Microglia are brain-resident immune cells that contribute to the maintenance of brain homeostasis.In the epileptic brain, microglia show various activation phenotypes depending on the stage of epileptogenesis.Therefor...Microglia are brain-resident immune cells that contribute to the maintenance of brain homeostasis.In the epileptic brain, microglia show various activation phenotypes depending on the stage of epileptogenesis.Therefore, it remains unclear whether microglial activation acts in a pro-epileptic or anti-epileptic manner.In mesial temporal lobe epilepsy, one of the most common form of epilepsies, microglia exhibit at least two distinct morphologies, amoeboid shape and ramified shape.Amoeboid microglia are often found in sclerotic area, whereas ramified microglia are mainly found in non-sclerotic area;however, it remains unclear whether these structurally distinct microglia share separate roles in the epileptic brain.Here, we review the roles of the two distinct microglial phenotypes, focusing on their pro-and anti-epileptic roles in terms of inflammatory response, regulation of neurogenesis and microglia-neuron interaction.展开更多
Millions of people worldwide are affected by traumatic spinal cord injury,which usually results in permanent sensorimotor disability.Damage to the spinal cord leads to a series of detrimental events including ischaemi...Millions of people worldwide are affected by traumatic spinal cord injury,which usually results in permanent sensorimotor disability.Damage to the spinal cord leads to a series of detrimental events including ischaemia,haemorrhage and neuroinflammation,which over time result in further neural tissue loss.Eventually,at chronic stages of traumatic spinal cord injury,the formation of a glial scar,cystic cavitation and the presence of numerous inhibitory molecules act as physical and chemical barriers to axonal regrowth.This is further hindered by a lack of intrinsic regrowth ability of adult neurons in the central nervous system.The intracellular signalling molecule,cyclic adenosine 3′,5′-monophosphate(cAMP),is known to play many important roles in the central nervous system,and elevating its levels as shown to improve axonal regeneration outcomes following traumatic spinal cord injury in animal models.However,therapies directly targeting cAMP have not found their way into the clinic,as cAMP is ubiquitously present in all cell types and its manipulation may have additional deleterious effects.A downstream effector of cAMP,exchange protein directly activated by cAMP 2(Epac2),is mainly expressed in the adult central nervous system,and its activation has been shown to mediate the positive effects of cAMP on axonal guidance and regeneration.Recently,using ex vivo modelling of traumatic spinal cord injury,Epac2 activation was found to profoundly modulate the post-lesion environment,such as decreasing the activation of astrocytes and microglia.Pilot data with Epac2 activation also suggested functional improvement assessed by in vivo models of traumatic spinal cord injury.Therefore,targeting Epac2 in traumatic spinal cord injury could represent a novel strategy in traumatic spinal cord injury repair,and future work is needed to fully establish its therapeutic potential.展开更多
We previously found that argon exerts its neuroprotective effect in part by inhibition of the toll-like receptors(TLR)2 and 4.The downstream transcription factors signal transducer and activator of transcription 3(STA...We previously found that argon exerts its neuroprotective effect in part by inhibition of the toll-like receptors(TLR)2 and 4.The downstream transcription factors signal transducer and activator of transcription 3(STAT3)and nuclear factor kappa B(NF-κB)are also affected by argon and may play a role in neuroprotection.It also has been demonstrated that argon treatment could mitigate brain damage,reduce excessive microglial activation,and subsequently attenuate brain inflammation.Despite intensive research,the further exact mechanism remains unclear.In this study,human neuroblastoma cells were damaged in vitro with rotenone over a period of 4 hours(to mimic cerebral ischemia and reperfusion damage),followed by a 2-hour post-conditioning with argon(75%).In a separate in vivo experiment,retinal ischemia/reperfusion injury was induced in rats by increasing intraocular pressure for 1 hour.Upon reperfusion,argon was administered by inhalation for 2 hours.Argon reduced the binding of the transcription factors signal transducer and activator of transcription 3,nuclear factor kappa B,activator protein 1,and nuclear factor erythroid 2-related factor 2,which are involved in regulation of neuronal damage.Flow cytometry analysis showed that argon downregulated the Fas ligand.Some transcription factors were regulated by toll-like receptors;therefore,their effects could be eliminated,at least in part,by the TLR2 and TLR4 inhibitor oxidized phospholipid 1-palmitoyl-2-arachidonoyl-sn-glycero-3-phosphorylcholine(OxPAPC).Argon treatment reduced microglial activation after retinal ischemia/reperfusion injury.Subsequent quantitative polymerase chain reaction analysis revealed a reduction in the pro-inflammatory cytokines interleukin(IL-1α),IL-1β,IL-6,tumor necrosis factorα,and inducible nitric oxide synthase.Our results suggest that argon reduced the extent of inflammation in retinal neurons after ischemia/reperfusion injury by suppression of transcription factors crucial for microglial activation.Argon has no known side effects o展开更多
Our previous studies have demonstrated that TP53-induced glycolysis and apoptosis regulator(TIGAR)can protect neurons after cerebral ischemia/reperfusion.However,the role of TIGAR in neonatal hypoxic-ischemic brain da...Our previous studies have demonstrated that TP53-induced glycolysis and apoptosis regulator(TIGAR)can protect neurons after cerebral ischemia/reperfusion.However,the role of TIGAR in neonatal hypoxic-ischemic brain damage(HIBD)remains unknown.In the present study,7-day-old Sprague-Dawley rat models of HIBD were established by permanent occlusion of the left common carotid artery followed by 2-hour hypoxia.At 6 days before induction of HIBD,a lentiviral vector containing short hairpin RNA of either TIGAR or gasdermin D(LV-sh_TIGAR or LV-sh_GSDMD)was injected into the left lateral ventricle and striatum.Highly aggressively proliferating immortalized(HAPI)microglial cell models of in vitro HIBD were established by 2-hour oxygen/glucose deprivation followed by 24-hour reoxygenation.Three days before in vitro HIBD induction,HAPI microglial cells were transfected with LV-sh_TIGAR or LV-sh_GSDMD.Our results showed that TIGAR expression was increased in the neonatal rat cortex after HIBD and in HAPI microglial cells after oxygen/glucose deprivation/reoxygenation.Lentivirusmediated TIGAR knockdown in rats markedly worsened pyroptosis and brain damage after hypoxia/ischemia in vivo and in vitro.Application of exogenous nicotinamide adenine dinucleotide phosphate(NADPH)increased the NADPH level and the glutathione/oxidized glutathione ratio and decreased reactive oxygen species levels in HAPI microglial cells after oxygen/glucose deprivation/reoxygenation.Additionally,exogenous NADPH blocked the effects of TIGAR knockdown in neonatal HIBD in vivo and in vitro.These findings show that TIGAR can inhibit microglial pyroptosis and play a protective role in neonatal HIBD.The study was approved by the Animal Ethics Committee of Soochow University of China(approval No.2017LW003)in 2017.展开更多
Osteopontin is a broadly expressed pleiotropic protein,and is attracting increased attention because of its role in the pathophysiology of several inflammatory,degenerative,autoimmune,and oncologic diseases.In fact,in...Osteopontin is a broadly expressed pleiotropic protein,and is attracting increased attention because of its role in the pathophysiology of several inflammatory,degenerative,autoimmune,and oncologic diseases.In fact,in the last decade,several studies have shown that osteopontin contributes to tissue damage not only by recruiting harmful inflammatory cells to the site of lesion,but also increasing their survival.The detrimental role of osteopontin has been indeed well documented in the context of different neurological conditions(i.e.,multiple sclerosis,Parkinson’s,and Alzheimer’s diseases).Intriguingly,recent findings show that osteopontin is involved not only in promoting tissue damage(the Yin),but also in repair/regenerative mechanisms(the Yang),mostly triggered by the inflammatory response.These two apparently discordant roles are partly related to the presence of different functional domains in the osteopontin molecule,which are exposed after thrombin or metalloproteases cleavages.Such functional domains may in turn activate intracellular signaling pathways and mediate cell-cell and cell-matrix interactions.This review describes the current knowledge on the Yin and Yang features of osteopontin in nervous system diseases.Understanding the mechanisms behind the Yin/Yang would be relevant to develop highly specific tools targeting this multifunctional protein.展开更多
Microglia,the tissue resident macrophages of the brain,are increasingly recognized as key players for central nervous system development and homeostasis.They are long-lived cells deriving from a transient wave of yolk...Microglia,the tissue resident macrophages of the brain,are increasingly recognized as key players for central nervous system development and homeostasis.They are long-lived cells deriving from a transient wave of yolk-sac derived erythro-myeloid progenitors early in development.Their unique ontology has prompted the search for specific markers to be used for their selective investigation and manipulation.The first generation of genomewide expression studies has provided a bundle of transcripts(such as Olfml3,Fcrls,Tmem119,P2ry12,Gpr34,and Siglech)useful to distinguish microglia from peripheral macrophages.However,more recent reports have revealed that microglial phenotype is constantly shaped by the microenvironment in a time-,and context-dependent manner.In this article,we review data that provide additional pieces to this complex scenario and show the existence of unexpected phenotypic convergence between microglia and peripheral macrophages at certain developmental stages and under pathological conditions.These observations suggest that the two cell types act synergically boosting their mutual activities depending on the microenvironment.This novel information about the biology of microglia and peripheral macrophages sheds new light about their therapeutic potential for neuroinflammatory and neurodegenerative diseases.展开更多
Infusion of the colloid hydroxyethylstarch has been used for volume substitution to maintain hemodynamics and microcirculation after e.g., severe blood loss.In the last decade it was revealed that hydroxyethylstarch c...Infusion of the colloid hydroxyethylstarch has been used for volume substitution to maintain hemodynamics and microcirculation after e.g., severe blood loss.In the last decade it was revealed that hydroxyethylstarch can aggravate acute kidney injury, especially in septic patients.Because of the serious risk for critically ill patients, the administration of hydroxyethylstarch was restricted for clinical use.Animal studies and recently published in vitro experiments showed that hydroxyethylstarch might exert protective effects on the blood-brain barrier.Since the prevention of blood-brain barrier disruption was shown to go along with the reduction of brain damage after several kinds of insults, we revisit the topic hydroxyethylstarch and discuss a possible niche for the application of hydroxyethylstarch in acute brain injury treatment.展开更多
Sterile inflammatory processes are essential for the maintenance of central nervous system homeostasis,but they also contribute to various neurological disorders,including neurotrauma,stroke,and demyelinating or neuro...Sterile inflammatory processes are essential for the maintenance of central nervous system homeostasis,but they also contribute to various neurological disorders,including neurotrauma,stroke,and demyelinating or neurodegenerative diseases.Immune mechanisms in the central nervous system and periphery are regulated by a diverse group of endogenous proteins,which can be broadly divided into the pro-inflammatory damageassociated molecular patterns(DAMPs)and anti-inflammatory resolution-associated molecular patterns(RAMPs),even though there is notable overlap between the DAMPand RAMP-like activities for some of these molecules.Both groups of molecular patterns were initially described in peripheral immune processes and pathologies;however,it is now evident that at least some,if not all,of these immunomodulators also regulate neuroimmune processes and contribute to neuroinflammation in diverse central nervous system disorders.The review of recent literature demonstrates that studies on DAMPs and RAMPs of the central nervous system still lag behind the much broader research effort focused on their peripheral counterparts.Nevertheless,this review also reveals that over the last five years,significant advances have been made in our understanding of the neuroimmune functions of several well-established DAMPs,including high-mobility group box 1 protein and interleukin 33.Novel neuroimmune functions have been demonstrated for other DAMPs that previously were considered almost exclusively as peripheral immune regulators;they include mitochondrial transcription factor A and cytochrome C.RAMPs of the central nervous system are an emerging area of neuroimmunology with very high translational potential since some of these molecules have already been used in preclinical and clinical studies as candidate therapeutic agents for inflammatory conditions,such as multiple sclerosis and rheumatoid arthritis.The therapeutic potential of DAMP antagonists and neutralizing antibodies in central nervous system neuroinflammatory diseases is al展开更多
Ischemic brain injury causes neuronal death and inflammation.Inflammation activates protein-tyrosine phosphatase 1B(PTP1B).Here,we tested the significance of PTP1B activation in glutamatergic projection neurons on fun...Ischemic brain injury causes neuronal death and inflammation.Inflammation activates protein-tyrosine phosphatase 1B(PTP1B).Here,we tested the significance of PTP1B activation in glutamatergic projection neurons on functional recovery in two models of stroke:by photothrombosis,focal ischemic lesions were induced in the sensorimotor cortex(SM stroke)or in the peri-prefrontal cortex(peri-PFC stroke).Elevated PTP1B expression was detected at 4 days and up to 6 weeks after stroke.While ablation of PTP1B in neurons of neuronal knockout(NKO)mice had no effect on the volume or resorption of ischemic lesions,markedly different effects on functional recovery were observed.SM stroke caused severe sensory and motor deficits(adhesive removal test)in wild type and NKO mice at 4 days,but NKO mice showed drastically improved sensory and motor functional recovery at 8 days.In addition,peri-PFC stroke caused anxiety-like behaviors(elevated plus maze and open field tests),and depression-like behaviors(forced swimming and tail suspension tests)in wild type mice 9 and 28 days after stroke,respectively,with minimal effect on sensory and motor function.Peri-PFC stroke-induced affective disorders were associated with fewer active(FosB+)neurons in the PFC and nucleus accumbens but more FosB+neurons in the basolateral amygdala,compared to sham-operated mice.In contrast,mice with neuronal ablation of PTP1B were protected from anxiety-like and depression-like behaviors and showed no change in FosB+neurons after peri-PFC stroke.Taken together,our study identifies neuronal PTP1B as a key component that hinders sensory and motor functional recovery and also contributes to the development of anxiety-like and depression-like behaviors after stroke.Thus,PTP1B may represent a novel therapeutic target to improve stroke recovery.All procedures for animal use were approved by the Animal Care and Use Committee of the University of Ottawa Animal Care and Veterinary Service(protocol 1806)on July 27,2018.展开更多
Previous studies have shown that Ninjurin-1 participates in cell trafficking and axonal growth following central and peripheral nervous system neuroinflammation.But its precise roles in these processes and involvement...Previous studies have shown that Ninjurin-1 participates in cell trafficking and axonal growth following central and peripheral nervous system neuroinflammation.But its precise roles in these processes and involvement in spinal cord injury pathophysiology remain unclear.Western blot assay revealed that Ninjurin-1 levels in rats with spinal cord injury exhibited an upregulation until day 4 post-injury and slightly decreased thereafter compared with sham controls.Immunohistochemistry analysis revealed that Ninjurin-1 immunoreactivity in rats with spinal cord injury sharply increased on days 1 and 4 post-injury and slightly decreased on days 7 and 21 post-injury compared with sham controls.Ninjurin-1 immunostaining was weak in vascular endothelial cells, ependymal cells, and some glial cells in sham controls while it was relatively strong in macrophages, microglia, and reactive astrocytes.These findings suggest that a variety of cells, including vascular endothelial cells, macrophages, and microglia, secrete Ninjurin-1 and they participate in the pathophysiology of compression-induced spinal cord injury.All experimental procedures were approved by the Care and Use of Laboratory Animals of Jeju National University(approval No.2018-0029) on July 6, 2018.展开更多
Traumatic brain injury(TBI)is a major cause of mortality and morbidity in the pediatric population.With advances in medical care,the mortality rate of pediatric TBI has declined.However,more children and adolescents a...Traumatic brain injury(TBI)is a major cause of mortality and morbidity in the pediatric population.With advances in medical care,the mortality rate of pediatric TBI has declined.However,more children and adolescents are living with TBI-related cognitive and emotional impairments,which negatively affects the quality of their life.Adult hippocampal neurogenesis plays an important role in cognition and mood regulation.Alterations in adult hippocampal neurogenesis are associated with a variety of neurological and neurodegenerative diseases,including TBI.Promoting endogenous hippocampal neurogenesis after TBI merits significant attention.However,TBI affects the function of neural stem/progenitor cells in the dentate gyrus of hippocampus,which results in aberrant migration and impaired dendrite development of adult-born neurons.Therefore,a better understanding of adult hippocampal neurogenesis after TBI can facilitate a more successful neuro-restoration of damage in immature brains.Secondary injuries,such as neuroinflammation and oxidative stress,exert a significant impact on hippocampal neurogenesis.Currently,a variety of therapeutic approaches have been proposed for ameliorating secondary TBI injuries.In this review,we discuss the uniqueness of pediatric TBI,adult hippocampal neurogenesis after pediatric TBI,and current efforts that promote neuroprotection to the developing brains,which can be leveraged to facilitate neuroregeneration.展开更多
Previous studies have shown that Lycium barbarum polysaccharide,the main active component of Lycium barbarum,exhibits antiinflammatory and antioxidant effects in treating neurological diseases.However,the therapeutic ...Previous studies have shown that Lycium barbarum polysaccharide,the main active component of Lycium barbarum,exhibits antiinflammatory and antioxidant effects in treating neurological diseases.However,the therapeutic action of Lycium barbarum polysaccharide on depression has not been studied.In this investigation,we established mouse models of depression using aversive stimuli including exposure to fox urine,air puff and foot shock and physical restraint.Concurrently,we administered 5 mg/kg per day Lycium barbarum polysaccharide-glycoprotein to each mouse intragastrically for the 28 days.Our results showed that long-term exposure to aversive stimuli significantly enhanced depressive-like behavior evaluated by the sucrose preference test and the forced swimming test and increased anxietylike behaviors evaluated using the open field test.In addition,aversive stimuli-induced depressed mice exhibited aberrant neuronal activity in the lateral habenula.Importantly,concurrent Lycium barbarum polysaccharide-glycoprotein treatment significantly reduced these changes.These findings suggest that Lycium barbarum polysaccharide-glycoprotein is a potential preventative intervention for depression and may act by preventing aberrant neuronal activity and microglial activation in the lateral habenula.The study was approved by the Jinan University Institutional Animal Care and Use Committee(approval No.20170301003)on March 1,2017.展开更多
Astrocytes are integral components of the central nervous system,where they are involved in numerous functions critical for neuronal development and functioning,including maintenance of blood-brain barrier,formation o...Astrocytes are integral components of the central nervous system,where they are involved in numerous functions critical for neuronal development and functioning,including maintenance of blood-brain barrier,formation of synapses,supporting neurons with nutrients and trophic factors,and protecting them from injury.These roles are markedly affected in the course of chronic neurodegenerative disorders,often before the onset of the disease.In this review,we summarize the recent findings supporting the hypothesis that astrocytes play a fundamental role in the processes contributing to neurodegeneration.We focus onα-synucleinopathies and tauopathies as the most common neurodegenerative diseases.The mechanisms implicated in the development and progression of these disorders appear not to be exclusively neuronal,but are often related to the astrocytic-neuronal integrity and the response of astrocytes to the altered microglial function.A profound understanding of the multifaceted functions of astrocytes and identification of their communication pathways with neurons and microglia in health and in the disease is of critical significance for the development of novel mechanism-based therapies against neurodegenerative disorders.展开更多
Several studies have confirmed that microglia are involved in neuropathic pain.Inhibition of guanosine-5′-triphosphate cyclohydrolase 1(GTPCH1)can reduce the inflammation of microglia.However,the precise mechanism by...Several studies have confirmed that microglia are involved in neuropathic pain.Inhibition of guanosine-5′-triphosphate cyclohydrolase 1(GTPCH1)can reduce the inflammation of microglia.However,the precise mechanism by which GTPCH1 regulates neuropathic pain remains unclear.In this study,BV2 microglia were transfected with adenovirus to knockdown GTPCH1 expression.High throughput sequencing analysis revealed that the mitogen-activated protein kinase(MAPK)related pathways and proteins were the most significantly downregulated molecular function.Co-expression network analysis of Mapk14 mRNA and five long noncoding RNAs(lnc RNAs)revealed their correlation.Quantitative reverse transcription-polymerase chain reaction revealed that among five lnc RNAs,ENSMUST00000205634,ENSMUST00000218450 and ENSMUST00000156079 were related to the downregulation of Mapk14 mRNA expression.These provide some new potential targets for the involvement of GTPCH1 in neuropathic pain.This study is the first to note the differential expression of lnc RNAs and mRNA in GTPCH1 knockdown BV2 microglia.Findings from this study reveal the mechanism by which GTPCH1 activates microglia and provide new potential targets for microglial activation in neuropathic pain.展开更多
A major feature of neurodegeneration is disruption of central nervous system homeostasis,during which microglia play diverse roles.In the central nervous system,microglia serve as the first line of immune defense and ...A major feature of neurodegeneration is disruption of central nervous system homeostasis,during which microglia play diverse roles.In the central nervous system,microglia serve as the first line of immune defense and function in synapse pruning,injury repair,homeostasis maintenance,and regulation of brain development through scavenging and phagocytosis.Under pathological conditions or various stimulations,microglia proliferate,aggregate,and undergo a variety of changes in cell morphology,immunophenotype,and function.This review presents the features of microglia,especially their diversity and ability to change dynamically,and reinterprets their role as sensors for multiple stimulations and as effectors for brain aging and neurodegeneration.This review also summarizes some therapeutic approaches for neurodegenerative diseases that target microglia.展开更多
The discovery that new neurons are produced in some regions of the adult mammalian brain is a paradigm-shift in neuroscience research.These new-born cells are produced from neuroprogenitors mainly in the subventricula...The discovery that new neurons are produced in some regions of the adult mammalian brain is a paradigm-shift in neuroscience research.These new-born cells are produced from neuroprogenitors mainly in the subventricular zone at the margin of the lateral ventricle,subgranular zone in the hippocampal dentate gyrus and in the striatum,a component of the basal ganglia,even in humans.In the human hippocampus,neuroblasts are produced even in elderlies.The regulation of adult neurogenesis is a complex phenomenon involving a multitude of molecules,neurotransmitters and soluble factors released by different sources including glial cells.Microglia,the resident macrophages of the central nervous system,are considered to play an important role on the regulation of adult neurogenesis both in physiological and pathological conditions.Following stroke and other acute neural disorders,there is an increase in the numbers of neuroblast production in the neurogenic niches.Microglial activation is believed to display both beneficial and detrimental role on adult neurogenesis after stroke,depending on the activation level and brain location.In this article,we review the scientific evidence addressing the role of microglial activation on adult neurogenesis after ischemia.A comprehensive understanding of the microglial role after stroke and other neural disorders it is an important step for development of future therapies based on manipulation of adult neurogenesis.展开更多
基金supported in part by a Grant-in-Aid for Scientific Research (B)(17H03988 to RK) from JSPS and JST PRESTO (JPMJPR18H4 to RK)。
文摘Microglia are brain-resident immune cells that contribute to the maintenance of brain homeostasis.In the epileptic brain, microglia show various activation phenotypes depending on the stage of epileptogenesis.Therefore, it remains unclear whether microglial activation acts in a pro-epileptic or anti-epileptic manner.In mesial temporal lobe epilepsy, one of the most common form of epilepsies, microglia exhibit at least two distinct morphologies, amoeboid shape and ramified shape.Amoeboid microglia are often found in sclerotic area, whereas ramified microglia are mainly found in non-sclerotic area;however, it remains unclear whether these structurally distinct microglia share separate roles in the epileptic brain.Here, we review the roles of the two distinct microglial phenotypes, focusing on their pro-and anti-epileptic roles in terms of inflammatory response, regulation of neurogenesis and microglia-neuron interaction.
基金supported by Scottish Rugby Union funding to WH and DSthe NRB PhD scholarship from the International Spinal Rsesarch Trust to AGBa Hot-Start Scholarship from the University of aberdeen to DD。
文摘Millions of people worldwide are affected by traumatic spinal cord injury,which usually results in permanent sensorimotor disability.Damage to the spinal cord leads to a series of detrimental events including ischaemia,haemorrhage and neuroinflammation,which over time result in further neural tissue loss.Eventually,at chronic stages of traumatic spinal cord injury,the formation of a glial scar,cystic cavitation and the presence of numerous inhibitory molecules act as physical and chemical barriers to axonal regrowth.This is further hindered by a lack of intrinsic regrowth ability of adult neurons in the central nervous system.The intracellular signalling molecule,cyclic adenosine 3′,5′-monophosphate(cAMP),is known to play many important roles in the central nervous system,and elevating its levels as shown to improve axonal regeneration outcomes following traumatic spinal cord injury in animal models.However,therapies directly targeting cAMP have not found their way into the clinic,as cAMP is ubiquitously present in all cell types and its manipulation may have additional deleterious effects.A downstream effector of cAMP,exchange protein directly activated by cAMP 2(Epac2),is mainly expressed in the adult central nervous system,and its activation has been shown to mediate the positive effects of cAMP on axonal guidance and regeneration.Recently,using ex vivo modelling of traumatic spinal cord injury,Epac2 activation was found to profoundly modulate the post-lesion environment,such as decreasing the activation of astrocytes and microglia.Pilot data with Epac2 activation also suggested functional improvement assessed by in vivo models of traumatic spinal cord injury.Therefore,targeting Epac2 in traumatic spinal cord injury could represent a novel strategy in traumatic spinal cord injury repair,and future work is needed to fully establish its therapeutic potential.
基金This work was financially supported by the Department of Anesthesiology and Critical Care,Medical Center-University of Freiburg,GermanyThe article processing charge was funded by the Baden-Württemberg Ministry of Science,Research and Art and the University of Freiburg in the funding programme Open Access Publishing.
文摘We previously found that argon exerts its neuroprotective effect in part by inhibition of the toll-like receptors(TLR)2 and 4.The downstream transcription factors signal transducer and activator of transcription 3(STAT3)and nuclear factor kappa B(NF-κB)are also affected by argon and may play a role in neuroprotection.It also has been demonstrated that argon treatment could mitigate brain damage,reduce excessive microglial activation,and subsequently attenuate brain inflammation.Despite intensive research,the further exact mechanism remains unclear.In this study,human neuroblastoma cells were damaged in vitro with rotenone over a period of 4 hours(to mimic cerebral ischemia and reperfusion damage),followed by a 2-hour post-conditioning with argon(75%).In a separate in vivo experiment,retinal ischemia/reperfusion injury was induced in rats by increasing intraocular pressure for 1 hour.Upon reperfusion,argon was administered by inhalation for 2 hours.Argon reduced the binding of the transcription factors signal transducer and activator of transcription 3,nuclear factor kappa B,activator protein 1,and nuclear factor erythroid 2-related factor 2,which are involved in regulation of neuronal damage.Flow cytometry analysis showed that argon downregulated the Fas ligand.Some transcription factors were regulated by toll-like receptors;therefore,their effects could be eliminated,at least in part,by the TLR2 and TLR4 inhibitor oxidized phospholipid 1-palmitoyl-2-arachidonoyl-sn-glycero-3-phosphorylcholine(OxPAPC).Argon treatment reduced microglial activation after retinal ischemia/reperfusion injury.Subsequent quantitative polymerase chain reaction analysis revealed a reduction in the pro-inflammatory cytokines interleukin(IL-1α),IL-1β,IL-6,tumor necrosis factorα,and inducible nitric oxide synthase.Our results suggest that argon reduced the extent of inflammation in retinal neurons after ischemia/reperfusion injury by suppression of transcription factors crucial for microglial activation.Argon has no known side effects o
基金supported by the National Natural Science Foundation of China,Nos.81872845(to ML),81771625(to XF)the Natural Science Foundation of Jiangsu Province of China,No.BK20180207(to ML)+4 种基金Jiangsu Provincial Medical Youth Talent of China,No.QNRC2016762(to ML)the Pediatric Clinical Center of Suzhou City of China,No.Szzx201504(to XF)Postgraduate Research&Practice Innovation Program of Jiangsu Province of China,No.KYCX19_1998(to LLT)Jiangsu Government Scholarship for Overseas Studies of China,No.JS-2017-127(to ML)the Fifth Batch of Gusu Health Talent Plan of China(to ML).
文摘Our previous studies have demonstrated that TP53-induced glycolysis and apoptosis regulator(TIGAR)can protect neurons after cerebral ischemia/reperfusion.However,the role of TIGAR in neonatal hypoxic-ischemic brain damage(HIBD)remains unknown.In the present study,7-day-old Sprague-Dawley rat models of HIBD were established by permanent occlusion of the left common carotid artery followed by 2-hour hypoxia.At 6 days before induction of HIBD,a lentiviral vector containing short hairpin RNA of either TIGAR or gasdermin D(LV-sh_TIGAR or LV-sh_GSDMD)was injected into the left lateral ventricle and striatum.Highly aggressively proliferating immortalized(HAPI)microglial cell models of in vitro HIBD were established by 2-hour oxygen/glucose deprivation followed by 24-hour reoxygenation.Three days before in vitro HIBD induction,HAPI microglial cells were transfected with LV-sh_TIGAR or LV-sh_GSDMD.Our results showed that TIGAR expression was increased in the neonatal rat cortex after HIBD and in HAPI microglial cells after oxygen/glucose deprivation/reoxygenation.Lentivirusmediated TIGAR knockdown in rats markedly worsened pyroptosis and brain damage after hypoxia/ischemia in vivo and in vitro.Application of exogenous nicotinamide adenine dinucleotide phosphate(NADPH)increased the NADPH level and the glutathione/oxidized glutathione ratio and decreased reactive oxygen species levels in HAPI microglial cells after oxygen/glucose deprivation/reoxygenation.Additionally,exogenous NADPH blocked the effects of TIGAR knockdown in neonatal HIBD in vivo and in vitro.These findings show that TIGAR can inhibit microglial pyroptosis and play a protective role in neonatal HIBD.The study was approved by the Animal Ethics Committee of Soochow University of China(approval No.2017LW003)in 2017.
基金funded by the Italian Ministry of Education,University and Research(MIUR)Program“Departments of Excellence 2018-2022”,AGING and FOHN Projects,Fondazione Cariplo 2019-3277 and Associazione Ricerca sul Cancro(IG 20714,AIRC,Milano).
文摘Osteopontin is a broadly expressed pleiotropic protein,and is attracting increased attention because of its role in the pathophysiology of several inflammatory,degenerative,autoimmune,and oncologic diseases.In fact,in the last decade,several studies have shown that osteopontin contributes to tissue damage not only by recruiting harmful inflammatory cells to the site of lesion,but also increasing their survival.The detrimental role of osteopontin has been indeed well documented in the context of different neurological conditions(i.e.,multiple sclerosis,Parkinson’s,and Alzheimer’s diseases).Intriguingly,recent findings show that osteopontin is involved not only in promoting tissue damage(the Yin),but also in repair/regenerative mechanisms(the Yang),mostly triggered by the inflammatory response.These two apparently discordant roles are partly related to the presence of different functional domains in the osteopontin molecule,which are exposed after thrombin or metalloproteases cleavages.Such functional domains may in turn activate intracellular signaling pathways and mediate cell-cell and cell-matrix interactions.This review describes the current knowledge on the Yin and Yang features of osteopontin in nervous system diseases.Understanding the mechanisms behind the Yin/Yang would be relevant to develop highly specific tools targeting this multifunctional protein.
基金This work was supported by Merk-Serono,TargetBrain(EU Framework 7 Project,No.HEALTH-F2–2012-279017 to GM)Fondazione Italiana Sclerosi Multipla(FISM,No.grant 2016/R/14 to CF)cofinanced with the 5 per mille public funding.
文摘Microglia,the tissue resident macrophages of the brain,are increasingly recognized as key players for central nervous system development and homeostasis.They are long-lived cells deriving from a transient wave of yolk-sac derived erythro-myeloid progenitors early in development.Their unique ontology has prompted the search for specific markers to be used for their selective investigation and manipulation.The first generation of genomewide expression studies has provided a bundle of transcripts(such as Olfml3,Fcrls,Tmem119,P2ry12,Gpr34,and Siglech)useful to distinguish microglia from peripheral macrophages.However,more recent reports have revealed that microglial phenotype is constantly shaped by the microenvironment in a time-,and context-dependent manner.In this article,we review data that provide additional pieces to this complex scenario and show the existence of unexpected phenotypic convergence between microglia and peripheral macrophages at certain developmental stages and under pathological conditions.These observations suggest that the two cell types act synergically boosting their mutual activities depending on the microenvironment.This novel information about the biology of microglia and peripheral macrophages sheds new light about their therapeutic potential for neuroinflammatory and neurodegenerative diseases.
基金supported by a grant from the Forschungskommission der Medizinischen Fakult?t, Albert-Ludwigs-Universit?t Freiburg(SCHI1123/17, to MAS)。
文摘Infusion of the colloid hydroxyethylstarch has been used for volume substitution to maintain hemodynamics and microcirculation after e.g., severe blood loss.In the last decade it was revealed that hydroxyethylstarch can aggravate acute kidney injury, especially in septic patients.Because of the serious risk for critically ill patients, the administration of hydroxyethylstarch was restricted for clinical use.Animal studies and recently published in vitro experiments showed that hydroxyethylstarch might exert protective effects on the blood-brain barrier.Since the prevention of blood-brain barrier disruption was shown to go along with the reduction of brain damage after several kinds of insults, we revisit the topic hydroxyethylstarch and discuss a possible niche for the application of hydroxyethylstarch in acute brain injury treatment.
基金supported by grants from the Natural Sciences and Engineering Research Council of Canada and the Jack Brown and Family Alzheimer's Disease Research Foundation。
文摘Sterile inflammatory processes are essential for the maintenance of central nervous system homeostasis,but they also contribute to various neurological disorders,including neurotrauma,stroke,and demyelinating or neurodegenerative diseases.Immune mechanisms in the central nervous system and periphery are regulated by a diverse group of endogenous proteins,which can be broadly divided into the pro-inflammatory damageassociated molecular patterns(DAMPs)and anti-inflammatory resolution-associated molecular patterns(RAMPs),even though there is notable overlap between the DAMPand RAMP-like activities for some of these molecules.Both groups of molecular patterns were initially described in peripheral immune processes and pathologies;however,it is now evident that at least some,if not all,of these immunomodulators also regulate neuroimmune processes and contribute to neuroinflammation in diverse central nervous system disorders.The review of recent literature demonstrates that studies on DAMPs and RAMPs of the central nervous system still lag behind the much broader research effort focused on their peripheral counterparts.Nevertheless,this review also reveals that over the last five years,significant advances have been made in our understanding of the neuroimmune functions of several well-established DAMPs,including high-mobility group box 1 protein and interleukin 33.Novel neuroimmune functions have been demonstrated for other DAMPs that previously were considered almost exclusively as peripheral immune regulators;they include mitochondrial transcription factor A and cytochrome C.RAMPs of the central nervous system are an emerging area of neuroimmunology with very high translational potential since some of these molecules have already been used in preclinical and clinical studies as candidate therapeutic agents for inflammatory conditions,such as multiple sclerosis and rheumatoid arthritis.The therapeutic potential of DAMP antagonists and neutralizing antibodies in central nervous system neuroinflammatory diseases is al
基金This work was supported by grants from the Heart and Stroke Foundation of Canada(Nos.G-13-0002596&G-18-0022157,to HHCNo.G-16-00014085,to AFRS)+2 种基金the Natural Science and Engineering Research Council of Canada(No.RGPIN/06212-2014,to HHC,No.RGPIN/2016-04985,to AFRS)the Canadian Institutes of Health Research(No.201610PJT,to HHC)HHC is also supported by a Mid-Career Investigator Award(No.7506)from the Heart and Stroke Foundation of Ontario.How to cite this article:Cruz SA。
文摘Ischemic brain injury causes neuronal death and inflammation.Inflammation activates protein-tyrosine phosphatase 1B(PTP1B).Here,we tested the significance of PTP1B activation in glutamatergic projection neurons on functional recovery in two models of stroke:by photothrombosis,focal ischemic lesions were induced in the sensorimotor cortex(SM stroke)or in the peri-prefrontal cortex(peri-PFC stroke).Elevated PTP1B expression was detected at 4 days and up to 6 weeks after stroke.While ablation of PTP1B in neurons of neuronal knockout(NKO)mice had no effect on the volume or resorption of ischemic lesions,markedly different effects on functional recovery were observed.SM stroke caused severe sensory and motor deficits(adhesive removal test)in wild type and NKO mice at 4 days,but NKO mice showed drastically improved sensory and motor functional recovery at 8 days.In addition,peri-PFC stroke caused anxiety-like behaviors(elevated plus maze and open field tests),and depression-like behaviors(forced swimming and tail suspension tests)in wild type mice 9 and 28 days after stroke,respectively,with minimal effect on sensory and motor function.Peri-PFC stroke-induced affective disorders were associated with fewer active(FosB+)neurons in the PFC and nucleus accumbens but more FosB+neurons in the basolateral amygdala,compared to sham-operated mice.In contrast,mice with neuronal ablation of PTP1B were protected from anxiety-like and depression-like behaviors and showed no change in FosB+neurons after peri-PFC stroke.Taken together,our study identifies neuronal PTP1B as a key component that hinders sensory and motor functional recovery and also contributes to the development of anxiety-like and depression-like behaviors after stroke.Thus,PTP1B may represent a novel therapeutic target to improve stroke recovery.All procedures for animal use were approved by the Animal Care and Use Committee of the University of Ottawa Animal Care and Veterinary Service(protocol 1806)on July 27,2018.
基金supported by the National Research Foundation of Korea (Grant No.NRF-2018R1D1A1B07050916)。
文摘Previous studies have shown that Ninjurin-1 participates in cell trafficking and axonal growth following central and peripheral nervous system neuroinflammation.But its precise roles in these processes and involvement in spinal cord injury pathophysiology remain unclear.Western blot assay revealed that Ninjurin-1 levels in rats with spinal cord injury exhibited an upregulation until day 4 post-injury and slightly decreased thereafter compared with sham controls.Immunohistochemistry analysis revealed that Ninjurin-1 immunoreactivity in rats with spinal cord injury sharply increased on days 1 and 4 post-injury and slightly decreased on days 7 and 21 post-injury compared with sham controls.Ninjurin-1 immunostaining was weak in vascular endothelial cells, ependymal cells, and some glial cells in sham controls while it was relatively strong in macrophages, microglia, and reactive astrocytes.These findings suggest that a variety of cells, including vascular endothelial cells, macrophages, and microglia, secrete Ninjurin-1 and they participate in the pathophysiology of compression-induced spinal cord injury.All experimental procedures were approved by the Care and Use of Laboratory Animals of Jeju National University(approval No.2018-0029) on July 6, 2018.
基金This work was supported by the Startup Grant for ZZ from the Department of Natural Sciences,University of Michigan-Dearborn and“CASL Faculty Summer Research Grant”for ZZ from Office of Research&Sponsored Programs,University of Michigan-Dearborn.
文摘Traumatic brain injury(TBI)is a major cause of mortality and morbidity in the pediatric population.With advances in medical care,the mortality rate of pediatric TBI has declined.However,more children and adolescents are living with TBI-related cognitive and emotional impairments,which negatively affects the quality of their life.Adult hippocampal neurogenesis plays an important role in cognition and mood regulation.Alterations in adult hippocampal neurogenesis are associated with a variety of neurological and neurodegenerative diseases,including TBI.Promoting endogenous hippocampal neurogenesis after TBI merits significant attention.However,TBI affects the function of neural stem/progenitor cells in the dentate gyrus of hippocampus,which results in aberrant migration and impaired dendrite development of adult-born neurons.Therefore,a better understanding of adult hippocampal neurogenesis after TBI can facilitate a more successful neuro-restoration of damage in immature brains.Secondary injuries,such as neuroinflammation and oxidative stress,exert a significant impact on hippocampal neurogenesis.Currently,a variety of therapeutic approaches have been proposed for ameliorating secondary TBI injuries.In this review,we discuss the uniqueness of pediatric TBI,adult hippocampal neurogenesis after pediatric TBI,and current efforts that promote neuroprotection to the developing brains,which can be leveraged to facilitate neuroregeneration.
基金supported by the National Natural Science Foundation of China,Nos.31900825(to SL),31922030(to CRR),31771170(to CRR)Science and Technology Program of Guangdong Province of China,No.2018B030334001(to CRR)+3 种基金Science and Techology of Guangzhou of China,No.202007030012(to CRR)Guangdong Special Support Program of China,No.2017TQ04R173(to CRR)Pearl River S&T Nova Program of Guangzhou Province of China,No.201806010198(to CRR)Outstanding Scholar Program of Guangzhou Regenerative Medicine and Health Guangdong Laboratory of China,No.2018GZR110102002(to KFS)。
文摘Previous studies have shown that Lycium barbarum polysaccharide,the main active component of Lycium barbarum,exhibits antiinflammatory and antioxidant effects in treating neurological diseases.However,the therapeutic action of Lycium barbarum polysaccharide on depression has not been studied.In this investigation,we established mouse models of depression using aversive stimuli including exposure to fox urine,air puff and foot shock and physical restraint.Concurrently,we administered 5 mg/kg per day Lycium barbarum polysaccharide-glycoprotein to each mouse intragastrically for the 28 days.Our results showed that long-term exposure to aversive stimuli significantly enhanced depressive-like behavior evaluated by the sucrose preference test and the forced swimming test and increased anxietylike behaviors evaluated using the open field test.In addition,aversive stimuli-induced depressed mice exhibited aberrant neuronal activity in the lateral habenula.Importantly,concurrent Lycium barbarum polysaccharide-glycoprotein treatment significantly reduced these changes.These findings suggest that Lycium barbarum polysaccharide-glycoprotein is a potential preventative intervention for depression and may act by preventing aberrant neuronal activity and microglial activation in the lateral habenula.The study was approved by the Jinan University Institutional Animal Care and Use Committee(approval No.20170301003)on March 1,2017.
基金statutory funds provided by the Polish Ministry of Science and Higher Education for Mossakowski Medical Research Centre Polish Academy of Sciences,Warsaw,Poland(9/2018,to LS)。
文摘Astrocytes are integral components of the central nervous system,where they are involved in numerous functions critical for neuronal development and functioning,including maintenance of blood-brain barrier,formation of synapses,supporting neurons with nutrients and trophic factors,and protecting them from injury.These roles are markedly affected in the course of chronic neurodegenerative disorders,often before the onset of the disease.In this review,we summarize the recent findings supporting the hypothesis that astrocytes play a fundamental role in the processes contributing to neurodegeneration.We focus onα-synucleinopathies and tauopathies as the most common neurodegenerative diseases.The mechanisms implicated in the development and progression of these disorders appear not to be exclusively neuronal,but are often related to the astrocytic-neuronal integrity and the response of astrocytes to the altered microglial function.A profound understanding of the multifaceted functions of astrocytes and identification of their communication pathways with neurons and microglia in health and in the disease is of critical significance for the development of novel mechanism-based therapies against neurodegenerative disorders.
基金supported by the National Natural Science Foundation of China,Nos.81572205 and 81974345(both to CYM)。
文摘Several studies have confirmed that microglia are involved in neuropathic pain.Inhibition of guanosine-5′-triphosphate cyclohydrolase 1(GTPCH1)can reduce the inflammation of microglia.However,the precise mechanism by which GTPCH1 regulates neuropathic pain remains unclear.In this study,BV2 microglia were transfected with adenovirus to knockdown GTPCH1 expression.High throughput sequencing analysis revealed that the mitogen-activated protein kinase(MAPK)related pathways and proteins were the most significantly downregulated molecular function.Co-expression network analysis of Mapk14 mRNA and five long noncoding RNAs(lnc RNAs)revealed their correlation.Quantitative reverse transcription-polymerase chain reaction revealed that among five lnc RNAs,ENSMUST00000205634,ENSMUST00000218450 and ENSMUST00000156079 were related to the downregulation of Mapk14 mRNA expression.These provide some new potential targets for the involvement of GTPCH1 in neuropathic pain.This study is the first to note the differential expression of lnc RNAs and mRNA in GTPCH1 knockdown BV2 microglia.Findings from this study reveal the mechanism by which GTPCH1 activates microglia and provide new potential targets for microglial activation in neuropathic pain.
基金the National Natural Science Foundation of China,Nos.81401279(to ZYY),81873740(to ZYY)China International Medical Exchange Fund,No.2019-anesthesia-14(to ZYY)+3 种基金the Natural Science Foundation of Shanghai of China,No.18ZR1443100(to ZYY)Wuxin Project of International Peace Maternity and Child Health Hospital Shanghai Jiao Tong University School of Medicine of China,No.2018-38(to ZYY)Shanghai Jiao Tong University School of Medicine,Innovation Center of Translational Medicine Collaboration of China,No.TM201729(to ZYY)the 12th Undergraduate Training Programs for Innovation of Shanghai Jiao Tong University School of Medicine of China,No.1218201(to YX,MZJ and WLJ)。
文摘A major feature of neurodegeneration is disruption of central nervous system homeostasis,during which microglia play diverse roles.In the central nervous system,microglia serve as the first line of immune defense and function in synapse pruning,injury repair,homeostasis maintenance,and regulation of brain development through scavenging and phagocytosis.Under pathological conditions or various stimulations,microglia proliferate,aggregate,and undergo a variety of changes in cell morphology,immunophenotype,and function.This review presents the features of microglia,especially their diversity and ability to change dynamically,and reinterprets their role as sensors for multiple stimulations and as effectors for brain aging and neurodegeneration.This review also summarizes some therapeutic approaches for neurodegenerative diseases that target microglia.
基金supported by the Brazilian National Council for Scientific Research。
文摘The discovery that new neurons are produced in some regions of the adult mammalian brain is a paradigm-shift in neuroscience research.These new-born cells are produced from neuroprogenitors mainly in the subventricular zone at the margin of the lateral ventricle,subgranular zone in the hippocampal dentate gyrus and in the striatum,a component of the basal ganglia,even in humans.In the human hippocampus,neuroblasts are produced even in elderlies.The regulation of adult neurogenesis is a complex phenomenon involving a multitude of molecules,neurotransmitters and soluble factors released by different sources including glial cells.Microglia,the resident macrophages of the central nervous system,are considered to play an important role on the regulation of adult neurogenesis both in physiological and pathological conditions.Following stroke and other acute neural disorders,there is an increase in the numbers of neuroblast production in the neurogenic niches.Microglial activation is believed to display both beneficial and detrimental role on adult neurogenesis after stroke,depending on the activation level and brain location.In this article,we review the scientific evidence addressing the role of microglial activation on adult neurogenesis after ischemia.A comprehensive understanding of the microglial role after stroke and other neural disorders it is an important step for development of future therapies based on manipulation of adult neurogenesis.