Major depressive disorder(MDD)is a prevalent psychiatric disease that involves malfunctions of different cell types in the brain.Accumulating studies started to reveal that microglia,the primary resident immune cells,...Major depressive disorder(MDD)is a prevalent psychiatric disease that involves malfunctions of different cell types in the brain.Accumulating studies started to reveal that microglia,the primary resident immune cells,play an important role in the development and progression of depression.Microglia respond to stress-triggered neuroinflammation,and through the release of proinflammatory cytokines and their metabolic products,microglia may modulate the function of neurons and astrocytes to regulate depression.In this review,we focused on the role of microglia in the etiology of depression.We discussed the dynamic states of microglia;the correlative and causal evidence of microglial abnormalities in depression;possible mechanisms of how microglia sense depression-related stress and modulate depression state;and how antidepressive therapies affect microglia.Understanding the role of microglia in depression may shed light on developing new treatment strategies to fight against this devastating mental illness.展开更多
Postoperative cognitive dysfunction （POCD） is a multifactorial process with a huge number of predisposing, causal, and precipitating factors. In this scenario, the neuroinflammation and the microglial activation pla...Postoperative cognitive dysfunction （POCD） is a multifactorial process with a huge number of predisposing, causal, and precipitating factors. In this scenario, the neuroinflammation and the microglial activation play a pivotal role by triggering and amplifying a complex cascade involving the immuno-hormonal acti- vation, the micro circle alterations, the hippocampal oxidative stress activation and, finally, an increased blood-brain barrier＇s permeability. While the role of anesthetics in the POCD＇s genesis in humans is debated, a huge number of preclinical studies have been conducted on the topic and many mechanisms have been proposed to explain the potential neurodegenerative effects of general anesthetics. Probably, the problem concerns on what we are searching for and how we are searching and, surprisingly, preclinical studies showed that anesthetics may also manifest neuroprotective properties. The aim of this paper is to offer an overview on the potential impact of general anesthetics on POCD. Mechanisms of hippocampal and extra-hippocampal dysfunction due to neuroinflammation are discussed, whereas further research perspectives are also given.展开更多
Viral encephalitis is a devastating disease with high mortality,and survivors often suffer from severe neurological complications.Microglia are innate immune cells of the central nervous system(CNS)parenchyma whose tu...Viral encephalitis is a devastating disease with high mortality,and survivors often suffer from severe neurological complications.Microglia are innate immune cells of the central nervous system(CNS)parenchyma whose turnover is reliant on local proliferation.Microglia express a diverse range of proteins,which allows them to continuously sense the environment and quickly react to changes.Under inflammatory conditions such as CNS viral infection,microglia promote innate and adaptive immune responses to protect the host.However,during viral infection,a dysregulated microglia-T-cell interplay may result in altered phagocytosis of neuronal synapses by microglia that causes neurocognitive impairment.In this review,we summarize the current knowledge on the role of microglia in viral encephalitis,propose questions to be answered in the future and suggest possible therapeutic targets.展开更多
The 18 kDa translocator protein(TSPO),previously known as the peripheral benzodiazepine receptor,is predominately localized to the outer mitochondrial membrane in steroidogenic cells.Brain TSPO expression is relativel...The 18 kDa translocator protein(TSPO),previously known as the peripheral benzodiazepine receptor,is predominately localized to the outer mitochondrial membrane in steroidogenic cells.Brain TSPO expression is relatively low under physiological conditions,but is upregulated in response to glial cell activation.As the primary index of neuroinflammation,TSPO is implicated in the pathogenesis and progression of numerous neuropsychiatric disorders and neurodegenerative diseases,including Alzheimer’s disease(AD),amyotrophic lateral sclerosis(ALS),Parkinson’s disease(PD),multiple sclerosis(MS),major depressive disorder(MDD)and obsessive compulsive disorder(OCD).In this context,numerous TSPO-targeted positron emission tomography(PET)tracers have been developed.Among them,several radioligands have advanced to clinical research studies.In this review,we will overview the recent development of TSPO PET tracers,focusing on the radioligand design,radioisotope labeling,pharmacokinetics,and PET imaging evaluation.Additionally,we will consider current limitations,as well as translational potential for future application of TSPO radiopharmaceuticals.This review aims to not only present the challenges in current TSPO PET imaging,but to also provide a new perspective on TSPO targeted PET tracer discovery efforts.Addressing these challenges will facilitate the translation of TSPO in clinical studies of neuroinflammation associated with central nervous system diseases.展开更多
Fluoxetine, an anti-depressant drug, has recently been shown to provide neuroprotection in central nervous system injury, but its roles in subarachnoid hemorrhage(SAH) remain unclear. In this study, we aimed to evalua...Fluoxetine, an anti-depressant drug, has recently been shown to provide neuroprotection in central nervous system injury, but its roles in subarachnoid hemorrhage(SAH) remain unclear. In this study, we aimed to evaluate whether fluoxetine attenuates early brain injury(EBI) after SAH. We demonstrated that intraperitoneal injection of fluoxetine(10 mg/kg per day) significantly attenuated brain edema and blood-brain barrier(BBB) disruption, microglial activation, and neuronal apoptosis in EBI after experimental SAH, as evidenced by the reduction of brain water content and Evans blue dye extravasation, prevention of disruption of the tight junction proteins zonula occludens-1, claudin-5, and occludin, a decrease of cells staining positive for Iba-1, ED-1, and TUNEL and a decline in IL-1 b, IL-6, TNF-a, MDA, 3-nitrotyrosine, and 8-OHDG levels. Moreover, fluoxetine significantly improved the neurological deficits of EBI and long-term sensorimotor behavioral deficits following SAH in a rat model. These results indicated that fluoxetine has a neuroprotective effect after experimental SAH.展开更多
Background:Neuron-microglia communication plays a crucial role in the motor neurons(MNs)death in amyotrophic lateral sclerosis(ALS).Neurons can express chemokine(C-X3-C motif)ligand 1(CX3CL1),which mediates microglial...Background:Neuron-microglia communication plays a crucial role in the motor neurons(MNs)death in amyotrophic lateral sclerosis(ALS).Neurons can express chemokine(C-X3-C motif)ligand 1(CX3CL1),which mediates microglial activation via interacting with its sole receptor CX3CR1 in microglia.In the present study,we aimed to investigate the dynamic changes of CX3CL1/CX3CR1 axis during microglial activation and MNs loss in SOD1G93A mouse model of ALS.Methods:qPCR,western blot and immunofluorescent staining were used to examine the mRNA and protein levels and localization of CX3CL1/CX3CR1 in the anterior horn region of spinal cord in both SOD1G93A mice and their agematched wild type(WT)littermates at 40,60,90 and 120 days of age.The M1/M2 microglial activation in the spinal cord tissues of SOD1G93A mice and WT mice were evaluated by immunofluorescent staining of M1/M2 markers and further confirmed by qPCR analysis of M1/M2-related cytokines.Results:The immunofluorescent staining revealed that CX3CL1 was predominately expressed in MNs,while CX3CR1 was highly expressed in microglia in the anterior horn region of spinal cord.Compared with age-matched WT mice,CX3CL1 mRNA level was elevated at 40 days but decreased at 90 and 120 days in the anterior horn region of spinal cords in ALS mice.Consistently,CX3CR1 mRNA level was increased at 90 and 120 days.Western blot assay further confirmed the dynamic changes of CX3CL1/CX3CR1 axis in ALS mice.Additionally,the levels of M1/M2 markers of microglia and their related cytokines in the anterior horn region of spinal cord in ALS mice were increased at 90 and 120 days.Moreover,while M1-related cytokines in ALS mice were persistently increased at 120 days,the upregulated M2-related cytokines started to decline at 120 days,suggesting an altered microglial activation.Conclusions:Our data revealed the dynamic changes of CX3CL1/CX3CR1 axis and an imbalanced M1/M2 microglial activation during ALS pathological progression.These findings may help identify potential molecular targets for ALS th展开更多
Microglia,which are the resident macrophages of the central nervous system,are an important part of the inflammatory response that occurs after cerebral ischemia.Vav guanine nucleotide exchange factor 1(Vav1) is a gua...Microglia,which are the resident macrophages of the central nervous system,are an important part of the inflammatory response that occurs after cerebral ischemia.Vav guanine nucleotide exchange factor 1(Vav1) is a guanine nucleotide exchange factor that is related to microglial activation.However,how Vav1 participates in the inflammato ry response after cerebral ischemia/reperfusion inj ury remains unclea r.In this study,we subjected rats to occlusion and repe rfusion of the middle cerebral artery and subjected the BV-2 mic roglia cell line to oxygen-glucose deprivatio n/reoxygenation to mimic cerebral ischemia/repe rfusion in vivo and in vitro,respectively.We found that Vav1 levels were increased in the brain tissue of rats subjected to occlusion and reperfusion of the middle cerebral arte ry and in BV-2 cells subjected to oxygen-glucose deprivation/reoxygenation.Silencing Vav1 reduced the cerebral infarct volume and brain water content,inhibited neuronal loss and apoptosis in the ischemic penumbra,and im p roved neurological function in rats subjected to occlusion and repe rfusion of the middle cerebral artery.Further analysis showed that Vav1 was almost exclusively localized to microglia and that Vav1 downregulation inhibited microglial activation and the NOD-like receptor pyrin 3(NLRP3) inflammasome in the ischemic penumbra,as well as the expression of inflammato ry facto rs.In addition,Vov1 knoc kdown decreased the inflammatory response exhibited by BV-2 cells after oxygen-glucose deprivation/reoxyge nation.Taken together,these findings show that silencing Vav1 attenuates inflammation and neuronal apoptosis in rats subjected to cerebral ischemia/repe rfusion through inhibiting the activation of mic roglia and NLRP3 inflammasome.展开更多
The accumulation of pathological α-synuclein(α-syn)in the central nervous system and the progressive loss of dopaminergic neurons in the substantia nigra pars compacta are the neuropathological features of Parkinson...The accumulation of pathological α-synuclein(α-syn)in the central nervous system and the progressive loss of dopaminergic neurons in the substantia nigra pars compacta are the neuropathological features of Parkinson's disease(PD).Recently,the findings of prion-like transmission of α-syn pathology have expanded our understanding of the region-specific distribution ofα-syn in PD patients.Accumulating evidence suggests that α-syn aggregates are released from neurons and endocytosed by glial cells,which contributes to the clearance of α-syn.However,the activation of glial cells by α-syn species produces pro-inflammatory factors that decrease the uptake of α-syn aggregates by glial cells and promote the transmission of α-syn between neurons,which promotes the spread of α-syn pathology.In this article,we provide an overview of current knowledge on the role of glia and α-syn pathology in PD pathogenesis,highlighting the relationships between glial responses and the spread ofα-syn pathology.展开更多
Aging brain becomes susceptible to neurodegenerative diseases due to the shifting of microglia and astrocyte phenotypes to an active“pro-inflammatory”state,causing chronic low-grade neuroinflammation.Despite the fac...Aging brain becomes susceptible to neurodegenerative diseases due to the shifting of microglia and astrocyte phenotypes to an active“pro-inflammatory”state,causing chronic low-grade neuroinflammation.Despite the fact that the role of neuroinflammation during aging has been extensively studied in recent years,the underlying causes remain unclear.The identification of relevant proteins and understanding their potential roles in neuroinflammation can help explain their potential of becoming biomarkers in the aging brain and as drug targets for prevention and treatment.This will eventually reduce the chances of developing neurodegenerative diseases and promote healthier lives in the elderly.In this review,we have summarized the morphological and cellular changes in the aging brain,the effects of age-related neuroinflammation,and the potential role of cofilin-1 during neuroinflammation.We also discuss other factors contributing to brain aging and neuroinflammation.展开更多
Traumatic brain injury induces secondary injury that contributes to neuroinflammation, neuronal loss, and neurological dysfunction. One important injury mechanism is cell cycle activation which causes neuronal apoptos...Traumatic brain injury induces secondary injury that contributes to neuroinflammation, neuronal loss, and neurological dysfunction. One important injury mechanism is cell cycle activation which causes neuronal apoptosis and glial activation. The neuroprotective effects of both non-selective （Flavopiridol） and selective （Roscovitine and CR-8） cyclin-dependent kinase inhibitors have been shown across mukiple experimental traumatic brain injury models and species. Cyclin-depen- dent kinaseinhibitors, administered as a single systemic dose up to 24 hours after traumatic brain injury, provide strong neuroprotection-reducing neuronal cell death, neuroinflammation and neurological dysfunction. Given their effectiveness and long therapeutic window, cyclin-dependent kinase inhibitors appear to be promising candidates for clinical traumatic brain injury trials.展开更多
目的探究丁酸钠对坏死性小肠结肠炎(necrotizing enterocolitis,NEC)小鼠脑损伤的影响。方法137只3 d龄C57BL/6新生鼠分为:对照组(CON组,n=40,不与母鼠分离)、NEC+PBS灌胃组(NP组,n=57)和NEC+丁酸钠灌胃组(NB组,n=40),NP组和NB组分别从...目的探究丁酸钠对坏死性小肠结肠炎(necrotizing enterocolitis,NEC)小鼠脑损伤的影响。方法137只3 d龄C57BL/6新生鼠分为:对照组(CON组,n=40,不与母鼠分离)、NEC+PBS灌胃组(NP组,n=57)和NEC+丁酸钠灌胃组(NB组,n=40),NP组和NB组分别从3 d龄开始予PBS或丁酸钠灌胃,干预7 d后与母鼠分离,采用人工喂养联合缺氧冷刺激的方法连续3 d刺激建立NEC模型。分析各组小鼠存活率,肠组织病理损伤情况,脑组织TNF-α、IL-6 mRNA水平以及活化的小胶质细胞和星形胶质细胞的表达情况。采用水迷宫实验和透射电镜检测各组成年小鼠学习记忆能力和髓鞘微结构改变。Western blot检测肠组织HMGB1和脑组织TLR4、NF-κB蛋白表达水平。结果与CON组相比,NP组小鼠大脑中TNF-α、IL-6 mRNA表达显著上调(1.51±0.20 vs 0.67±0.14,P<0.05;2.03±0.39 vs 1.01±0.17,P<0.05),活化的小胶质细胞增加(751.00±82.35 vs 284.70±52.01,P<0.05),星形胶质细胞数量增加(P<0.05),肠组织HMGB1和脑组织TLR4、NF-κB蛋白表达水平显著升高(1.76±0.19 vs 0.73±0.06,P<0.05;1.14±0.16 vs 0.81±0.01,P<0.05;1.21±0.19 vs 0.60±0.15,P<0.05);NP组成年小鼠水迷宫逃避潜伏期延长(P<0.05),平台穿越次数减少(P<0.05),G-ratio显著升高(P<0.05)。而与NP组相比,NB组小鼠大脑中TNF-α、IL-6 mRNA表达水平降低(0.81±0.12 vs 1.51±0.20,P<0.05;0.93±0.38 vs 2.03±0.39,P<0.05),小胶质细胞活化减少(468.00±99.59 vs 751.00±82.35,P<0.05),星形胶质细胞减少(P<0.05),肠组织HMGB1和脑组织TLR4、NF-κB蛋白表达降低(1.22±0.11 vs 1.76±0.19,P<0.05;0.88±0.06 vs 1.14±0.16,P<0.05;0.70±0.19 vs 1.21±0.19,P<0.05);成年小鼠水迷宫逃避潜伏期缩短(P<0.05),平台穿越次数增加(P<0.05),髓鞘厚度增加(P<0.05)。结论丁酸钠可通过抑制大脑中的TLR4-NF-κB通路减轻神经炎症反应,从而发挥对NEC远期相关脑损伤的保护作用。展开更多
To date there is no treatment able to stop or slow down the loss of dopaminergic neurons that characterizes Parkinson’s disease.It was recently observed in a rodent model of Alzheimer’s disease that the interaction ...To date there is no treatment able to stop or slow down the loss of dopaminergic neurons that characterizes Parkinson’s disease.It was recently observed in a rodent model of Alzheimer’s disease that the interaction between the α7 subtype of nicotinic acetylcholine receptor(α7-nAChR)and sigma-1 receptor(σ1-R)could exert neuroprotective effects through the modulation of neuroinflammation which is one of the key components of the pathophysiology of Parkinson’s disease.In this context,the aim of the present study was to assess the effects of the concomitant administration of N-(3R)-1-azabicyclo[2.2.2]oct-3-yl-furo[2,3-c]pyridine-5-carboxamide(PHA)543613 as an α7-nAChR agonist and 2-(4-morpholinethyl)1-phenylcyclohexanecarboxylate(PRE)-084 as aσ1-R agonist in a well-characterized 6-hydroxydopamine rat model of Parkinson’s disease.The animals received either vehicle separately or the dual therapy PHA/PRE once a day until day 14 postlesion.Although no effect was noticed in the amphetamine-induced rotation test,our data has shown that the PHA/PRE treatment induced partial protection of the dopaminergic neurons(15-20%),assessed by the dopamine transporter density in the striatum and immunoreactive tyrosine hydroxylase in the substantia nigra.Furthermore,this dual therapy reduced the degree of glial activation consecutive to the 6-hydroxydopamine lesion,i.e,the 18 kDa translocation protein density and glial fibrillary acidic protein staining in the striatum,and the CD11b and glial fibrillary acidic protein staining in the substantia nigra.Hence,this study reports for the first time that concomitant activation of α7-nAChR andσ1-R can provide a partial recovery of the nigro-striatal dopaminergic neurons through the modulation of microglial activation.The study was approved by the Regional Ethics Committee(CEEA Val de Loire n°19)validated this protocol(Authorization N°00434.02)on May 15,2014.展开更多
基金supported by the National Natural Science Foundation of China(31830032,81527901,and 31671057)the non-profit Central Research Institute Fund of the Chinese Academy of Medical Sciences(2017PT31038,2018PT31041)+3 种基金the National Key Research and Development Program of China(2016YFA0501000)Key-Area Research and Development Program of Guangdong Province(2018B030334001,2018B030331001)the 111 Project(B13026)the Fountain-Valley Life Sciences Fund of University of Chinese Academy of Sciences Education Foundation and the CAMS Innovation Fund for Medical Sciences(2019-I2M-5-057)。
文摘Major depressive disorder(MDD)is a prevalent psychiatric disease that involves malfunctions of different cell types in the brain.Accumulating studies started to reveal that microglia,the primary resident immune cells,play an important role in the development and progression of depression.Microglia respond to stress-triggered neuroinflammation,and through the release of proinflammatory cytokines and their metabolic products,microglia may modulate the function of neurons and astrocytes to regulate depression.In this review,we focused on the role of microglia in the etiology of depression.We discussed the dynamic states of microglia;the correlative and causal evidence of microglial abnormalities in depression;possible mechanisms of how microglia sense depression-related stress and modulate depression state;and how antidepressive therapies affect microglia.Understanding the role of microglia in depression may shed light on developing new treatment strategies to fight against this devastating mental illness.
文摘Postoperative cognitive dysfunction （POCD） is a multifactorial process with a huge number of predisposing, causal, and precipitating factors. In this scenario, the neuroinflammation and the microglial activation play a pivotal role by triggering and amplifying a complex cascade involving the immuno-hormonal acti- vation, the micro circle alterations, the hippocampal oxidative stress activation and, finally, an increased blood-brain barrier＇s permeability. While the role of anesthetics in the POCD＇s genesis in humans is debated, a huge number of preclinical studies have been conducted on the topic and many mechanisms have been proposed to explain the potential neurodegenerative effects of general anesthetics. Probably, the problem concerns on what we are searching for and how we are searching and, surprisingly, preclinical studies showed that anesthetics may also manifest neuroprotective properties. The aim of this paper is to offer an overview on the potential impact of general anesthetics on POCD. Mechanisms of hippocampal and extra-hippocampal dysfunction due to neuroinflammation are discussed, whereas further research perspectives are also given.
基金Open Access funding enabled and organized by Projekt DEAL.M.P.was supported by the Sobek Foundation,the Ernst-Jung Foundation,the DFG(SFB 992,SFB1160,SFB/TRR167,Reinhart-Koselleck-Grant,and Gottfried Wilhelm Leibniz-Prize)and the Ministry of Science,Research and Arts,Baden-Wuerttemberg(Sonderlinie“Neuroinflammation”).This study was supported by the DFG under Germany’s Excellence Strategy(CIBSS-EXC-2189-Project ID390939984).The figures were created with BioRender.com。
文摘Viral encephalitis is a devastating disease with high mortality,and survivors often suffer from severe neurological complications.Microglia are innate immune cells of the central nervous system(CNS)parenchyma whose turnover is reliant on local proliferation.Microglia express a diverse range of proteins,which allows them to continuously sense the environment and quickly react to changes.Under inflammatory conditions such as CNS viral infection,microglia promote innate and adaptive immune responses to protect the host.However,during viral infection,a dysregulated microglia-T-cell interplay may result in altered phagocytosis of neuronal synapses by microglia that causes neurocognitive impairment.In this review,we summarize the current knowledge on the role of microglia in viral encephalitis,propose questions to be answered in the future and suggest possible therapeutic targets.
基金support of K.C.Wong Education Foundation(China)the Project of Innovative Team for the Guangdong Universities(2018KCXTD001,China)+1 种基金financially supported by the National Natural Science Foundation of China(Nos.81701751 and 81871383)Guangdong Basic and Applied Basic Research Foundation(2020A1515011192,China)
文摘The 18 kDa translocator protein(TSPO),previously known as the peripheral benzodiazepine receptor,is predominately localized to the outer mitochondrial membrane in steroidogenic cells.Brain TSPO expression is relatively low under physiological conditions,but is upregulated in response to glial cell activation.As the primary index of neuroinflammation,TSPO is implicated in the pathogenesis and progression of numerous neuropsychiatric disorders and neurodegenerative diseases,including Alzheimer’s disease(AD),amyotrophic lateral sclerosis(ALS),Parkinson’s disease(PD),multiple sclerosis(MS),major depressive disorder(MDD)and obsessive compulsive disorder(OCD).In this context,numerous TSPO-targeted positron emission tomography(PET)tracers have been developed.Among them,several radioligands have advanced to clinical research studies.In this review,we will overview the recent development of TSPO PET tracers,focusing on the radioligand design,radioisotope labeling,pharmacokinetics,and PET imaging evaluation.Additionally,we will consider current limitations,as well as translational potential for future application of TSPO radiopharmaceuticals.This review aims to not only present the challenges in current TSPO PET imaging,but to also provide a new perspective on TSPO targeted PET tracer discovery efforts.Addressing these challenges will facilitate the translation of TSPO in clinical studies of neuroinflammation associated with central nervous system diseases.
基金supported by the National Natural Science Foundation of China (81601938)the Natural Science Fund of Shaanxi Province (2016JQ8010)the Science and Technology Projects Fund of Xi’an city (2016050SF/YX06(6))
文摘Fluoxetine, an anti-depressant drug, has recently been shown to provide neuroprotection in central nervous system injury, but its roles in subarachnoid hemorrhage(SAH) remain unclear. In this study, we aimed to evaluate whether fluoxetine attenuates early brain injury(EBI) after SAH. We demonstrated that intraperitoneal injection of fluoxetine(10 mg/kg per day) significantly attenuated brain edema and blood-brain barrier(BBB) disruption, microglial activation, and neuronal apoptosis in EBI after experimental SAH, as evidenced by the reduction of brain water content and Evans blue dye extravasation, prevention of disruption of the tight junction proteins zonula occludens-1, claudin-5, and occludin, a decrease of cells staining positive for Iba-1, ED-1, and TUNEL and a decline in IL-1 b, IL-6, TNF-a, MDA, 3-nitrotyrosine, and 8-OHDG levels. Moreover, fluoxetine significantly improved the neurological deficits of EBI and long-term sensorimotor behavioral deficits following SAH in a rat model. These results indicated that fluoxetine has a neuroprotective effect after experimental SAH.
基金This work was supported by funding from the National Natural Sciences Foundation of China(NSFC 81430021 and 81370470)the Program for Liaoning Innovative Research Team in University(LT2015009)Liaoning Science and Technology Project(2015225008).
文摘Background:Neuron-microglia communication plays a crucial role in the motor neurons(MNs)death in amyotrophic lateral sclerosis(ALS).Neurons can express chemokine(C-X3-C motif)ligand 1(CX3CL1),which mediates microglial activation via interacting with its sole receptor CX3CR1 in microglia.In the present study,we aimed to investigate the dynamic changes of CX3CL1/CX3CR1 axis during microglial activation and MNs loss in SOD1G93A mouse model of ALS.Methods:qPCR,western blot and immunofluorescent staining were used to examine the mRNA and protein levels and localization of CX3CL1/CX3CR1 in the anterior horn region of spinal cord in both SOD1G93A mice and their agematched wild type(WT)littermates at 40,60,90 and 120 days of age.The M1/M2 microglial activation in the spinal cord tissues of SOD1G93A mice and WT mice were evaluated by immunofluorescent staining of M1/M2 markers and further confirmed by qPCR analysis of M1/M2-related cytokines.Results:The immunofluorescent staining revealed that CX3CL1 was predominately expressed in MNs,while CX3CR1 was highly expressed in microglia in the anterior horn region of spinal cord.Compared with age-matched WT mice,CX3CL1 mRNA level was elevated at 40 days but decreased at 90 and 120 days in the anterior horn region of spinal cords in ALS mice.Consistently,CX3CR1 mRNA level was increased at 90 and 120 days.Western blot assay further confirmed the dynamic changes of CX3CL1/CX3CR1 axis in ALS mice.Additionally,the levels of M1/M2 markers of microglia and their related cytokines in the anterior horn region of spinal cord in ALS mice were increased at 90 and 120 days.Moreover,while M1-related cytokines in ALS mice were persistently increased at 120 days,the upregulated M2-related cytokines started to decline at 120 days,suggesting an altered microglial activation.Conclusions:Our data revealed the dynamic changes of CX3CL1/CX3CR1 axis and an imbalanced M1/M2 microglial activation during ALS pathological progression.These findings may help identify potential molecular targets for ALS th
基金Natural Science Foundation of Liaoning Province (General Program),No.2017010825 (to JQ)。
文摘Microglia,which are the resident macrophages of the central nervous system,are an important part of the inflammatory response that occurs after cerebral ischemia.Vav guanine nucleotide exchange factor 1(Vav1) is a guanine nucleotide exchange factor that is related to microglial activation.However,how Vav1 participates in the inflammato ry response after cerebral ischemia/reperfusion inj ury remains unclea r.In this study,we subjected rats to occlusion and repe rfusion of the middle cerebral artery and subjected the BV-2 mic roglia cell line to oxygen-glucose deprivatio n/reoxygenation to mimic cerebral ischemia/repe rfusion in vivo and in vitro,respectively.We found that Vav1 levels were increased in the brain tissue of rats subjected to occlusion and reperfusion of the middle cerebral arte ry and in BV-2 cells subjected to oxygen-glucose deprivation/reoxygenation.Silencing Vav1 reduced the cerebral infarct volume and brain water content,inhibited neuronal loss and apoptosis in the ischemic penumbra,and im p roved neurological function in rats subjected to occlusion and repe rfusion of the middle cerebral artery.Further analysis showed that Vav1 was almost exclusively localized to microglia and that Vav1 downregulation inhibited microglial activation and the NOD-like receptor pyrin 3(NLRP3) inflammasome in the ischemic penumbra,as well as the expression of inflammato ry facto rs.In addition,Vov1 knoc kdown decreased the inflammatory response exhibited by BV-2 cells after oxygen-glucose deprivation/reoxyge nation.Taken together,these findings show that silencing Vav1 attenuates inflammation and neuronal apoptosis in rats subjected to cerebral ischemia/repe rfusion through inhibiting the activation of mic roglia and NLRP3 inflammasome.
基金supported by the National Natural Science Foundation of China(32271039,32070970 and 31871023)the Joint Program RFBR-BRICS(17-54-80006)a Project Funded by the Priority Academic Program Development of Jiangsu Higher Education Institutions.
文摘The accumulation of pathological α-synuclein(α-syn)in the central nervous system and the progressive loss of dopaminergic neurons in the substantia nigra pars compacta are the neuropathological features of Parkinson's disease(PD).Recently,the findings of prion-like transmission of α-syn pathology have expanded our understanding of the region-specific distribution ofα-syn in PD patients.Accumulating evidence suggests that α-syn aggregates are released from neurons and endocytosed by glial cells,which contributes to the clearance of α-syn.However,the activation of glial cells by α-syn species produces pro-inflammatory factors that decrease the uptake of α-syn aggregates by glial cells and promote the transmission of α-syn between neurons,which promotes the spread of α-syn pathology.In this article,we provide an overview of current knowledge on the role of glia and α-syn pathology in PD pathogenesis,highlighting the relationships between glial responses and the spread ofα-syn pathology.
基金supported by Fellowship from Saudi Arabia Cultural Mission,College of Pharmacy,Department of Pharmaceutical Chemistry,King Saud University,Riyadh,Saudi Arabia
文摘Aging brain becomes susceptible to neurodegenerative diseases due to the shifting of microglia and astrocyte phenotypes to an active“pro-inflammatory”state,causing chronic low-grade neuroinflammation.Despite the fact that the role of neuroinflammation during aging has been extensively studied in recent years,the underlying causes remain unclear.The identification of relevant proteins and understanding their potential roles in neuroinflammation can help explain their potential of becoming biomarkers in the aging brain and as drug targets for prevention and treatment.This will eventually reduce the chances of developing neurodegenerative diseases and promote healthier lives in the elderly.In this review,we have summarized the morphological and cellular changes in the aging brain,the effects of age-related neuroinflammation,and the potential role of cofilin-1 during neuroinflammation.We also discuss other factors contributing to brain aging and neuroinflammation.
文摘Traumatic brain injury induces secondary injury that contributes to neuroinflammation, neuronal loss, and neurological dysfunction. One important injury mechanism is cell cycle activation which causes neuronal apoptosis and glial activation. The neuroprotective effects of both non-selective （Flavopiridol） and selective （Roscovitine and CR-8） cyclin-dependent kinase inhibitors have been shown across mukiple experimental traumatic brain injury models and species. Cyclin-depen- dent kinaseinhibitors, administered as a single systemic dose up to 24 hours after traumatic brain injury, provide strong neuroprotection-reducing neuronal cell death, neuroinflammation and neurological dysfunction. Given their effectiveness and long therapeutic window, cyclin-dependent kinase inhibitors appear to be promising candidates for clinical traumatic brain injury trials.
文摘目的探究丁酸钠对坏死性小肠结肠炎(necrotizing enterocolitis,NEC)小鼠脑损伤的影响。方法137只3 d龄C57BL/6新生鼠分为:对照组(CON组,n=40,不与母鼠分离)、NEC+PBS灌胃组(NP组,n=57)和NEC+丁酸钠灌胃组(NB组,n=40),NP组和NB组分别从3 d龄开始予PBS或丁酸钠灌胃,干预7 d后与母鼠分离,采用人工喂养联合缺氧冷刺激的方法连续3 d刺激建立NEC模型。分析各组小鼠存活率,肠组织病理损伤情况,脑组织TNF-α、IL-6 mRNA水平以及活化的小胶质细胞和星形胶质细胞的表达情况。采用水迷宫实验和透射电镜检测各组成年小鼠学习记忆能力和髓鞘微结构改变。Western blot检测肠组织HMGB1和脑组织TLR4、NF-κB蛋白表达水平。结果与CON组相比,NP组小鼠大脑中TNF-α、IL-6 mRNA表达显著上调(1.51±0.20 vs 0.67±0.14,P<0.05;2.03±0.39 vs 1.01±0.17,P<0.05),活化的小胶质细胞增加(751.00±82.35 vs 284.70±52.01,P<0.05),星形胶质细胞数量增加(P<0.05),肠组织HMGB1和脑组织TLR4、NF-κB蛋白表达水平显著升高(1.76±0.19 vs 0.73±0.06,P<0.05;1.14±0.16 vs 0.81±0.01,P<0.05;1.21±0.19 vs 0.60±0.15,P<0.05);NP组成年小鼠水迷宫逃避潜伏期延长(P<0.05),平台穿越次数减少(P<0.05),G-ratio显著升高(P<0.05)。而与NP组相比,NB组小鼠大脑中TNF-α、IL-6 mRNA表达水平降低(0.81±0.12 vs 1.51±0.20,P<0.05;0.93±0.38 vs 2.03±0.39,P<0.05),小胶质细胞活化减少(468.00±99.59 vs 751.00±82.35,P<0.05),星形胶质细胞减少(P<0.05),肠组织HMGB1和脑组织TLR4、NF-κB蛋白表达降低(1.22±0.11 vs 1.76±0.19,P<0.05;0.88±0.06 vs 1.14±0.16,P<0.05;0.70±0.19 vs 1.21±0.19,P<0.05);成年小鼠水迷宫逃避潜伏期缩短(P<0.05),平台穿越次数增加(P<0.05),髓鞘厚度增加(P<0.05)。结论丁酸钠可通过抑制大脑中的TLR4-NF-κB通路减轻神经炎症反应,从而发挥对NEC远期相关脑损伤的保护作用。
基金supported by Inserm(to SV,LFF,CT,JV,SB,SS,SC)by the Labex IRON(ANR-11-LABX-18-01:to all authors).
文摘To date there is no treatment able to stop or slow down the loss of dopaminergic neurons that characterizes Parkinson’s disease.It was recently observed in a rodent model of Alzheimer’s disease that the interaction between the α7 subtype of nicotinic acetylcholine receptor(α7-nAChR)and sigma-1 receptor(σ1-R)could exert neuroprotective effects through the modulation of neuroinflammation which is one of the key components of the pathophysiology of Parkinson’s disease.In this context,the aim of the present study was to assess the effects of the concomitant administration of N-(3R)-1-azabicyclo[2.2.2]oct-3-yl-furo[2,3-c]pyridine-5-carboxamide(PHA)543613 as an α7-nAChR agonist and 2-(4-morpholinethyl)1-phenylcyclohexanecarboxylate(PRE)-084 as aσ1-R agonist in a well-characterized 6-hydroxydopamine rat model of Parkinson’s disease.The animals received either vehicle separately or the dual therapy PHA/PRE once a day until day 14 postlesion.Although no effect was noticed in the amphetamine-induced rotation test,our data has shown that the PHA/PRE treatment induced partial protection of the dopaminergic neurons(15-20%),assessed by the dopamine transporter density in the striatum and immunoreactive tyrosine hydroxylase in the substantia nigra.Furthermore,this dual therapy reduced the degree of glial activation consecutive to the 6-hydroxydopamine lesion,i.e,the 18 kDa translocation protein density and glial fibrillary acidic protein staining in the striatum,and the CD11b and glial fibrillary acidic protein staining in the substantia nigra.Hence,this study reports for the first time that concomitant activation of α7-nAChR andσ1-R can provide a partial recovery of the nigro-striatal dopaminergic neurons through the modulation of microglial activation.The study was approved by the Regional Ethics Committee(CEEA Val de Loire n°19)validated this protocol(Authorization N°00434.02)on May 15,2014.
