Cells of the central nervous system(CNS)are privileged in lying behind the blood-brain barrier(BBB).Unlike blood vessels in other organs,CNS blood vessels are unique in displaying high electrical resistance and low pe...Cells of the central nervous system(CNS)are privileged in lying behind the blood-brain barrier(BBB).Unlike blood vessels in other organs,CNS blood vessels are unique in displaying high electrical resistance and low permeability.With this unique structure and function,the BBB prevents potentially harmful blood components such as serum proteins,inflammatory cytokines,and inflammatory leukocytes from entering the hallowed space of the CNS and wreaking havoc.In addition to these“tightness”properties,the BBB has an array of specialized transporters designed to import essential nutrients.展开更多
Microglial activation plays an important role in a panel of neurological disorders such as multiple sclerosis(MS) and Parkinson's disease(PD),and is a key target for developing therapeutic strategies for these dis...Microglial activation plays an important role in a panel of neurological disorders such as multiple sclerosis(MS) and Parkinson's disease(PD),and is a key target for developing therapeutic strategies for these diseases.Ketogenic diet (KD),which is able to inhibit microglial activation in substantia nigra pars compacta of mice,has been shown effective in a mouse model of PD,possibly through increasing D-β-hydroxybutyrate(D-β-HB),a major component of ketone bodies.To verify this,we developed an in vitro model of microglia activation with a microglia line,BV-2,and investigated how D-β-HB have an effect on the LPS-stimulated BV-2 cells.We found D-β-HB is able to recover the cell viability,and inhibit the production of inflammatory mediators and cytokines such as ROS,nitrite,IL-1β,TNF-α,and IL-6,which otherwise were increased in LPS-stimulated BV-2 cells.We conclude that the LPS induced BV-2 cells activation is a valid in vitro model of microglia activation.D-β-HB is able to suppress the activation of BV-2 cells, which might account for one of the possible reasons of KD therapy on the PD model.展开更多
Traumatic brain injury（TBI）remains one of the leading causes of disability and death in infants and children.Studies have demonstrated that the youngest age group（especially≤4 years old）exhibit worse functional o...Traumatic brain injury（TBI）remains one of the leading causes of disability and death in infants and children.Studies have demonstrated that the youngest age group（especially≤4 years old）exhibit worse functional outcome following moderate to severe TBI compared to older children or adults（Anderson et al.,2005;Emami et al.,2017）.These data suggest that age-at-injury may be an important determinant of outcome,展开更多
A recent publication by Qin et al.in Cell reported on the first-inhuman application of anti-BCMA chimeric antigen receptor(CAR)-T cell therapy in patients with treatment-refractory progressive multiple sclerosis(MS)wi...A recent publication by Qin et al.in Cell reported on the first-inhuman application of anti-BCMA chimeric antigen receptor(CAR)-T cell therapy in patients with treatment-refractory progressive multiple sclerosis(MS)with a good tolerability and efficacy.1 CAR-T cells rank among the breakthrough therapeutic approaches,transforming the field of cancer and autoimmune conditions including neuroimmunological disorders.B-cell maturation antigen(BCMA)and CD19 antigen are B-cell target antigens frequently used in CAR constructs for autoimmune diseases.1,2 In addition to the B-cell depletion in the peripheral blood,CAR-T cells allow deep depletion of tissue-resident B cells e.g.,in lymphoid tissues and hard-to-reach compartments such as the central nervous system(CNS),an effect that has not been observed with antibody-based B-cell depletion therapies.However,little is known about direct and indirect effects of CAR-T cells on microglia,even though CNS-resident microglial cells are involved as one of the key drivers and maintainers of the compartmentalized neuroinflammation and neurodegeneration during MS progression.This is confirmed by emerging evidence that smoldering neurodegenerative processes are hallmarked by chronic microglia-mediated neuroinflammation with progressive axonal injury,resulting in disability progression independent of relapse activity(PIRA)and brain atrophy.1 To date,none of the available therapies for MS are fully effective at preventing disease progression and PIRA.展开更多
Opioid analgesics,including morphine,pose significant challenges in clinical pain management due to the development of tolerance-a phenomenon that necessitates escalating dosages to maintain analgesic efficacy while i...Opioid analgesics,including morphine,pose significant challenges in clinical pain management due to the development of tolerance-a phenomenon that necessitates escalating dosages to maintain analgesic efficacy while increasing risks of adverse effects and addiction.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
Neuroinflammation is a major contributor to secondary neuronal injury that accounts for a significant proportion of final brain cell loss in neonatal hypoxic-ischemic encephalopathy(HIE).However,the immunological mech...Neuroinflammation is a major contributor to secondary neuronal injury that accounts for a significant proportion of final brain cell loss in neonatal hypoxic-ischemic encephalopathy(HIE).However,the immunological mechanisms that underlie HIE remain unclear.MicroRNA-210(miR-210)is the master“hypoxamir”and plays a key role in hypoxic-ischemic tissue damage.Herein,we report in an animal model of neonatal rats that HIE significantly upregulated miR-210 expression in microglia in the neonatal brain and strongly induced activated microglia.Intracerebroventricular administration of miR-210 antagomir effectively suppressed microglia-mediated neuroinflammation and significantly reduced brain injury caused by HIE.We demonstrated that miR-210 induced microglial M1 activation partly by targeting SIRT1,thereby reducing the deacetylation of the NF-κB subunit p65 and increasing NF-κB signaling activity.Thus,our study identified miR-210 as a novel regulator of microglial activation in neonatal HIE,highlighting a potential therapeutic target in the treatment of infants with hypoxic-ischemic brain injury.展开更多
Multiple sclerosis (MS) is characterized by chronic,slowly expanding lesions with the accumulation of myeloid cells,which lead to brain atrophy and progressive disability.The role of mitochondria,especially mitochondr...Multiple sclerosis (MS) is characterized by chronic,slowly expanding lesions with the accumulation of myeloid cells,which lead to brain atrophy and progressive disability.The role of mitochondria,especially mitochondrial respiratory complexes and metabolites,in controlling myeloid immune responses,is well-documented but not fully understood in diseases of the central nervous system (CNS).The groundbreaking study by Prof.Peruzzotti-Jametti et al.[1],entitled"Mitochondrial complexⅠactivity in microglia sustains neuroinflammation"published in Nature,delves into the intricate dynamics between mitochondrial function within microglia and the perpetuation of chronic neuroinflammation,specifically in MS.The core point of their investigation is the hypothesis that mitochondrial complexⅠ(CI) activity,through a mechanism known as reverse electron transport (RET),generates reactive oxygen species (ROS) in microglia,thereby sustaining inflammatory response in the CNS.This increases ROS production from the mitochondria,which is thought to be a crucial factor in the maintenance of a pro-inflammatory state in the microglia,contributing to the pathology of MS and similar neuroinflammatory diseases.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
Neuronal activity,synaptic transmission,and molecular changes in the basolateral amygdala play critical roles in fear memory.Cylindromatosis(CYLD)is a deubiquitinase that negatively regulates the nuclear factor kappa-...Neuronal activity,synaptic transmission,and molecular changes in the basolateral amygdala play critical roles in fear memory.Cylindromatosis(CYLD)is a deubiquitinase that negatively regulates the nuclear factor kappa-B pathway.CYLD is well studied in non-neuronal cells,yet underinvestigated in the brain,where it is highly expressed.Emerging studies have shown involvement of CYLD in the remodeling of glutamatergic synapses,neuroinflammation,fear memory,and anxiety-and autism-like behaviors.However,the precise role of CYLD in glutamatergic neurons is largely unknown.Here,we first proposed involvement of CYLD in cued fear expression.We next constructed transgenic model mice with specific deletion of Cyld from glutamatergic neurons.Our results show that glutamatergic CYLD deficiency exaggerated the expression of cued fear in only male mice.Further,loss of CYLD in glutamatergic neurons resulted in enhanced neuronal activation,impaired excitatory synaptic transmission,and altered levels of glutamate receptors accompanied by over-activation of microglia in the basolateral amygdala of male mice.Altogether,our study suggests a critical role of glutamatergic CYLD in maintaining normal neuronal,synaptic,and microglial activation.This may contribute,at least in part,to cued fear expression.展开更多
Microglia,the resident immune cells in the central nervous system(CNS),rapidly transition from a resting to an active state in the acute phase of ischemic brain injury.This active state mediates a pro-inflammatory res...Microglia,the resident immune cells in the central nervous system(CNS),rapidly transition from a resting to an active state in the acute phase of ischemic brain injury.This active state mediates a pro-inflammatory response that can exacerbate the injury.Targeting the pro-inflammatory response of microglia in the semi-dark band during this acute phase may effectively reduce brain injury.Shionone(SH),an active ingredient extracted from the dried roots and rhizomes of the genus Aster(Asteraceae),has been reported to regulate the inflammatory response of macrophages in sepsis-induced acute lung injury.However,its function in post-stroke neuroinflammation,particularly microglia-mediated neuroinflammation,remains uninvestigated.This study found that SH significantly inhibited lipopolysaccharide(LPS)-induced elevation of inflammatory cytokines,including interleukin-1β(IL-1β),tumor necrosis factor-α(TNF-α),and inducible nitric oxide synthase(iNOS),in microglia in vitro.Furthermore,the results demonstrated that SH alleviated infarct volume and improved behavioral performance in middle cerebral artery occlusion(MCAO)mice,which may be attributed to the inhibition of the microglial inflammatory response induced by SH treatment.Mechanistically,SH potently inhibited the phosphorylation of serine-threonine protein kinase B(AKT),mammalian target of rapamycin(mTOR),and signal transducer and activator of transcription 3(STAT3).These findings suggest that SH may be a potential therapeutic agent for relieving ischemic stroke(IS)by alleviating microglia-associated neuroinflammation.展开更多
Objective:To investigate the efficacy and mechanism of Ditan Qingnao decoction(DTQND)in alleviating schizophrenia-like symptoms in a maternal immune activation(MIA)-induced rat model.Methods:DTQND components were anal...Objective:To investigate the efficacy and mechanism of Ditan Qingnao decoction(DTQND)in alleviating schizophrenia-like symptoms in a maternal immune activation(MIA)-induced rat model.Methods:DTQND components were analyzed using high-performance liquid chromatography-tandem mass spectrometry.An MIA-induced rat model was established by injecting Poly Ⅰ:C into pregnant dams on gestational day 9.Male offspring were administered DTQND(14.1 g/kg),risperidone(RIS;0.4 mg/kg),or distilled water,while the controls received only distilled water via gavage for 4 weeks.Behavioral assessments were conducted using the open-field,Y-maze,prepulse inhibition,and sucrose preference tests.Serum levels of interleukin(IL)-6,IL-18,IL-1β,and tumor necrosis factor-α(TNF-α)were measured via an enzyme-linked immunosorbent assay.Hippocampal protein levels of nuclear factor kappa B p65(NF-κB p65),phospho-NF-κB p65(p-p65),inhibitor of kappa B-alpha(IκB-α),phospho-IκB-α(p-IκB-α),and nucleotide-binding oligomerization domain-like receptor family pyrin domain-containing protein 3(NLRP3)were assessed via western blots.Immunohistochemistry detected hippocampal expression of ionized calcium-binding adapter molecule 1(Iba1)and cluster of differentiation 68(CD68).Results:Multiple DTQND compounds were identified,including stachyose,β-syringin,and isofraxidin,among others.DTQND treatment considerably enhanced spontaneous activity,reduced anxiety,improved spatial working memory,and alleviated sensory gating defects in male offspring with MIA.The DTQND group showed significantly lower serum levels of IL-1β(P=.002)and IL-18(P=.046)than the model group,with no discernible variations in IL-6 or TNF-α levels.In the hippocampus,DTQND significantly suppressed the expression of p-p65(P<.001),p-IκB-α(P=.023),and NLRP3(P<.001)compared to the model group.Additionally,DTQND modulated microglial activation markers,decreasing CD68 expression(P=.004)without affecting Iba1 levels.Conclusions:DTQND alleviated schizophrenia-like behavioral deficits and cognitive impairment by inhibiting the NF-κB/NLRP3 pathway,supporting its potential as an alternative therapy for schizophrenia.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
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
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
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
Inflammation plays an important role in the pathological process of ischemic stroke,and systemic inflammation affects patient prognosis.As resident immune cells in the brain,microglia are significantly involved in imm...Inflammation plays an important role in the pathological process of ischemic stroke,and systemic inflammation affects patient prognosis.As resident immune cells in the brain,microglia are significantly involved in immune defense and tissue repair under various pathological conditions,including cerebral ischemia.Although the differentiation of M1 and M2 microglia is certainly oversimplified,changing the activation state of microglia appears to be an intriguing therapeutic strategy for cerebral ischemia.Recent evidence indicates that both mesenchymal stem cells(MSCs)and MSC-derived extracellular vesicles(EVs)regulate inflammation and modify tissue repair under preclinical stroke conditions.However,the precise mechanisms of these signaling pathways,especially in the context of the mutual interaction between MSCs or MSC-derived EVs and resident microglia,have not been sufficiently unveiled.Hence,this review summarizes the state-ofthe-art knowledge on MSC-and MSC-EV-mediated regulation of microglial activity under ischemic stroke conditions with respect to various signaling pathways,including cytokines,neurotrophic factors,transcription factors,and microRNAs.展开更多
While degenerative diseases of the central nervous system are commonly linked to age-related macular degeneration and glaucoma,they have also been infrequently associated with retinitis pigmentosa,a condition defined ...While degenerative diseases of the central nervous system are commonly linked to age-related macular degeneration and glaucoma,they have also been infrequently associated with retinitis pigmentosa,a condition defined by retinal degeneration that can be caused by an isoform of receptor expression enhancing protein 6(REEP6)expressed in rod photoreceptors.In this study,we used REEP6 knockout mice(REEP6^(-/-))and wild-type mice(REEP6^(+/+))to examine neurodegenerative pathology within the visual pathways and neural activity in the primary visual cortex(V1)at three specific time points(1,6,and 10 months)during retinitis pigmentosa progression.Microglial activation was observed in both the retina and the primary visual cortex starting at 1 month of age,but no such activation was detected in the lateral geniculate nucleus at any time point.Not only was increased microglial activation observed at 6 and 10 months within the primary visual cortex of REEP6^(-/-)mice,but also coinciding with elevated levels of phosphorylated Tau expression.At 6 and 10 months of age,primary visual cortex neurons in REEP6^(-/-)mice exhibited reduced responses to grating stimuli and increased spontaneous activity compared with neurons in the primary visual cortex of mice in the control group.Our findings show that retinitis pigmentosa induces neurodegenerative pathology within the visual pathway of mice,particularly in the primary visual cortex,suggesting that ocular disease contributes substantially to central nervous system degeneration.It may provide new clues for the selection of treatment opportunities and the development of therapeutic measures for the subsequent treatment of retinitis pigmentosa or even other retinal degenerative diseases.展开更多
Objective:Multiple sclerosis(MS)is a chronic inflammatory demyelinating disease of the central nervous system(CNS).Soluble interleukin-2 receptor alpha(sIL-2Rα)has been implicated inMS pathogenesis,but its mechanisms...Objective:Multiple sclerosis(MS)is a chronic inflammatory demyelinating disease of the central nervous system(CNS).Soluble interleukin-2 receptor alpha(sIL-2Rα)has been implicated inMS pathogenesis,but its mechanisms remain unclear.This study investigates how sIL-2Rαexacerbates MS by modulating microglial activation and antibody-dependent cellular cytotoxicity(ADCC)in an experimental autoimmune encephalomyelitis(EAE)mouse model.Methods:Female C57BL/6J mice were induced with EAE and treated with sIL-2Rα.Clinical symptoms,histopathology,and molecular changes were analyzed.Microglial activation was assessed via immunohistochemistry,Western blot,and RNA sequencing.In vitro,ADCC-mediated oligodendrocyte injury was evaluated using Fc receptor inhibition and PI3K-Akt pathway blockade.Results:sIL-2Rα accelerated EAE onset and severity,increasingmicroglial M1 polarization and CNS inflammation.RNA-seq revealed PI3K-Akt pathway activation,upregulating Fc receptors(FcγR)on microglia,which enhanced ADCC against oligodendrocytes(p<0.001).Inhibiting FcγR or PI3K-Akt reduced oligodendrocyte damage.Conclusion:sIL-2Rαexacerbates MS by activating microglia via the PI3K-Aktaxis,promoting ADCC and demyelination.Targeting this pathway may offer novel therapeutic strategies for MS.展开更多
基金supported by the NIH RF1 grant NS119477 jointly funded by NINDS and NIA(to RM).
文摘Cells of the central nervous system(CNS)are privileged in lying behind the blood-brain barrier(BBB).Unlike blood vessels in other organs,CNS blood vessels are unique in displaying high electrical resistance and low permeability.With this unique structure and function,the BBB prevents potentially harmful blood components such as serum proteins,inflammatory cytokines,and inflammatory leukocytes from entering the hallowed space of the CNS and wreaking havoc.In addition to these“tightness”properties,the BBB has an array of specialized transporters designed to import essential nutrients.
文摘Microglial activation plays an important role in a panel of neurological disorders such as multiple sclerosis(MS) and Parkinson's disease(PD),and is a key target for developing therapeutic strategies for these diseases.Ketogenic diet (KD),which is able to inhibit microglial activation in substantia nigra pars compacta of mice,has been shown effective in a mouse model of PD,possibly through increasing D-β-hydroxybutyrate(D-β-HB),a major component of ketone bodies.To verify this,we developed an in vitro model of microglia activation with a microglia line,BV-2,and investigated how D-β-HB have an effect on the LPS-stimulated BV-2 cells.We found D-β-HB is able to recover the cell viability,and inhibit the production of inflammatory mediators and cytokines such as ROS,nitrite,IL-1β,TNF-α,and IL-6,which otherwise were increased in LPS-stimulated BV-2 cells.We conclude that the LPS induced BV-2 cells activation is a valid in vitro model of microglia activation.D-β-HB is able to suppress the activation of BV-2 cells, which might account for one of the possible reasons of KD therapy on the PD model.
文摘Traumatic brain injury（TBI）remains one of the leading causes of disability and death in infants and children.Studies have demonstrated that the youngest age group（especially≤4 years old）exhibit worse functional outcome following moderate to severe TBI compared to older children or adults（Anderson et al.,2005;Emami et al.,2017）.These data suggest that age-at-injury may be an important determinant of outcome,
文摘A recent publication by Qin et al.in Cell reported on the first-inhuman application of anti-BCMA chimeric antigen receptor(CAR)-T cell therapy in patients with treatment-refractory progressive multiple sclerosis(MS)with a good tolerability and efficacy.1 CAR-T cells rank among the breakthrough therapeutic approaches,transforming the field of cancer and autoimmune conditions including neuroimmunological disorders.B-cell maturation antigen(BCMA)and CD19 antigen are B-cell target antigens frequently used in CAR constructs for autoimmune diseases.1,2 In addition to the B-cell depletion in the peripheral blood,CAR-T cells allow deep depletion of tissue-resident B cells e.g.,in lymphoid tissues and hard-to-reach compartments such as the central nervous system(CNS),an effect that has not been observed with antibody-based B-cell depletion therapies.However,little is known about direct and indirect effects of CAR-T cells on microglia,even though CNS-resident microglial cells are involved as one of the key drivers and maintainers of the compartmentalized neuroinflammation and neurodegeneration during MS progression.This is confirmed by emerging evidence that smoldering neurodegenerative processes are hallmarked by chronic microglia-mediated neuroinflammation with progressive axonal injury,resulting in disability progression independent of relapse activity(PIRA)and brain atrophy.1 To date,none of the available therapies for MS are fully effective at preventing disease progression and PIRA.
基金supported by the National Key R&D Program of China(2024YFC3505405)National Natural Science Foundation of China(No.82474341 and 82174498)+3 种基金Jiangsu Leading Talents in Traditional Chinese Medicine(SLJ0303)Jiangsu Province Acupuncture Moxibustion Integrated Education Ministry Key Laboratory Open Project(AML202306)the Subject of Academic Priority Discipline of Jiangsu Higher Education Institutions(2024)National Administration of Traditional Chinese Medicine Youth Qihuang Scholars Support Project(2022).
文摘Opioid analgesics,including morphine,pose significant challenges in clinical pain management due to the development of tolerance-a phenomenon that necessitates escalating dosages to maintain analgesic efficacy while increasing risks of adverse effects and addiction.
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.
文摘Neuroinflammation is a major contributor to secondary neuronal injury that accounts for a significant proportion of final brain cell loss in neonatal hypoxic-ischemic encephalopathy(HIE).However,the immunological mechanisms that underlie HIE remain unclear.MicroRNA-210(miR-210)is the master“hypoxamir”and plays a key role in hypoxic-ischemic tissue damage.Herein,we report in an animal model of neonatal rats that HIE significantly upregulated miR-210 expression in microglia in the neonatal brain and strongly induced activated microglia.Intracerebroventricular administration of miR-210 antagomir effectively suppressed microglia-mediated neuroinflammation and significantly reduced brain injury caused by HIE.We demonstrated that miR-210 induced microglial M1 activation partly by targeting SIRT1,thereby reducing the deacetylation of the NF-κB subunit p65 and increasing NF-κB signaling activity.Thus,our study identified miR-210 as a novel regulator of microglial activation in neonatal HIE,highlighting a potential therapeutic target in the treatment of infants with hypoxic-ischemic brain injury.
基金supported by the Taishan Scholars Program of Shandong Province(tsqn202312344).
文摘Multiple sclerosis (MS) is characterized by chronic,slowly expanding lesions with the accumulation of myeloid cells,which lead to brain atrophy and progressive disability.The role of mitochondria,especially mitochondrial respiratory complexes and metabolites,in controlling myeloid immune responses,is well-documented but not fully understood in diseases of the central nervous system (CNS).The groundbreaking study by Prof.Peruzzotti-Jametti et al.[1],entitled"Mitochondrial complexⅠactivity in microglia sustains neuroinflammation"published in Nature,delves into the intricate dynamics between mitochondrial function within microglia and the perpetuation of chronic neuroinflammation,specifically in MS.The core point of their investigation is the hypothesis that mitochondrial complexⅠ(CI) activity,through a mechanism known as reverse electron transport (RET),generates reactive oxygen species (ROS) in microglia,thereby sustaining inflammatory response in the CNS.This increases ROS production from the mitochondria,which is thought to be a crucial factor in the maintenance of a pro-inflammatory state in the microglia,contributing to the pathology of MS and similar neuroinflammatory diseases.
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 the National Natural Science Foundation of China,Nos.32371065(to CL)and 32170950(to LY)the Natural Science Foundation of the Guangdong Province,No.2023A1515010899(to CL)the Science and Technology Projects in Guangzhou,Nos.2023A4J0578 and 2024A03J0180(to CW)。
文摘Neuronal activity,synaptic transmission,and molecular changes in the basolateral amygdala play critical roles in fear memory.Cylindromatosis(CYLD)is a deubiquitinase that negatively regulates the nuclear factor kappa-B pathway.CYLD is well studied in non-neuronal cells,yet underinvestigated in the brain,where it is highly expressed.Emerging studies have shown involvement of CYLD in the remodeling of glutamatergic synapses,neuroinflammation,fear memory,and anxiety-and autism-like behaviors.However,the precise role of CYLD in glutamatergic neurons is largely unknown.Here,we first proposed involvement of CYLD in cued fear expression.We next constructed transgenic model mice with specific deletion of Cyld from glutamatergic neurons.Our results show that glutamatergic CYLD deficiency exaggerated the expression of cued fear in only male mice.Further,loss of CYLD in glutamatergic neurons resulted in enhanced neuronal activation,impaired excitatory synaptic transmission,and altered levels of glutamate receptors accompanied by over-activation of microglia in the basolateral amygdala of male mice.Altogether,our study suggests a critical role of glutamatergic CYLD in maintaining normal neuronal,synaptic,and microglial activation.This may contribute,at least in part,to cued fear expression.
基金supported by the National Natural Science Foundation of China(Nos.81920108017 and 82130036)the Key Research and Development Program of Jiangsu Province of China(No.BE2020620)Jiangsu Province Key Medical Discipline(No.ZDXKA2016020)。
文摘Microglia,the resident immune cells in the central nervous system(CNS),rapidly transition from a resting to an active state in the acute phase of ischemic brain injury.This active state mediates a pro-inflammatory response that can exacerbate the injury.Targeting the pro-inflammatory response of microglia in the semi-dark band during this acute phase may effectively reduce brain injury.Shionone(SH),an active ingredient extracted from the dried roots and rhizomes of the genus Aster(Asteraceae),has been reported to regulate the inflammatory response of macrophages in sepsis-induced acute lung injury.However,its function in post-stroke neuroinflammation,particularly microglia-mediated neuroinflammation,remains uninvestigated.This study found that SH significantly inhibited lipopolysaccharide(LPS)-induced elevation of inflammatory cytokines,including interleukin-1β(IL-1β),tumor necrosis factor-α(TNF-α),and inducible nitric oxide synthase(iNOS),in microglia in vitro.Furthermore,the results demonstrated that SH alleviated infarct volume and improved behavioral performance in middle cerebral artery occlusion(MCAO)mice,which may be attributed to the inhibition of the microglial inflammatory response induced by SH treatment.Mechanistically,SH potently inhibited the phosphorylation of serine-threonine protein kinase B(AKT),mammalian target of rapamycin(mTOR),and signal transducer and activator of transcription 3(STAT3).These findings suggest that SH may be a potential therapeutic agent for relieving ischemic stroke(IS)by alleviating microglia-associated neuroinflammation.
基金supported by the Beijing Natural Science Foundation(7222274)the Fifth Batch of National Outstanding Talents in Clinical Chinese Medicine(20221)。
文摘Objective:To investigate the efficacy and mechanism of Ditan Qingnao decoction(DTQND)in alleviating schizophrenia-like symptoms in a maternal immune activation(MIA)-induced rat model.Methods:DTQND components were analyzed using high-performance liquid chromatography-tandem mass spectrometry.An MIA-induced rat model was established by injecting Poly Ⅰ:C into pregnant dams on gestational day 9.Male offspring were administered DTQND(14.1 g/kg),risperidone(RIS;0.4 mg/kg),or distilled water,while the controls received only distilled water via gavage for 4 weeks.Behavioral assessments were conducted using the open-field,Y-maze,prepulse inhibition,and sucrose preference tests.Serum levels of interleukin(IL)-6,IL-18,IL-1β,and tumor necrosis factor-α(TNF-α)were measured via an enzyme-linked immunosorbent assay.Hippocampal protein levels of nuclear factor kappa B p65(NF-κB p65),phospho-NF-κB p65(p-p65),inhibitor of kappa B-alpha(IκB-α),phospho-IκB-α(p-IκB-α),and nucleotide-binding oligomerization domain-like receptor family pyrin domain-containing protein 3(NLRP3)were assessed via western blots.Immunohistochemistry detected hippocampal expression of ionized calcium-binding adapter molecule 1(Iba1)and cluster of differentiation 68(CD68).Results:Multiple DTQND compounds were identified,including stachyose,β-syringin,and isofraxidin,among others.DTQND treatment considerably enhanced spontaneous activity,reduced anxiety,improved spatial working memory,and alleviated sensory gating defects in male offspring with MIA.The DTQND group showed significantly lower serum levels of IL-1β(P=.002)and IL-18(P=.046)than the model group,with no discernible variations in IL-6 or TNF-α levels.In the hippocampus,DTQND significantly suppressed the expression of p-p65(P<.001),p-IκB-α(P=.023),and NLRP3(P<.001)compared to the model group.Additionally,DTQND modulated microglial activation markers,decreasing CD68 expression(P=.004)without affecting Iba1 levels.Conclusions:DTQND alleviated schizophrenia-like behavioral deficits and cognitive impairment by inhibiting the NF-κB/NLRP3 pathway,supporting its potential as an alternative therapy for schizophrenia.
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.
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.
文摘Inflammation plays an important role in the pathological process of ischemic stroke,and systemic inflammation affects patient prognosis.As resident immune cells in the brain,microglia are significantly involved in immune defense and tissue repair under various pathological conditions,including cerebral ischemia.Although the differentiation of M1 and M2 microglia is certainly oversimplified,changing the activation state of microglia appears to be an intriguing therapeutic strategy for cerebral ischemia.Recent evidence indicates that both mesenchymal stem cells(MSCs)and MSC-derived extracellular vesicles(EVs)regulate inflammation and modify tissue repair under preclinical stroke conditions.However,the precise mechanisms of these signaling pathways,especially in the context of the mutual interaction between MSCs or MSC-derived EVs and resident microglia,have not been sufficiently unveiled.Hence,this review summarizes the state-ofthe-art knowledge on MSC-and MSC-EV-mediated regulation of microglial activity under ischemic stroke conditions with respect to various signaling pathways,including cytokines,neurotrophic factors,transcription factors,and microRNAs.
基金supported by STI 2030-Major Projects,No.2022ZD0208503(to DY)the Fund of Chinese Academy of Science(“Xi Bu Zhi Guang”Project)(to YY)the Sichuan Science and Technology Program,No.2023YFS0312(to YY).
文摘While degenerative diseases of the central nervous system are commonly linked to age-related macular degeneration and glaucoma,they have also been infrequently associated with retinitis pigmentosa,a condition defined by retinal degeneration that can be caused by an isoform of receptor expression enhancing protein 6(REEP6)expressed in rod photoreceptors.In this study,we used REEP6 knockout mice(REEP6^(-/-))and wild-type mice(REEP6^(+/+))to examine neurodegenerative pathology within the visual pathways and neural activity in the primary visual cortex(V1)at three specific time points(1,6,and 10 months)during retinitis pigmentosa progression.Microglial activation was observed in both the retina and the primary visual cortex starting at 1 month of age,but no such activation was detected in the lateral geniculate nucleus at any time point.Not only was increased microglial activation observed at 6 and 10 months within the primary visual cortex of REEP6^(-/-)mice,but also coinciding with elevated levels of phosphorylated Tau expression.At 6 and 10 months of age,primary visual cortex neurons in REEP6^(-/-)mice exhibited reduced responses to grating stimuli and increased spontaneous activity compared with neurons in the primary visual cortex of mice in the control group.Our findings show that retinitis pigmentosa induces neurodegenerative pathology within the visual pathway of mice,particularly in the primary visual cortex,suggesting that ocular disease contributes substantially to central nervous system degeneration.It may provide new clues for the selection of treatment opportunities and the development of therapeutic measures for the subsequent treatment of retinitis pigmentosa or even other retinal degenerative diseases.
基金supported by the National Natural Science Foundation of China[82201489,2022].
文摘Objective:Multiple sclerosis(MS)is a chronic inflammatory demyelinating disease of the central nervous system(CNS).Soluble interleukin-2 receptor alpha(sIL-2Rα)has been implicated inMS pathogenesis,but its mechanisms remain unclear.This study investigates how sIL-2Rαexacerbates MS by modulating microglial activation and antibody-dependent cellular cytotoxicity(ADCC)in an experimental autoimmune encephalomyelitis(EAE)mouse model.Methods:Female C57BL/6J mice were induced with EAE and treated with sIL-2Rα.Clinical symptoms,histopathology,and molecular changes were analyzed.Microglial activation was assessed via immunohistochemistry,Western blot,and RNA sequencing.In vitro,ADCC-mediated oligodendrocyte injury was evaluated using Fc receptor inhibition and PI3K-Akt pathway blockade.Results:sIL-2Rα accelerated EAE onset and severity,increasingmicroglial M1 polarization and CNS inflammation.RNA-seq revealed PI3K-Akt pathway activation,upregulating Fc receptors(FcγR)on microglia,which enhanced ADCC against oligodendrocytes(p<0.001).Inhibiting FcγR or PI3K-Akt reduced oligodendrocyte damage.Conclusion:sIL-2Rαexacerbates MS by activating microglia via the PI3K-Aktaxis,promoting ADCC and demyelination.Targeting this pathway may offer novel therapeutic strategies for MS.
