningeal anastomoses,and mesenteric arteries were studied using pressure myography.ResultsPrevious ePE worsened stroke outcome in the PP period,significantly increasing infarction and edema in ePE-PP compared to NormP-PP animals(40.6±7.6%vs.13.7±6.5%,p<0.01;5.1±2.0%vs.2.6±0.4%,p<0.01)despite comparable changes in cerebral blood flow in the middle cerebral artery and pial collateral territories during ischemia and reperfusion.When infarction was analyzed as a function of perfusion deficit,the ePE-PP animals showed greater sensitivity to ischemia.Pial collaterals had increased pressure-induced myogenic tone in ePE-PP compared to NormP-PP rats.Percentage tone at 80 mmHg for ePE-PP vs.NormP-PP was 15.5±1.6%vs.8.6±1.9%(p<0.01).ePE-PP animals showed significantly elevated levels of circulating 8-isoprostane and 3-nitrotyrosine but not oxidized low-density lipoprotein after transient middle cerebral artery occlusion(p<0.05,and p<0.01,respectively).ConclusionsWorsened stroke outcomes after ePE pregnancy were related to increased ischemia sensitivity,increased pial collateral tone,and elevated levels of oxidative stress markers.Thus,the pathological effects of ePE persisted PP and negatively affected stroke outcomes.展开更多
Neuroinflammation is increasingly recognized as a critical driver of central nervous system(CNS)disorders,and network pharmacology has emerged as a promising approach to elucidate its complex mechanisms and therapeuti...Neuroinflammation is increasingly recognized as a critical driver of central nervous system(CNS)disorders,and network pharmacology has emerged as a promising approach to elucidate its complex mechanisms and therapeutic strategies.This study provides a comprehensive bibliometric and scientometric analysis of publications over the past 13 years to characterize research trends,identify key contributors,and uncover core therapeutic targets in this field.Articles published between January 2012 and May 2024 were retrieved from the Web of Science Core Collection.Visualization and quantitative analyses were performed using CiteSpace(version 6.3.R1,Drexel University,PA,United States)and VOSviewer(version 1.6.20,Leiden University-CWTS,Netherlands)followed by network interaction analysis to identify central targets implicated in neuroinflammation.A total of 156 publications were analyzed,with the United States,China,and Germany leading global output.Beijing University of Chinese Medicine,Case Western Reserve University,and University System of Ohio were identified as the most influential institutions.Nucleic Acids Research was the most frequently cited journal,whereas Journal of Ethnopharmacology contributed the largest number of publications.Co-occurrence clustering revealed 13 thematic research areas,highlighting apoptosis,Panax notoginseng,dihydrochalcones,and quercetin as representative hotspots.Target interaction analysis identified signal transducer and activator of transcription 3(STAT3),jun proto-oncogene(JUN),AKT serine/threonine kinase 1(AKT1),tumor protein 53(TP53),and interleukin-6(IL6)as core molecular targets.The findings delineate a dynamic and evolving research landscape in this domain and clarify its organization around several pivotal molecular targets.The field is shifting away from the conventional"one drug,one target"paradigm toward multi-target therapeutic strategies,reflecting the multifactorial nature of neuroinflammation in CNS disorders.These insights highlight key molecular nodes and research directions,providing a foundation for precision medicine approaches and innovative drug development to improve treatment outcomes in neuroinflammatory CNS diseases.展开更多
Neuroinflammation, a key defense mechanism of the nervous system, is associated with changes in inflammatory markers and stimulation of neuroimmune cells such as microglia and astrocytes. Growing evidence indicates th...Neuroinflammation, a key defense mechanism of the nervous system, is associated with changes in inflammatory markers and stimulation of neuroimmune cells such as microglia and astrocytes. Growing evidence indicates that the gut microbiota and its metabolites directly or indirectly regulate host health. According to recent studies, bacterial dysbiosis in the gut is closely linked to several central nervous system disorders that cause neuroinflammation, including multiple sclerosis, Alzheimer's disease, Parkinson's disease, sepsis-associated encephalopathy, and ischemic stroke. Recent findings indicate a bidirectional communication network between the gut microbiota and central nervous system that influences neuroinflammation and cognitive function. Dysregulation of this system can affect the generation of cytotoxic metabolites, promote neuroinflammation, and impair cognition. This review explores the lesser-studied microbiota-derived metabolites involved in neuroinflammation—bile acids, trimethylamine-N-oxide, and indole derivatives—as targets for creating new treatment tools for neuroinflammatory illnesses, as well as possible biomarkers for early diagnosis and prognosis.展开更多
Glial cells,alongside neurons,are the major cells of the central nervous system.More than just supporting neurons,glial cells are vital in central nervous system homeostasis and actively shape neurodegenerative diseas...Glial cells,alongside neurons,are the major cells of the central nervous system.More than just supporting neurons,glial cells are vital in central nervous system homeostasis and actively shape neurodegenerative disease mechanisms.They exhibit dual roles in promoting neuroprotection through glutamate clearance,mitochondrial transfer,extracellular vesicle signaling,and remyelination,yet also contributing to excitotoxicity,neuroinflammation,and myelin loss.Recent studies emphasize their therapeutic potential,such as enhancing excitatory amino acid transporters,engineering extracellular vesicles,and boosting oligodendrocyte precursor cell function in combating neurodegeneration.This mini review comments on previous articles published in Neuroprotection alongside others,and discusses how enhancing glial protective roles may serve as novel neuroprotective interventions.展开更多
基金NIH/NIDA,Grant/Award Number:R01DA056739 to Piotr Walczak。
文摘Controlling and mitigating the burden and impact of neurodegenerative diseases has three major components.The first is prevention,for instance,aiming at risk factors and comorbidities that increase the incidence of acute or chronic neurodegenerative diseases.This requires a detailed understanding of the prevalence of these factors as well as their pathomechanistical impact on neurodegenerative diseases,plus of efficient ways to control them.It also requires knowledge about potential protective factors.The second component is active medical treatment of a manifesting neurodegenerative conditions by either targeting its cause or at least its most disabling symptoms.This component is addressed by most therapeutic research activities.The third component focuses on long-term outcome.It requires a better mechanistic understanding of neurodegeneration sequelae as well as of the brain's unique capacity to respond to pathological challenges,for instance,by synaptic and circuit plasticity.Whereas previous issues of Neuroprotection often focused on the second component,the recent one will put more emphasis on the first and third component.It will deal with both central nervous system(CNS)disorders caused by acute neurodegeneration,such as ischemic stroke,as well as less acute diseases,including Alzheimer's(AD)and Parkinson's disease(PD).
基金Piotr Walczak is supported by a NIH/NIDA grant(R01 DA056739)。
文摘Investigating causes of and treatments for neurological diseases originally focused almost exclusively on the central nervous system(CNS).However,a more holistic understanding of neurological diseases emerged in recent years.Contemporary research increasingly considers organs,organ systems,and pathobiological processes outside the CNS as well as their contribution to the course of neurological diseases.Prominent examples are the systemic immunological responses after ischemic,hemorrhagic,or traumatic brain injury1 as well as the gut–brain axis modulating numerous CNS conditions.2,3 Focusing on the interactions between central and peripheral pathobiological processes may result in a considerable increase of experimental strategy complexity and the necessity for additional research efforts.
文摘Major depressive disorder(MDD)is a complex psychiatric condition increasingly linked to chronic neuroinflammation,particularly in the context of aging,stress,and systemic comorbidities.While microglia have traditionally been the focus of neuroimmune studies,growing evidence highlights astrocytes as central regulators in the pathogenesis of MDD.This review synthesizes current findings on the multifaceted roles of astrocytes in neuroplasticity,neurotransmission,metabolic support,and blood‐brain barrier regulation.It explores how astrocyte reactivity and the release of pro‐inflammatory cytokines are often triggered by psychosocial stress,aging,and peripheral immune activation and contribute to synaptic dysfunction and cognitive impairment.The review also examines the bidirectional crosstalk between astrocytes and microglia,astrocytic calcium signaling,epigenetic modulation via histone lactylation,and metabolic pathways involving lactate.Special attention is given to the region‐specific and phenotypedependent responses of astrocytes,as well as their influence on the onset and maintenance of depressive symptoms.Additionally,therapeutic strategies targeting astrocyte‐mediated pathways,including anti‐inflammatory agents,metabolic modulators,repetitive transcranial magnetic stimulation,and inflammasome inhibitors,are discussed.Finally,methodological challenges and future research directions are outlined,emphasizing the need for precision medicine approaches in developing astrocyte‐targeted interventions for MDD.
基金Natural Science Foundation of Beijing Municipality,Grant/Award Numbers:IS24047,L223002National Natural Science Foundation of China,Grant/Award Numbers:81961128006,81973132Peking University Shi-Ji Jin-Yuan Medical Foundation,Grant/Award Number:48014Y0243。
文摘Background:Despite the World Health Organization's prioritization of familial hypercholesterolemia(FH),its global diagnostic rate remains critically low,leading to inadequate treatment and control,thereby increasing the risk of atherosclerotic cardiovascular disease.This study aimed to investigate the comorbidity burden of FH in China and analyze the differences between familial and general hypercholesterolemia(HC)populations.Methods:Using a national medical insurance database from 2013 to 2017 including 13,976 patients with FH and 13,976 matched control patients with HC,we utilized case-control methods to compare the composition ratio,comorbidity rates,medical expenses,and healthcare burden of patients with FH to those of control patients.Results:The FH population had a higher comorbidity rate of more than one cardiometabolic disease(83.7%[11,697/13,976])compared to the HC group(70.3%[9279/13,976];χ2=250.45,p<0.0001).The rates of coronary heart disease,hypertension,stroke,and diabetes were higher in patients with FH(39.2%[5475/13,976],71.0%[9925/13,976],14.2%[1982/13,976],and 31.2%[4363/13,976],respectively)compared to those in the HC group(30.4%[4255/13,976],61.4%[8587/13,976],11.5%[1601/13,976],and 28.1%[3923/13,976],respectively;all p<0.0001).In the 40−49 age group,patients with FH had a significantly higher average number of comorbidities compared to control patients with HC(1.2 vs.0.9;t=15.67,p<0.0001).Notably,the comorbidity count in patients with FH aged 40−49 years even exceeded that in patients with HC aged 50−59 years.Furthermore,the annual per capita medical cost for patients with FH was significantly higher at 5045.5 Chinese yuan(CNY)compared to 4184.7 CNY for patients with HC(t=12.54,p<0.0001).Conclusion:With a large number of patients with dyslipidemia,the type and number of comorbidities significantly impact the healthcare burden.FH presents with earlier onset,more comorbidities,and heavier cardiovascularrelated medical burdens than HC.Early identification,intervention,and comprehensive management of comorbidities in the FH population are crucial for neuroprotection and prevention of atherosclerotic cardiovascular disease.
文摘Central nervous system(CNS)disorders are usually characterized by a complex pathophysiology.The last issue of Neuroprotection featured reviews and research articles looking at peripheral factors such as the gut microbiome1,2 or a history of pre‐eclampsia3 and their impact on CNS conditions.Articles presented in the current issue of Neuroprotection will shift the focus back to the CNS but will continue to provide insights from recent research that help to better understand the pathophysiological complexity of CNS conditions.
文摘Highlights Fatiguing syndromes affect millions of patients in the United States and globally,but are grossly underserved in the clinic and in the contemplative design of basic research.
文摘Most conditions of the central nervous system(CNS)and the peripheral nervous system are not stand-alone disorders but are modulated and influenced by other pathobiological processes.For instance,the impact of frequent comorbidities such as hypertension1 or dyslipidemia2 as factors contributing to and aggravating CNS diseases has been much better understood in recent years.Another prominent disease-modifying factor is the gut microbiome which can exert both protective and detrimental effects on the nervous system in health and disease.3 An even better understanding of these factors will contribute to the development of individualized treatment approaches,a major research objective in the era of precision medicine.4 The current issue of Neuroprotection presents articles focusing on diseasemodifying factors or novel treatment approaches for a broad spectrum of conditions.
基金Natural Sciences and Engineering Research Council(NSERC)of Canada Discovery,Grant/Award Number:5628NSERC Discovery Accelerator Supplement,Grant/Award Number:#31(GM)。
文摘The human brain functions as a highly integrated system.Interconnected cellular and molecular networks within this system process sensory information,cognitive functions,and motor responses.The brain also exhibits a remarkable potential for plasticity-driven adaptive learning and memory.Importantly,neuroplasticity serves as a key mechanism of neuroprotection while also enabling the brain to compensate for injury through adaptive structural remodeling.Understanding the brain as a dynamic system requires examining how its components interact to produce adaptive physiological responses and complex behaviors,such as social interactions.Key molecules,such as brain-derived neurotrophic factor(BDNF)and oxytocin(OT),play pivotal roles in maintaining the brain's dynamic complexity and integrative functioning.In this review,we introduce the concept of“neurosocial plasticity”,which refers to the brain's ability to adapt both neural circuitry and social behavior through the dynamic interaction between BDNF and OT.This concept highlights how BDNF–OT interactions may support both neural plasticity and the capacity for adaptive social functioning.We then explore how their co-localization,co-expression,and co-regulation may regulate neural and social plasticity,ultimately shaping the brain's adaptability and the development of social behaviors across various contexts.
文摘Adaptive plasticity,the brain's ability to reorganize and form new neural connections after injury,is crucial for recovery following acquired brain injury(ABI).This process involves axonal sprouting,dendritic remodeling,and neurogenesis,which restore neural connections and compensate for lost functions.While neuroinflammation and reactive astrocytes aid tissue repair,optimizing these responses to minimize secondary damage remains a challenge.Brain‐derived neurotrophic factor(BDNF)plays a vital role in neurogenesis and dendritic growth,positioning it as a potential therapeutic target for brain repair.Rehabilitation strategies that stimulate these adaptive changes can enhance neuroplasticity and functional recovery.The complexity of ABI recovery is influenced by factors such as injury severity,age,and genetic and epigenetic factors,which regulate neuronal repair and synaptic plasticity.Maladaptive plasticity refers to compensatory mechanisms that initially aid recovery but ultimately become harmful.Severe injuries like traumatic brain injury(TBI)and stroke can trigger adaptive responses,such as axonal sprouting,but excessive reliance on these processes may become maladaptive.In contrast,mild TBIs offer greater recovery potential.Age‐related differences in plasticity complicate recovery,with younger individuals exhibiting greater plasticity and older adults experiencing reduced plasticity and increased likelihood of maladaptive changes.Genetic factors,such as BDNF gene polymorphisms and DNA methylation,influence recovery outcomes.Neuroinflammation plays a dual role:acute inflammation supports recovery,while chronic inflammation can exacerbate damage.Precision medicine,tailored to an individual's genetic and epigenetic profile,offers promising strategies to optimize recovery.Growth factors like BDNF and insulin‐like growth factor 1(IGF‐1)are essential for neurogenesis,synaptic plasticity,and neural network reorganization,supporting both structural and functional recovery.However,maladaptive plasticity must be managed carefully for effective recovery.Targeted rehabilitation therapies,along with pharmacological agents and neuromodulation techniques,offer insights into personalized treatment strategies to enhance adaptive plasticity and optimize ABI recovery outcomes.This review explores the mechanisms of adaptive plasticity following ABI and discusses therapeutic interventions to support and optimize recovery,offering promising avenues for improving patient outcomes.
基金supported by the Department of Health Research,Ministry of Health and Family Welfare,Government of IndiaIndian Council of Medical Research,Ministry of Health and Family Welfare,Government of IndiaCCRH,Ministry of Ayush,Government of India.
文摘Chronic neuroinflammation and protein aggregation are the fundamental events mainly responsible for the progression of neurodegenerative diseases(NDs).Potential neurotoxic changes in the intra-and extracellular environment are typical hallmarks of many NDs.Treatment of ND is challenging,as the symptoms in these patients arises when a significant numbers of neurons have already been destroyed.Heat shock proteins(HSPs)can bind to recipient cells that are susceptible to stress,such as neurons,in the extracellular environment,therefore enhancing stress resistance.Among all,HSP60,HSP70,and HSP90 are highly conserved molecular chaperones involved in protein folding and assembly,maintaining cellular homeostasis in the central nervous system.Notably,α-synuclein accumulation is a major pathophysiology in Parkinson's disease,where HSP90 modulates the assembly ofα-synuclein in vesicles to prevent its accumulation.Moreover,HSP90 regulates the activity of the glycogen synthase kinase-3βprotein,which is crucial in diabetes mellitus-associated neurocognitive disorder.Therefore,understanding the molecular mechanism by which HSPs facilitate protein aggregation and respond to inflammatory stimuli,including metabolic disease such as diabetes,is essential for understanding the significance of HSPs in NDs.This review emphasizes the role of various HSPs in the progression of NDs such as Alzheimer's,Parkinson's,multiple sclerosis,and Huntington's disease,including diabetes,which is one of the major risk factors for neurodegeneration.
基金Department of Pharmaceuticals,Ministry of Chemical and Fertilizers,Government of IndiaIndian Council of Medical Research(ICMR),New Delhi,India,for the senior research fellowship grant to Ms.Aishika Datta(45/13/2020-PHA/BMS)ICMR Nanobio project grant to Dr.Pallab Bhattacharya(34/5/2019-TF/Nano/BMS).
文摘Stroke,a leading cause of mortality and morbidity worldwide,is a complex cerebrovascular disease.Stroke risk factors are diverse,encompassing age,sex,and ethnicity.Comorbid conditions,including hypertension,hyperglycemia,hyperlipidemia,and atrial fibrillation,exacerbate stroke outcomes,contributing to the overall stroke burden within populations.In addition to these factors,lifestyle-related diseases can impact individuals across all age groups,and often include as comorbidities linked to stroke.Socioeconomic conditions,healthcare access,and the quality of clinical data significantly influence the prevalence of comorbidities.Asia,the largest continent and home to 60%of the world's population,includes many developing nations undergoing diverse economic transitions.In Southeast Asian countries,stroke prevalence is high,imposing a substantial burden on healthcare systems and economies.Research disparities in stroke are often attributed to insufficient demographic data on comorbidities.Hence,the review discusses all previously published results of hospital-based studies and data from national registries.It has been noticed that due to insufficient documentation on stroke-related comorbidities in various developing countries of Southeast Asia,stroke management becomes difficult.Therefore,this review aims to discuss the association between various comorbidities and stroke,with special emphasis on the incidence and prevalence of stroke burden in Southeast Asian countries.
基金International Clinical Exchange Program of Health Commission of Zhejiang ProvinceNational Natural Science Foundation of China,Grant/Award Number:31900685+3 种基金Zhejiang Province Natural Science Foundation,Grant/Award Numbers:LTGY24H050004,LTGY23H050003Wenzhou Municipal Science and Technology Bureau of China,Grant/Award Number:Y2023065School Level Scientific Research Project of Wenzhou Medical University,Grant/Award Numbers:XY2022007,wyx2023101049Medical Innovation Discipline of Zhejiang Province,Grant/Award Number:Y2015。
文摘Background Alzheimer's disease(AD)is a neurodegenerative disorder that affects the central nervous system.Silent information regulator sirtuin 1(SIRT1)may deacetylate and suppress forkhead box O(FOXO)activities to promote neuronal survival.FOXO1 is involved in the regulation of metabolism,senescence,stress response,and apoptosis.Moreover,endoplasmic reticulum stress(ERS)mediates cell apoptosis.Therefore,this study aimed to determine whether the downregulation of SIRT1 expression exacerbates cognitive dysfunction by activating FOXO1 acetylation and promoting ERS-mediated apoptosis in amyloid precursor protein/presenilin 1(APP/PS1)transgenic mice.MethodsWe used APP/PS1 transgenic mice to construct an in vivo AD model.Additionally,we usedβ-amyloid(Aβ)-incubated HT22 cells and primary neurons(PNs)for in vitro analyses.Cognitive function was assessed using novel object recognition,the Morris water maze,and fear conditioning.Discrepancies between wild-type(WT)and APP/PS1 transgenic mice were evaluated using an unpaired t test.In addition,one-way analysis of variance was conducted for behavioral assessments and other tests involving four distinct groups,followed by a Tukey's honestly significant difference test for post hoc pairwise comparisons.ResultsThe expression of SIRT1 was downregulated(in animal experiments,WT mice vs.APP/PS1 mice,n=3,p=0.002;in cell experiments,HT22 cells vs.HT22 cells+Aβ_(1−42),n=3,p=0.001;primary neurons vs.primary neurons+Aβ_(1−42),n=3,p<0.001),whereas FOXO1 acetylation was upregulated both in vivo and in vitro(in animal experiments,WT mice vs.APP/PS1 mice,n=3,p<0.001;in cell experiments,HT22 cells vs.HT22 cells+Aβ_(1−42),n=3,p=0.004;primary neurons vs.primary neurons+Aβ_(1−42),n=3,p<0.001),leading to cognitive dysfunction,Aβplaque deposition,and neuronal apoptosis.Quercetin,a SIRT1 agonist,reversed these changes(For SIRT1,APP/PS1 mice vs.Quercetin-treated APP/PS1 mice,n=3,p=0.014;HT22 cells+Aβ_(1−42)vs.HT22 cells+Aβ_(1−42)+Quercetin,n=3,p=0.003;primary neurons+Aβ_(1−42)vs.primary neurons+Aβ1−42+Quercetin,n=3,p=0.014.For ac-FOXO1,APP/PS1 mice vs.Quercetin-treated APP/PS1 mice,n=3,p<0.001;HT22 cells+Aβ_(1−42)vs.HT22 cells+Aβ_(1−42)+Quercetin,n=3,p=0.023;primary neurons+Aβ_(1−42)vs.primary neurons+Aβ_(1−42)+Quercetin,n=3,p=0.003).However,the FOXO1 antagonist AS1842856 invalidated the positive effects of quercetin in APP/PS1 transgenic mice(ac-FOXO1:Quercetin-treated APP/PS1 mice vs.AS1842856-treated APP/PS1 mice,n=3,p<0.001).Quercetin counteracted FOXO1 acetylation and ERS-mediated apoptosis.In contrast,AS1842856 promoted these processes in vivo and in vitro.Conclusion Our findings demonstrate that the downregulation of SIRT1 expression exacerbates cognitive dysfunction by activating FOXO1 acetylation and promoting ERS-mediated apoptosis.
文摘Background:Aging affects almost all aspects of central nervous system(CNS)function,including the blood–brain barrier(BBB).Here,we use cell culture models to ask whether senescence,a cellular feature of aging,alters the BBB by modifying interactions between astrocytes and brain endothelial cells.Methods:Human astrocyte and Human brain microvascular endothelial cells were subcultured and maintained for cells at low and high passages,then confirmed with senescence‐associatedβ‐galactosidase staining and gene expression of cyclin‐dependent kinase inhibitor 2A(Cdkn2a).After coculturing with astrocyte,the Alexa Fluor 488‐labeled bovine serum albumin(Alexa 488‐BSA)was used as a tracer to measure the permeability of brain endothelial cells;the expression of related proteins was measured by quantitative real‐time polymerase chain reaction.Reducing the angiotensinogen(AGT)by small interfering RNA(siRNA)in senescent astrocyte to test the effect of angiotensin signals on endothelial permeability.Results:Young astrocytes(cumulative population doublings[CPD]≤4)modified the expression of barrier genes and decreased brain endothelial permeability in coculture,whereas aged senescent astrocytes(CPD≥9)had no effects(45.5%±18.0%vs.122.8%±28.6%,p=0.0016).Angiotensin is known to alter the BBB.Its precursor,AGT,is highly expressed in astrocytes in the brain.Therefore,we asked whether angiotensin signaling may mediate the loss of endothelial barrier‐promoting properties in senescent astrocytes.Both protein and messenger RNA(mRNA)levels of AGT were increased in high‐passage senescent astrocytes.Reducing AGT levels through siRNA restored the endothelial barrier‐promoting effects of high‐passage senescent astrocytes(F(2,15)=6.508,p=0.0092).By contrast,brain endothelial cells at different passages did not change the expression of AGT in astrocytes.Conclusion:Taken together,these findings suggest that increased angiotensin signaling from astrocytes to brain endothelium may partly mediate the decrease of BBB function in the aging CNS.
文摘Pediatric neurological disorders comprise diverse conditions that impair nervous system function in children and contribute substantially to global disease burden.Stem cell therapy has become a promising treatment in neurology due to the cells'ability to self-renew,ensuring a continuous supply of cells.Cells are harvested from various origins,notably embryonic tissues and adult sources such as bone marrow,adipose tissue,and umbilical cord.Therapeutic effects arise from cell or enzyme replacement,trophic support,immunomodulation,and paracrine actions of the secretome.This review summarizes clinical applications of stem cell therapies across pediatric neurological diseases—including autism spectrum disorder,cerebral palsy,traumatic brain and spinal cord injury,epilepsy,neuromuscular disorders,and lysosomal storage diseases—and appraises evidence from preliminary descriptive studies that update the field and reveal methodological limitations.Reported therapeutic effect differs markedly by cell type,disease biology,timing of intervention,dose,and delivery method,producing inconsistent clinical results.Positive functional or developmental improvements have been documented in selected reports,but safety concerns,heterogeneity in study design,short follow-up,and variable potency assays limit conclusions.Because stem cell populations share phenotypic features but vary in therapeutic capacity,a universal,onesize-fits-all strategy is unlikely to succeed.Critical gaps remain regarding long-term safety,durability,standardized manufacturing,and optimal clinical endpoints.Continued rigorous translational research,standardized clinical trials,and expanded long-term surveillance are essential to optimize these therapies and improve outcomes for affected children and to ensure equitable access for diverse pediatric populations worldwide and sustainable implementation.
基金Diputación Foral de Gipuzkoa,Grant/Award Number:2022-CIEN-000090-01NextGenerationEU,Grant/Award Number:2022-CIEN-000090-01+2 种基金Instituto de Salud Carlos III,Grant/Award Number:RD21/0006/0016Agencia Estatal de Investigación,Grant/Award Numbers:PID2020-118546RBI00a,PID2023-152005OB-I00Ikerbasque,Basque Foundation for Science,Grant/Award Number:Ikerbasque Professors Program。
文摘Background:Multiple sclerosis(MS)is a chronic demyelinating disease characterized by autoimmune attacks on myelin sheaths.Its deleterious effects may be reversed by remyelination,a process that restores the integrity of myelin sheaths and,consequently,neuronal function.However,the functional implications of demyelination and remyelination in MS,as well as the potential impact of therapeutic interventions,remain incompletely understood.We used noninvasive longitudinal resting-state functional magnetic resonance imaging in a cuprizone murine model of demyelination to investigate these unsolved questions.Methods:Three groups of(n=6)animals were studied.A control group was fed with standard food for 5 weeks while two treatment groups(cuprizone and clemastine)suffered progressive demyelination by feeding them with 2%cuprizone.At Week 5(W5),all animals returned to the standard diet and studied for another 5-week period to compare controls vs spontaneous(cuprizone group)vs clemastine-aided(clemastine group)remyelination group.Group clemastine was treated with this antihistaminic(oral gavage)during the remyelination period(Weeks 5–10).Anatomical magnetic resonance imaging(T2w-MRI)and resting state functional MRI(rs-FMRI)studies were conducted on weeks W0,W2,W5(maximal demyelination)W7 and W10(remyelination).MRI images were processed with the FMRIB Software Library,involving seed-free functional imaging and seed-based correlation.This study uses the t-test and the D'Agostino–Pearson normality test to make an assessment.Results:The principal findings of our research include:(1)cuprizone-treated animals suffer an initial phase of elevated connectivity at Week 2 with respect to controls,transitioning to reduced connectivity at Week 5;(2)different temporal trajectories across brain regions,reflecting varying susceptibility to demyelination;(3)while spontaneous remyelination normalizes connectivity in most networks at Week 10(5 weeks after ceasing cuprizone intoxication),the thalamocortical axis exhibits lasting disruption even 6 months after normalization of diet;and(4)on the contrary,clemastine-aided remyelination re-establishes normal thalamocortical connectivity at 6 months after demyelination.Conclusion:This approach provides insights into the dynamic processes of demyelination and remyelination,informing the development of more effective interventions for MS.
基金nternational Society for Neurochemistry(ISN)Career Development Grant 2023NIH-FIC,Grant/Award Number:K43TW011920。
文摘Recent evidence suggests a more important role of the gut microbiota in neurodegenerative diseases (NDDs) given its relationship through the microbiota-gut-brain as an active communication system aiding in maintaining homeostasis between the brain and the gut. This review focuses on how modulation of gut microbiota can serves as a therapeutic strategy for NDDs, emphasizing the neuroprotective effects of probiotics. Probiotics are live microorganisms that confer health benefits, and their interaction with gut-microbiota influences neurogenesis, neurotransmitter regulation, and neuroinflammation. Recent advancements, including germ-free animal models, fecal microbiota transplantation (FMT), and diverse probiotic strains, have revealed the underlying mechanisms linking gut health to brain function. Notably, several Lactobacillus and Bifidobacterium species have been shown to exert neuroprotective effects via the upregulation of neurotrophic factors such as brain-derived neurotrophic factor and enhancing mitochondrial function through reducing the impacts of oxidative stress. Interestingly, FMT has exhibited a degree of success in overcoming cognitive impairment and motor deficits in preclinical studies and clinical trials. However, further research is warranted to explore its therapeutic potential in humans. Overall, this review highlights the significant role of gut microbiota in NDDs and advocates for gut-targeted interventions as innovative approaches to mitigate these diseases.
基金support of the Centers of Biomedical Research Excellence(COBRE)Supplement from the National Institute of General Medicine grant P20 GM135007-04S1the National Institute of Neurological Disorders and Stroke Grant R01 NS093289.
文摘BackgroundPre-eclampsia(PE)is a serious hypertensive disorder of pregnancy with lifelong deleterious effects including an increased risk of stroke postpartum(PP).In the present study,we aimed to determine whether previous PE exacerbates ischemic injury during PP and investigate the underlying mechanisms.MethodsFemale Sprague-Dawley rats were studied at 4–9 months PP after either a normal pregnancy postpartum(NormP-PP,n=7)or experimental PE(ePE)induced using a high-cholesterol diet(ePE-PP,n=9).The animals underwent transient middle cerebral artery occlusion for 2 h with 1 h of reperfusion.Dual-site laser Doppler flowmetry was used to measure cerebral blood flow changes in the middle cerebral artery and collateral territories.Ischemic injury was measured using 2,3,5-triphenyl tetrazolium chloride staining.Circulating 8-isoprostane,3-nitrotyrosine,and oxidized low-density lipoprotein levels were measured using enzyme-linked immunosorbent assays.In separate groups of animals,NormP-PP(n=10)and ePE-PP(n=9)at 3–4 months PP,isolated pial collateral vessels,leptomeningeal anastomoses,and mesenteric arteries were studied using pressure myography.ResultsPrevious ePE worsened stroke outcome in the PP period,significantly increasing infarction and edema in ePE-PP compared to NormP-PP animals(40.6±7.6%vs.13.7±6.5%,p<0.01;5.1±2.0%vs.2.6±0.4%,p<0.01)despite comparable changes in cerebral blood flow in the middle cerebral artery and pial collateral territories during ischemia and reperfusion.When infarction was analyzed as a function of perfusion deficit,the ePE-PP animals showed greater sensitivity to ischemia.Pial collaterals had increased pressure-induced myogenic tone in ePE-PP compared to NormP-PP rats.Percentage tone at 80 mmHg for ePE-PP vs.NormP-PP was 15.5±1.6%vs.8.6±1.9%(p<0.01).ePE-PP animals showed significantly elevated levels of circulating 8-isoprostane and 3-nitrotyrosine but not oxidized low-density lipoprotein after transient middle cerebral artery occlusion(p<0.05,and p<0.01,respectively).ConclusionsWorsened stroke outcomes after ePE pregnancy were related to increased ischemia sensitivity,increased pial collateral tone,and elevated levels of oxidative stress markers.Thus,the pathological effects of ePE persisted PP and negatively affected stroke outcomes.
基金supported by the Yuan Du Scholars,the Affiliated Hospital of Shandong Second Medical University Horizontal Project(No.WYFYKY-HX202307,No.202201)the National Natural Science Foundation of China(No.81870943)+1 种基金the Health China•BuChang ZhiYuan Public welfare projects for heart and brain health under Grant(No.HIGHER2023072)the Shandong Second Medical University Affiliated Hospital Technology Development Project(No.2023FYM001,No.2023FYM006).
文摘Neuroinflammation is increasingly recognized as a critical driver of central nervous system(CNS)disorders,and network pharmacology has emerged as a promising approach to elucidate its complex mechanisms and therapeutic strategies.This study provides a comprehensive bibliometric and scientometric analysis of publications over the past 13 years to characterize research trends,identify key contributors,and uncover core therapeutic targets in this field.Articles published between January 2012 and May 2024 were retrieved from the Web of Science Core Collection.Visualization and quantitative analyses were performed using CiteSpace(version 6.3.R1,Drexel University,PA,United States)and VOSviewer(version 1.6.20,Leiden University-CWTS,Netherlands)followed by network interaction analysis to identify central targets implicated in neuroinflammation.A total of 156 publications were analyzed,with the United States,China,and Germany leading global output.Beijing University of Chinese Medicine,Case Western Reserve University,and University System of Ohio were identified as the most influential institutions.Nucleic Acids Research was the most frequently cited journal,whereas Journal of Ethnopharmacology contributed the largest number of publications.Co-occurrence clustering revealed 13 thematic research areas,highlighting apoptosis,Panax notoginseng,dihydrochalcones,and quercetin as representative hotspots.Target interaction analysis identified signal transducer and activator of transcription 3(STAT3),jun proto-oncogene(JUN),AKT serine/threonine kinase 1(AKT1),tumor protein 53(TP53),and interleukin-6(IL6)as core molecular targets.The findings delineate a dynamic and evolving research landscape in this domain and clarify its organization around several pivotal molecular targets.The field is shifting away from the conventional"one drug,one target"paradigm toward multi-target therapeutic strategies,reflecting the multifactorial nature of neuroinflammation in CNS disorders.These insights highlight key molecular nodes and research directions,providing a foundation for precision medicine approaches and innovative drug development to improve treatment outcomes in neuroinflammatory CNS diseases.
基金National Natural Science Foundation of China,Grant/Award Numbers:81960109,82460370Joint Special Funds for the Department of Science and Technology of Yunnan Province-Kunming Medical University,Grant/Award Number:202001AY070001-205+2 种基金Innovative Team of Yunnan Province and Clinical Research Center for Geriatric Diseases of Yunnan Province-Diagnosis and Treatment of Geriatric Comorbidity and Clinical Translational Research,Grant/Award Number:202102AA310069Yunnan Clinical Center for Emergency traumatic disease,Grant/Award Number:2023-2025The Innovative Team of Yunnan Province,Grant/Award Number:202305AS350019。
文摘Neuroinflammation, a key defense mechanism of the nervous system, is associated with changes in inflammatory markers and stimulation of neuroimmune cells such as microglia and astrocytes. Growing evidence indicates that the gut microbiota and its metabolites directly or indirectly regulate host health. According to recent studies, bacterial dysbiosis in the gut is closely linked to several central nervous system disorders that cause neuroinflammation, including multiple sclerosis, Alzheimer's disease, Parkinson's disease, sepsis-associated encephalopathy, and ischemic stroke. Recent findings indicate a bidirectional communication network between the gut microbiota and central nervous system that influences neuroinflammation and cognitive function. Dysregulation of this system can affect the generation of cytotoxic metabolites, promote neuroinflammation, and impair cognition. This review explores the lesser-studied microbiota-derived metabolites involved in neuroinflammation—bile acids, trimethylamine-N-oxide, and indole derivatives—as targets for creating new treatment tools for neuroinflammatory illnesses, as well as possible biomarkers for early diagnosis and prognosis.
文摘Glial cells,alongside neurons,are the major cells of the central nervous system.More than just supporting neurons,glial cells are vital in central nervous system homeostasis and actively shape neurodegenerative disease mechanisms.They exhibit dual roles in promoting neuroprotection through glutamate clearance,mitochondrial transfer,extracellular vesicle signaling,and remyelination,yet also contributing to excitotoxicity,neuroinflammation,and myelin loss.Recent studies emphasize their therapeutic potential,such as enhancing excitatory amino acid transporters,engineering extracellular vesicles,and boosting oligodendrocyte precursor cell function in combating neurodegeneration.This mini review comments on previous articles published in Neuroprotection alongside others,and discusses how enhancing glial protective roles may serve as novel neuroprotective interventions.
