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
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
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
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: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
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
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
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
The risk factors and neuropathologies of cognitive decline and the onset and progression of dementia-related disorders were, until recently, obtuse. A critical predisposing factor to Alzheimer's disease (AD) that ...The risk factors and neuropathologies of cognitive decline and the onset and progression of dementia-related disorders were, until recently, obtuse. A critical predisposing factor to Alzheimer's disease (AD) that has emerged is glucose dysmetabolism. It is now understood that energy imbalances or excess nutrient intake sit in the crosshairs of neurodegeneration. Within the brain, the regulation of glucose operates semiautonomously from the periphery to ensure a defended, uninterrupted supply of glucose for neuronal processes. In this localized brain energetic milieu, hyperglycemia, hyperinsulinemia, and insulin resistance constitute independent risk factors for AD. Disturbances in the blood‒brain barrier (BBB) and brain insulin resistance are two newly understood insults connecting glucose metabolism with AD. This dysglycemia waylays insulin signaling, an otherwise potentially protective mechanism against AD plaques. In parallel, studies in the clinical setting demonstrate that glucose-lowering in patients with type 2 diabetes (T2D) reduces the risk of AD. The American Diabetes Association (ADA) elevated its guidelines to include cognitive issues (or risk) as a comorbidity in T2D patient treatment plans. Choice of antidiabetes therapy is imperative: evidence supports the use of metformin, dipeptidyl peptidase 4 inhibitors, glucagon-like peptide-1 receptor analogs, and sodium glucose cotransporter 2 inhibitors to help prevent and mitigate cognitive outcomes and AD. Sulfonylureas, on the other hand, may actually worsen cognitive deficits and integrity. We are at a fascinating juncture: preclinical research is at a stage to inform the development of rational previously unexplored targets. Simultaneously, current clinical evidence is translatable now into real-world strategies to reduce the incidence and severity of comorbid AD in our aging population.展开更多
Stroke is the leading cause of acquired disability.The development of acute ischemic stroke treatments,such as mechanical thrombectomy and tissue plasminogen activator,has resulted in more patients surviving the initi...Stroke is the leading cause of acquired disability.The development of acute ischemic stroke treatments,such as mechanical thrombectomy and tissue plasminogen activator,has resulted in more patients surviving the initial insult.However,long-term complications,such as post-stroke cognitive impairment(PSCI)and dementia(PSD),are at an all-time high.Notably,80%of stroke survivors suffer from cognitive impairment,and a history of stroke doubles a patient's lifetime risk of developing dementia.A combination of greater life expectancy,an increase in the number of strokes in young individuals,and improved survival have inherently increased the number of years patients are living post-stroke,highlighting the critical need to understand the long-term effects of stroke,including how pathological changes in the brain might give rise to functional and behavioral changes in stroke survivors.Even with this increased risk of PSCI and PSD in stroke survivors,understanding of how the stroke itself develops into these conditions remains incomplete.Recently,secondary neurodegeneration(SND)following stroke has been linked with PSCI and PSD.SND is the degeneration of brain regions outside the original stroke site.Degeneration in these sites is thought to arise due to functional diaschisis with the infarct core;however,observation of SND pathology in multiple regions without direct connectivity to the stroke infarct suggests that the degeneration in these regions is likely more complex.Moreover,pathological hallmarks of dementia,such as a deposition of neurodegenerative proteins and iron,cell death,inflammation and blood–brain barrier alterations,have all been found in regions such as the thalamus,hippocampus,basal ganglia,amygdala and prefrontal cortex following stroke.Hence,in this review,we present the current understanding of PSCI and PSD in the context of SND and outline how remote anatomical and molecular changes may drive the development of these conditions.展开更多
BackgroundSome research suggests that vitamin E may help prevent intraventricular hemorrhage (IVH) in preterm neonates. However, consolidated evidence regarding its effects on brain vascular health in this population ...BackgroundSome research suggests that vitamin E may help prevent intraventricular hemorrhage (IVH) in preterm neonates. However, consolidated evidence regarding its effects on brain vascular health in this population is lacking. This study systematically reviews primary research on this topic. This study examines the effectiveness of vitamin E supplementation in preventing IVH in preterm neonates than a placebo, thus addressing gaps in the literature.MethodsThe Cochrane, Dimensions, Embase, and PubMed databases were searched for relevant studies based on specific inclusion criteria. Subsequently, the relevant data were extracted, and statistical analysis was conducted using R studio (version 4.3.1) by applying appropriate models to account for heterogeneity and generate a combined estimate. The results were interpreted considering potential biases and limitations.ResultsFive studies involving 554 patients were included. Among them, 274 (49.45%) received vitamin E. The results (relative ratio 0.57;95% confidence interval 0.35–0.92;p = 0.02;I2 = 56%) demonstrated a reduction in the incidence of IVH in patients who received administration of vitamin E (n = 274) compared with those who received a placebo (n = 280).ConclusionThese findings highlight the potential therapeutic benefits of vitamin E supplementation in preterm neonates, which show a significant reduction in IVH incidence than placebo. Further research and clinical trials are required to fully explore its protective effects in this population.展开更多
Oral microbiota is the second largest microbial colony in the body and forms a complex ecological community that influences oral and brain health.Impaired homeostasis of the oral microbiota can lead to pathological ch...Oral microbiota is the second largest microbial colony in the body and forms a complex ecological community that influences oral and brain health.Impaired homeostasis of the oral microbiota can lead to pathological changes,resulting in central nervous system(CNS)diseases.However,the mechanisms and clinical value of how the oral microbiome influences the brain remain unclear.This review summarizes recent clinical findings on the role of the oral microbiota in CNS diseases and proposes potential approaches to understand the way the oral microbiota and brain communicate.We propose three underlying patterns involving neuroinflammation,neuroendocrine regulation,and CNS signaling between oral microbiota and CNS diseases.We also summarize the clinical characteristics and potential utilization of the oral microbiota in ischemic stroke,Alzheimer's and Parkinson's disease,intracranial aneurysms,and mental disorders.Although the current findings are preliminary and clinical evidence is incomplete,oral microbiota is a potential biomarker for the clinical diagnosis and treatment of CNS diseases.展开更多
The global trend toward aging populations has resulted in an increase in the occurrence of Alzheimer's disease(AD)and associated socioeconomic burdens.Abnormal metabolism of amyloid-β(Aβ)has been proposed as a s...The global trend toward aging populations has resulted in an increase in the occurrence of Alzheimer's disease(AD)and associated socioeconomic burdens.Abnormal metabolism of amyloid-β(Aβ)has been proposed as a significant pathomechanism in AD,supported by results of recent clinical trials using anti-Aβantibodies.Nonetheless,the cognitive benefits of the current treatments are limited.The etiology of AD is multifactorial,encompassing Aβand tau accumulation,neuroinflammation,demyelination,vascular dysfunction,and comorbidities,which collectively lead to widespread neurodegeneration in the brain and cognitive impairment.Hence,solely removing Aβfrom the brain may be insufficient to combat neurodegeneration and preserve cognition.To attain effective treatment for AD,it is necessary to(1)conduct extensive research on various mechanisms that cause neurodegeneration,including advances in neuroimaging techniques for earlier detection and a more precise characterization of molecular events at scales ranging from cellular to the full system level;(2)identify neuroprotective intervention targets against different neurodegeneration mechanisms;and(3)discover novel and optimal combinations of neuroprotective intervention strategies to maintain cognitive function in AD patients.The Alzheimer's Disease Neuroprotection Research Initiative's objective is to facilitate coordinated,multidisciplinary efforts to develop systemic neuroprotective strategies to combat AD.The aim is to achieve mitigation of the full spectrum of pathological processes underlying AD,with the goal of halting or even reversing cognitive decline.展开更多
Stem cell-based therapies and extracellular vesicle(EV)treatment have demonstrated significant potential for neuroprotection against ischemic stroke.Although the neuroprotective mechanisms are not yet fully under-stoo...Stem cell-based therapies and extracellular vesicle(EV)treatment have demonstrated significant potential for neuroprotection against ischemic stroke.Although the neuroprotective mechanisms are not yet fully under-stood,targeting microglia is central to promoting neuroprotection.Microglia are the resident immune cells of the central nervous system.These cells are crucial in the pathogenesis of ischemic stroke.They respond rapidly to the site of injury by releasing pro-inflammatory cytokines,phagocytizing dead cells and debris,and recruiting peripheral immune cells to the ischemic area.Although these responses are essential for clearing damage and initiating tissue repair,excessive or prolonged microglial activation can exacerbate brain injury,leading to secondary neuroinflammation and neurodegeneration.Moreover,microglia exhibit a dynamic range of activation states with the so-called M1 pro-inflammatory and M2 anti-inflammatory phenotypes,representing the two ends of the spectrum.The delivery of both EVs and stem cells modulates microglial activation,suppressing pro-inflammatory genes,influencing the expression of transcription factors,and altering receptor expression,ultimately contributing to neuroprotection.These findings underscore the importance of understanding the complex and dynamic role of microglia in the development of effective neuroprotective strategies to reduce the effects of ischemic stroke.In this review,we examine the current state of knowledge regarding the role of microglia in ischemic stroke,including their molecular and cellular mechanisms,activation states,and interactions with other cells.We also discuss the multifaceted contributions of microglia to stem cell-and EV-based neuroprotection during an ischemic stroke to provide a comprehensive understanding of microglial functions and their potential implications in stroke therapies.展开更多
Recent advances in neuroscience have illuminated the central role of glutamate dysregulation in various neurological disorders.The glutamatergic system has emerged as a central player in the pathophysiology of various...Recent advances in neuroscience have illuminated the central role of glutamate dysregulation in various neurological disorders.The glutamatergic system has emerged as a central player in the pathophysiology of various neurological disorders.The dysregulation of glutamate signaling,leading to excitotoxicity and neuronal cell death,has been a focal point in understanding the underlying mechanisms of these conditions.This has prompted a paradigm shift in neuroprotection research,with a growing emphasis on targeting ionotropic glutamate receptors(iGluRs)to restore glutamatergic homeostasis.This review provides a comprehensive overview of recent advancements in the field of iGluR-targeted neuroprotection.We further investigate the implications of glutamate dysregulation in the central nervous system(CNS)disorders,highlighting the complex interplay between excitotoxicity and neuroprotection.We elucidate the multifaceted factors that render neurons vulnerable to excitotoxic damage,emphasizing the need for innovative therapeutic approaches.This review provides an extensive survey of the burgeoning field of iGluR-targeted neuroprotection.It showcases the significant potential of a wide array of compounds,encompassing both natural and synthetic agents,to modulate iGluRs and ameliorate excitotoxicity and oxidative stress-induced neuronal damage.These compounds have demonstrated impressive neuroprotective effects in diverse experimental models,from glutamate-induced toxicity to traumatic brain injuries.We advocate for further research and clinical investigations to harness the full therapeutic potential of iGluR modulation,heralding a promising era in neuroprotection and CNs disorder management.展开更多
Activation of neuroprotective and particularly later neurorestorative mechanisms after stroke attempts to restore or compensate for lost functions.This potentially opens a wide window for restorative therapies to prom...Activation of neuroprotective and particularly later neurorestorative mechanisms after stroke attempts to restore or compensate for lost functions.This potentially opens a wide window for restorative therapies to promote brain repair and improve long-term functional recovery.Although extensively demonstrated in the preclinical setting,the efficacy of cell-based therapies in stroke patients has been modest at best,if any at all.Translational failure may be due to the ineffective survival and integration of transplanted cells in pro-death stroke microenvironments that are not conducive for the structural reconstruction of damaged brain tissue and repair-related network reorganization.Optimal systemic delivery,timing,cell product,and dose remain open as well.Fortunately,a better understanding of the brain plasticity mechanisms underlying stroke recovery has ushered in a combination approach of cell-based therapy and rehabilitation that is aimed at achieving additive,synergistic,or even maximal beneficial effects.This novel combination therapy is not only targeted at promoting exogenous and endogenous cell survival and augmenting stand-alone restorative mechanisms but also at utilizing rehabilitation to facilitate a graft–host structural and functional integration and plasticity that would effectively remodel stroke tissue and restitute lost functions.This review presents an overview of the combination of cell-based therapy and experimental rehabilitation in stroke models.It also discusses associated shortcomings as well as proposes strategies to address them and help facilitate the advancement of this combination approach.展开更多
Neuroprotection holds particular significance in neurodegenerative diseases characterized by the death of brain cells.Despite differences in timeframe,location,pathology,and clinical outcomes,common pathophysiological...Neuroprotection holds particular significance in neurodegenerative diseases characterized by the death of brain cells.Despite differences in timeframe,location,pathology,and clinical outcomes,common pathophysiological mechanisms may exist,including oxidative stress and excitotoxicity.So far,neuroprotective therapies have yet to demonstrate significant benefits in clinical trials.1 Reasons for past translational failures may involve low experimental study quality,more complex pathophysiology than expected,challenging drug delivery,late intervention,and safety issues.However,recent advances offer renewed hope and potential breakthroughs that could change the treatment landscape in the future.These novel therapeutic strategies will be discussed in this issueofNeuroprotection.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.
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.
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.
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.
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The risk factors and neuropathologies of cognitive decline and the onset and progression of dementia-related disorders were, until recently, obtuse. A critical predisposing factor to Alzheimer's disease (AD) that has emerged is glucose dysmetabolism. It is now understood that energy imbalances or excess nutrient intake sit in the crosshairs of neurodegeneration. Within the brain, the regulation of glucose operates semiautonomously from the periphery to ensure a defended, uninterrupted supply of glucose for neuronal processes. In this localized brain energetic milieu, hyperglycemia, hyperinsulinemia, and insulin resistance constitute independent risk factors for AD. Disturbances in the blood‒brain barrier (BBB) and brain insulin resistance are two newly understood insults connecting glucose metabolism with AD. This dysglycemia waylays insulin signaling, an otherwise potentially protective mechanism against AD plaques. In parallel, studies in the clinical setting demonstrate that glucose-lowering in patients with type 2 diabetes (T2D) reduces the risk of AD. The American Diabetes Association (ADA) elevated its guidelines to include cognitive issues (or risk) as a comorbidity in T2D patient treatment plans. Choice of antidiabetes therapy is imperative: evidence supports the use of metformin, dipeptidyl peptidase 4 inhibitors, glucagon-like peptide-1 receptor analogs, and sodium glucose cotransporter 2 inhibitors to help prevent and mitigate cognitive outcomes and AD. Sulfonylureas, on the other hand, may actually worsen cognitive deficits and integrity. We are at a fascinating juncture: preclinical research is at a stage to inform the development of rational previously unexplored targets. Simultaneously, current clinical evidence is translatable now into real-world strategies to reduce the incidence and severity of comorbid AD in our aging population.
文摘Stroke is the leading cause of acquired disability.The development of acute ischemic stroke treatments,such as mechanical thrombectomy and tissue plasminogen activator,has resulted in more patients surviving the initial insult.However,long-term complications,such as post-stroke cognitive impairment(PSCI)and dementia(PSD),are at an all-time high.Notably,80%of stroke survivors suffer from cognitive impairment,and a history of stroke doubles a patient's lifetime risk of developing dementia.A combination of greater life expectancy,an increase in the number of strokes in young individuals,and improved survival have inherently increased the number of years patients are living post-stroke,highlighting the critical need to understand the long-term effects of stroke,including how pathological changes in the brain might give rise to functional and behavioral changes in stroke survivors.Even with this increased risk of PSCI and PSD in stroke survivors,understanding of how the stroke itself develops into these conditions remains incomplete.Recently,secondary neurodegeneration(SND)following stroke has been linked with PSCI and PSD.SND is the degeneration of brain regions outside the original stroke site.Degeneration in these sites is thought to arise due to functional diaschisis with the infarct core;however,observation of SND pathology in multiple regions without direct connectivity to the stroke infarct suggests that the degeneration in these regions is likely more complex.Moreover,pathological hallmarks of dementia,such as a deposition of neurodegenerative proteins and iron,cell death,inflammation and blood–brain barrier alterations,have all been found in regions such as the thalamus,hippocampus,basal ganglia,amygdala and prefrontal cortex following stroke.Hence,in this review,we present the current understanding of PSCI and PSD in the context of SND and outline how remote anatomical and molecular changes may drive the development of these conditions.
文摘BackgroundSome research suggests that vitamin E may help prevent intraventricular hemorrhage (IVH) in preterm neonates. However, consolidated evidence regarding its effects on brain vascular health in this population is lacking. This study systematically reviews primary research on this topic. This study examines the effectiveness of vitamin E supplementation in preventing IVH in preterm neonates than a placebo, thus addressing gaps in the literature.MethodsThe Cochrane, Dimensions, Embase, and PubMed databases were searched for relevant studies based on specific inclusion criteria. Subsequently, the relevant data were extracted, and statistical analysis was conducted using R studio (version 4.3.1) by applying appropriate models to account for heterogeneity and generate a combined estimate. The results were interpreted considering potential biases and limitations.ResultsFive studies involving 554 patients were included. Among them, 274 (49.45%) received vitamin E. The results (relative ratio 0.57;95% confidence interval 0.35–0.92;p = 0.02;I2 = 56%) demonstrated a reduction in the incidence of IVH in patients who received administration of vitamin E (n = 274) compared with those who received a placebo (n = 280).ConclusionThese findings highlight the potential therapeutic benefits of vitamin E supplementation in preterm neonates, which show a significant reduction in IVH incidence than placebo. Further research and clinical trials are required to fully explore its protective effects in this population.
基金National Natural Science Foundation of China,Grant/Award Number:82301715Wuxi Taihu Lake Talent Plan,Supports for Leading Talents in Medical and Health Profession,Grant/Award Number:2020THRC-DJ-SNW+1 种基金Jiangsu Province Double-Creation Doctoral Talent Plan,Grant/Award Number:JSSCBS20221995WuXi Municipal Health Commission,Grant/Award Number:Q202222。
文摘Oral microbiota is the second largest microbial colony in the body and forms a complex ecological community that influences oral and brain health.Impaired homeostasis of the oral microbiota can lead to pathological changes,resulting in central nervous system(CNS)diseases.However,the mechanisms and clinical value of how the oral microbiome influences the brain remain unclear.This review summarizes recent clinical findings on the role of the oral microbiota in CNS diseases and proposes potential approaches to understand the way the oral microbiota and brain communicate.We propose three underlying patterns involving neuroinflammation,neuroendocrine regulation,and CNS signaling between oral microbiota and CNS diseases.We also summarize the clinical characteristics and potential utilization of the oral microbiota in ischemic stroke,Alzheimer's and Parkinson's disease,intracranial aneurysms,and mental disorders.Although the current findings are preliminary and clinical evidence is incomplete,oral microbiota is a potential biomarker for the clinical diagnosis and treatment of CNS diseases.
基金National Natural Science Foundation of China,Grant/Award Numbers:92249305,82120108010,81930028,31921003Academy of Medical Sciences(Newton Advanced Fellowship),Grant/Award Number:NAF/R11/1010National Institutes of Health,Grant/Award Number:R01DA056739。
文摘The global trend toward aging populations has resulted in an increase in the occurrence of Alzheimer's disease(AD)and associated socioeconomic burdens.Abnormal metabolism of amyloid-β(Aβ)has been proposed as a significant pathomechanism in AD,supported by results of recent clinical trials using anti-Aβantibodies.Nonetheless,the cognitive benefits of the current treatments are limited.The etiology of AD is multifactorial,encompassing Aβand tau accumulation,neuroinflammation,demyelination,vascular dysfunction,and comorbidities,which collectively lead to widespread neurodegeneration in the brain and cognitive impairment.Hence,solely removing Aβfrom the brain may be insufficient to combat neurodegeneration and preserve cognition.To attain effective treatment for AD,it is necessary to(1)conduct extensive research on various mechanisms that cause neurodegeneration,including advances in neuroimaging techniques for earlier detection and a more precise characterization of molecular events at scales ranging from cellular to the full system level;(2)identify neuroprotective intervention targets against different neurodegeneration mechanisms;and(3)discover novel and optimal combinations of neuroprotective intervention strategies to maintain cognitive function in AD patients.The Alzheimer's Disease Neuroprotection Research Initiative's objective is to facilitate coordinated,multidisciplinary efforts to develop systemic neuroprotective strategies to combat AD.The aim is to achieve mitigation of the full spectrum of pathological processes underlying AD,with the goal of halting or even reversing cognitive decline.
文摘Stem cell-based therapies and extracellular vesicle(EV)treatment have demonstrated significant potential for neuroprotection against ischemic stroke.Although the neuroprotective mechanisms are not yet fully under-stood,targeting microglia is central to promoting neuroprotection.Microglia are the resident immune cells of the central nervous system.These cells are crucial in the pathogenesis of ischemic stroke.They respond rapidly to the site of injury by releasing pro-inflammatory cytokines,phagocytizing dead cells and debris,and recruiting peripheral immune cells to the ischemic area.Although these responses are essential for clearing damage and initiating tissue repair,excessive or prolonged microglial activation can exacerbate brain injury,leading to secondary neuroinflammation and neurodegeneration.Moreover,microglia exhibit a dynamic range of activation states with the so-called M1 pro-inflammatory and M2 anti-inflammatory phenotypes,representing the two ends of the spectrum.The delivery of both EVs and stem cells modulates microglial activation,suppressing pro-inflammatory genes,influencing the expression of transcription factors,and altering receptor expression,ultimately contributing to neuroprotection.These findings underscore the importance of understanding the complex and dynamic role of microglia in the development of effective neuroprotective strategies to reduce the effects of ischemic stroke.In this review,we examine the current state of knowledge regarding the role of microglia in ischemic stroke,including their molecular and cellular mechanisms,activation states,and interactions with other cells.We also discuss the multifaceted contributions of microglia to stem cell-and EV-based neuroprotection during an ischemic stroke to provide a comprehensive understanding of microglial functions and their potential implications in stroke therapies.
文摘Recent advances in neuroscience have illuminated the central role of glutamate dysregulation in various neurological disorders.The glutamatergic system has emerged as a central player in the pathophysiology of various neurological disorders.The dysregulation of glutamate signaling,leading to excitotoxicity and neuronal cell death,has been a focal point in understanding the underlying mechanisms of these conditions.This has prompted a paradigm shift in neuroprotection research,with a growing emphasis on targeting ionotropic glutamate receptors(iGluRs)to restore glutamatergic homeostasis.This review provides a comprehensive overview of recent advancements in the field of iGluR-targeted neuroprotection.We further investigate the implications of glutamate dysregulation in the central nervous system(CNS)disorders,highlighting the complex interplay between excitotoxicity and neuroprotection.We elucidate the multifaceted factors that render neurons vulnerable to excitotoxic damage,emphasizing the need for innovative therapeutic approaches.This review provides an extensive survey of the burgeoning field of iGluR-targeted neuroprotection.It showcases the significant potential of a wide array of compounds,encompassing both natural and synthetic agents,to modulate iGluRs and ameliorate excitotoxicity and oxidative stress-induced neuronal damage.These compounds have demonstrated impressive neuroprotective effects in diverse experimental models,from glutamate-induced toxicity to traumatic brain injuries.We advocate for further research and clinical investigations to harness the full therapeutic potential of iGluR modulation,heralding a promising era in neuroprotection and CNs disorder management.
基金European Commission under the Horizon 2020 program,Grant/Award Number:681044。
文摘Activation of neuroprotective and particularly later neurorestorative mechanisms after stroke attempts to restore or compensate for lost functions.This potentially opens a wide window for restorative therapies to promote brain repair and improve long-term functional recovery.Although extensively demonstrated in the preclinical setting,the efficacy of cell-based therapies in stroke patients has been modest at best,if any at all.Translational failure may be due to the ineffective survival and integration of transplanted cells in pro-death stroke microenvironments that are not conducive for the structural reconstruction of damaged brain tissue and repair-related network reorganization.Optimal systemic delivery,timing,cell product,and dose remain open as well.Fortunately,a better understanding of the brain plasticity mechanisms underlying stroke recovery has ushered in a combination approach of cell-based therapy and rehabilitation that is aimed at achieving additive,synergistic,or even maximal beneficial effects.This novel combination therapy is not only targeted at promoting exogenous and endogenous cell survival and augmenting stand-alone restorative mechanisms but also at utilizing rehabilitation to facilitate a graft–host structural and functional integration and plasticity that would effectively remodel stroke tissue and restitute lost functions.This review presents an overview of the combination of cell-based therapy and experimental rehabilitation in stroke models.It also discusses associated shortcomings as well as proposes strategies to address them and help facilitate the advancement of this combination approach.
文摘Neuroprotection holds particular significance in neurodegenerative diseases characterized by the death of brain cells.Despite differences in timeframe,location,pathology,and clinical outcomes,common pathophysiological mechanisms may exist,including oxidative stress and excitotoxicity.So far,neuroprotective therapies have yet to demonstrate significant benefits in clinical trials.1 Reasons for past translational failures may involve low experimental study quality,more complex pathophysiology than expected,challenging drug delivery,late intervention,and safety issues.However,recent advances offer renewed hope and potential breakthroughs that could change the treatment landscape in the future.These novel therapeutic strategies will be discussed in this issueofNeuroprotection.
