Recently,we have shown that manual stimulation of paralyzed vibrissal muscles after facial-facial anastomosis reduced the poly-innervation of neuromuscular junctions and restored vibrissal whisking.Using gene knock ou...Recently,we have shown that manual stimulation of paralyzed vibrissal muscles after facial-facial anastomosis reduced the poly-innervation of neuromuscular junctions and restored vibrissal whisking.Using gene knock outs,we found a differential dependence of manual stimulation effects on growth factors.Thus,insulin-like growth factor-1 and brain-derived neurotrophic factor are required to underpin manual stimulation-mediated improvements,whereas FGF-2 is not.The lack of dependence on FGF-2 in mediating these peripheral effects prompted us to look centrally,i.e.within the facial nucleus where increased astrogliosis after facial-facial anastomosis follows ＂synaptic stripping＂.We measured the intensity of Cy3-fluorescence after immunostaining for glial fibrillary acidic protein（GFAP） as an indirect indicator of synaptic coverage of axotomized neurons in the facial nucleus of mice lacking FGF-2（FGF-2^（-/-） mice）.There was no difference in GFAP-Cy3-fluorescence（pixel number,gray value range17-103） between intact wildtype mice（2.12± 0.37×10~7） and their intact FGF-2^（-/-） counterparts（2.12±0.27×10~7） nor after facial-facial anastomosis ＋handling（wildtype：4.06±0.32×10~7;FGF-2^（-/-）：4.39±0.17×10~7）.However,after facial-facial anastomosis,GFAP-Cy3-fluorescence remained elevated in FGF-2^（-/-）-animals（4.54±0.12×10~7）,whereas manual otimulation reduced the intensity of GFAP-immunofluorescence in wild type mice to values that were not significantly different from intact mice（2.63±0.39×10）.We conclude that FGF-2 is not required to underpin the beneficial effects of manual stimulation at the neuro-muscular junction,but it is required to minimize astrogliosis in the brainstem and,by implication,restore synaptic coverage of recovering facial motoneurons.展开更多
Background:Exposure to ethanol in utero leads to several brain development disorders including retinal abnormalities whose underlying cellular pathogenesis remains elusive.We have previously reported changes in electr...Background:Exposure to ethanol in utero leads to several brain development disorders including retinal abnormalities whose underlying cellular pathogenesis remains elusive.We have previously reported changes in electroretinogram recordings in moderate fetal alcohol exposure(MFAE)vervet monkeys.The goal of this study is to characterize the anatomical effects of moderate MFAE during the third trimester in the vervet monkey retina.Methods:Using immunohistochemistry and Western blots,we analyzed changes in the expression of cell-type specific proteins that may occur in the MFAE retina compared to the normal retina.We also compared the basic retinal anatomy across groups by examining retinal layering and thickness.Results:Our main result indicates that GFAP(a potent marker of astrocytes)immunoreactivity was increased in the MFAE retina indicating strong astrogliosis.There was no obvious change in the overall anatomy in the MFAE retina and no significant differences in the mean thickness of each retinal layer.Furthermore,no significant changes in the morphology of the photoreceptors,horizontal cells,bipolar cells,and amacrines cells was observed.Conclusions:These data indicate that astrogliosis is a consequence of prenatal alcohol exposure and might explain the reported changes in the electroretinographic responses.展开更多
Argatroban is a synthetic thrombin inhibitor approved by U.S.Food and Drug Administration for the treatment of thrombosis.However,whether it plays a role in the repair of spinal cord injury is unknown.In this study,we...Argatroban is a synthetic thrombin inhibitor approved by U.S.Food and Drug Administration for the treatment of thrombosis.However,whether it plays a role in the repair of spinal cord injury is unknown.In this study,we established a rat model of T10 moderate spinal cord injury using an NYU Impactor ModerⅢand performed intraperitoneal injection of argatroban for 3 consecutive days.Our results showed that argatroban effectively promoted neurological function recovery after spinal cord injury and decreased thrombin expression and activity in the local injured spinal cord.RNA sequencing transcriptomic analysis revealed that the differentially expressed genes in the argatroban-treated group were enriched in the JAK2/STAT3 pathway,which is involved in astrogliosis and glial scar formation.Western blotting and immunofluorescence results showed that argatroban downregulated the expression of the thrombin receptor PAR1 in the injured spinal cord and the JAK2/STAT3 signal pathway.Argatroban also inhibited the activation and proliferation of astrocytes and reduced glial scar formation in the spinal cord.Taken together,these findings suggest that argatroban may inhibit astrogliosis by inhibiting the thrombin-mediated PAR1/JAK2/STAT3 signal pathway,thereby promoting the recovery of neurological function after spinal cord injury.展开更多
Astrocytes are indispensable for central nervous system development and homeostasis.In response to injury and disease,astrocytes are integral to the immunological-and the,albeit limited,repair response.In this review,...Astrocytes are indispensable for central nervous system development and homeostasis.In response to injury and disease,astrocytes are integral to the immunological-and the,albeit limited,repair response.In this review,we will examine some of the functions reactive astrocytes play in the context of multiple sclerosis and related animal models.We will consider the heterogeneity or plasticity of astrocytes and the mechanisms by which they promote or mitigate demyelination.Finally,we will discuss a set of biomedical strategies that can stimulate astrocytes in their promyelinating response.展开更多
Neuronal damage, glial inflammation, and astrogliosis/astroglial scar formation are major secondary injury mechanisms that are significant contributors to functional deficits after spinal cord injury （SCI）. The obje...Neuronal damage, glial inflammation, and astrogliosis/astroglial scar formation are major secondary injury mechanisms that are significant contributors to functional deficits after spinal cord injury （SCI）. The objectives of the study were to evaluate the distinct roles of ERK2 vs. ERK1/2 and ERK1/2-calpain 1 -NF-r,B signal transduction in the tissue damage and astrogliosis/astroglial scar formation following SCI in rats. RNAi approaches, pharmacological intervention （U0126）, Western blot analysis, immunofluorescence analysis, and histological assessment were used to target ERK1/2-calpain 1-NF-KB signal transduction pathway for neuroprotection. Histological staining analysis demonstrated that selectively reducing pERK2 using ERK2 siRNA, but not inhibition of pERK1/2 with U0126, significantly reduced lesion volume and improved total tissue sparing, white matter sparing, and gray matter sparing in spinal cord two weeks after contusive SCI. An ERK1/2-calpain 1-NF-KB signal transduction pathway was involved in the astroglial scar formation after SCI. Blockade of ERK1/2 by U0126 decreased calpain 1 expression 4 h following SCI. Selective calpain 1 reduction by lentiviral shRNA attenuated astroglial NF-κB activity and astroglial scar formation after SCI in rats. Taken together, these results demonstrate the involvement of individual ERK2 and caipain 1 signaling pathways in tissue damage and astrogliosis/astroglial scar formation in animal models of SCI. Therefore, targeting individual ERK and its downstream signal transduction of calpain 1-NF-κB may provide greater potential as novel therapeutics for minimizing tissue damage and astroglial scar formation following SCI.展开更多
Ferroptosis is an iron-dependent novel cell death pathway. Deferoxamine, a ferroptosis inhibitor, has been reported to promote spinal cord injury repair. It has yet to be clarified whether ferroptosis inhibition repre...Ferroptosis is an iron-dependent novel cell death pathway. Deferoxamine, a ferroptosis inhibitor, has been reported to promote spinal cord injury repair. It has yet to be clarified whether ferroptosis inhibition represents the mechanism of action of Deferoxamine on spinal cord injury recovery. A rat model of Deferoxamine at thoracic 10 segment was established using a modified Allen's method. Ninety 8-week-old female Wistar rats were used. Rats in the Deferoxamine group were intraperitoneally injected with 100 mg/kg Deferoxamine 30 minutes before injury. Simultaneously, the Sham and Deferoxamine groups served as controls. Drug administration was conducted for 7 consecutive days. The results were as follows:(1) Electron microscopy revealed shrunken mitochondria in the spinal cord injury group.(2) The Basso, Beattie and Bresnahan locomotor rating score showed that recovery of the hindlimb was remarkably better in the Deferoxamine group than in the spinal cord injury group.(3) The iron concentration was lower in the Deferoxamine group than in the spinal cord injury group after injury.(4) Western blot assay revealed that, compared with the spinal cord injury group, GPX4, xCT, and glutathione expression was markedly increased in the Deferoxamine group.(5) Real-time polymerase chain reaction revealed that, compared with the Deferoxamine group, mRNA levels of ferroptosis-related genes Acyl-CoA synthetase family member 2(ACSF2) and iron-responsive element-binding protein 2(IREB2) were up-regulated in the Deferoxamine group.(6) Deferoxamine increased survival of neurons and inhibited gliosis. These findings confirm that Deferoxamine can repair spinal cord injury by inhibiting ferroptosis. Targeting ferroptosis is therefore a promising therapeutic approach for spinal cord injury.展开更多
Reactive astrogliosis occurs after central nervous system（CNS） injuries whereby resident astrocytes form rapid responses along a graded continuum. Following CNS lesions, na？ve astrocytes are converted into reactive...Reactive astrogliosis occurs after central nervous system（CNS） injuries whereby resident astrocytes form rapid responses along a graded continuum. Following CNS lesions, na？ve astrocytes are converted into reactive astrocytes and eventually into scar-forming astrocytes that block axon regeneration and neural repair. It has been known for decades that scarring development and its related extracellular matrix molecules interfere with regeneration of injured axons after CNS injury, but the cellular and molecular mechanisms for controlling astrocytic scar formation and maintenance are not well known. Recent use of various genetic tools has made tremendous progress in better understanding genesis of reactive astrogliosis. Especially, the latest experiments demonstrate environment-dependent plasticity of reactive astrogliosis because reactive astrocytes isolated from injured spinal cord form scarring astrocytes when transplanted into injured spinal cord, but revert in retrograde to naive astrocytes when transplanted into naive spinal cord. The interactions between upregulated type I collagen and its receptor integrin β1 and the N-cadherin-mediated cell adhesion appear to play major roles for local astrogliosis around the lesion. This review centers on the environment-dependent plasticity of reactive astrogliosis after spinal cord injury and its potential as a therapeutic target.展开更多
Parkinson’s disease（PD） is an age-related neurodegenerative disease for which the characteristic motor symptoms emerge after an extensive loss of dopamine containing neurons.The cell bodies of these neurons are pre...Parkinson’s disease（PD） is an age-related neurodegenerative disease for which the characteristic motor symptoms emerge after an extensive loss of dopamine containing neurons.The cell bodies of these neurons are present in the substantia nigra,with the nerve terminals being in the striatum.Both innate and adaptive immune responses may contribute to dopaminergic neurodegeneration and disease progression is potentially linked to these.Studies in the last twenty years have indicated an important role for neuroinflammation in PD through degeneration of the nigrostriatal dopaminergic pathway.Characteristic of neuroinflammation is the activation of brain glial cells,principally microglia and astrocytes that release various soluble factors.Many of these factors are proinflammatory and neurotoxic and harmful to nigral dopaminergic neurons.Recent studies have identified several different agents with immunomodulatory properties that protected dopaminergic neurons from degeneration and death in animal models of PD.All of the agents were effective in reducing the motor deficit and alleviating dopaminergic neurotoxicity and,when measured,preventing the decrease of dopamine upon being administered therapeutically after 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine,6-hydroxydopamine,rotenone-lesioning or delivery of adeno-associated virus-α-synuclein to the ventral midbrain of animals.Some of these agents were shown to exert an anti-inflammatory action,decrease oxidative stress,and reduce lipid peroxidation products.Activation of microglia and astrocytes was also decreased,as well as infiltration of T cells into the substantia nigra.Pretreatment with fingolimod,tanshinoine I,dimethyl fumarate,thalidomide,or cocaine-and amphetamine-regulated transcript peptide as a preventive strategy ameliorated motor deficits and nigral dopaminergic neurotoxicity in brain-lesioned animals.Immunomodulatory agents could be used to treat patients with early clinical signs of the disease or potentially even prior to disease onset in those identified as having pre-disposing risk,including genetic factors.展开更多
MicroRNAs are a class of recently discovered, small non-coding RNAs that have been shown to play essential roles in a vast majority of biological processes. Very little is known about the role of microRNAs during spin...MicroRNAs are a class of recently discovered, small non-coding RNAs that have been shown to play essential roles in a vast majority of biological processes. Very little is known about the role of microRNAs during spinal cord injury. This review summarizes the changes in expression levels of microRNAs after spinal cord injury. These aberrant changes suggest that microRNAs play an important role in inflammation, oxidative stress, apoptosis, glial scar formation and axonal regeneration. Given their small size and specificity of action, microRNAs could be potential therapeutics for treating spinal cord injury in the future. There are rapidly developing techniques for manipulating microRNA levels in animals; we review different chemical modification and delivery strategies. These may provide platforms for designing efficient microRNA delivery protocols for use in the clinic.展开更多
Temporal lobe epilepsy is associated with astrogliosis. Notchl signaling can induce astrogliosis in glioma. However, it remains unknown whether Notchl signaling is involved in the pathogenesis of epilepsy. This study ...Temporal lobe epilepsy is associated with astrogliosis. Notchl signaling can induce astrogliosis in glioma. However, it remains unknown whether Notchl signaling is involved in the pathogenesis of epilepsy. This study investigated the presence of Notchl, hairy and enhancer of split-l, and glial fibrillary acidic protein in the temporal neocortex and hippocampus of lithium-pilocar- pine-treated rats. The presence of Notchl and hairy and enhancer of split-1 was also explored in brain tissues of patients with intractable temporal lobe epilepsy. Quantitative electroencephalo- gram analysis and behavioral observations were used as auxiliary measures. Results revealed that the presence of Notchl, hairy and enhancer of split-l, and glial fibriUary acidic protein were en- hanced in status epilepticus and vehicle-treated spontaneous recurrent seizures rats, but remain unchanged in the following groups： control, absence of either status epilepticus or spontaneous recurrent seizures, and zileuton-treated spontaneous recurrent seizures. Compared with patient control cases, the presences of Notch1 and hairy and enhancer of split- 1 were upregulated in the temporal neocortex of patients with intractable temporal lobe epilepsy. Therefore, these results suggest that Notchl signaling may play an important role in the onset of temporal lobe epilepsy via astrogliosis. Furthermore, zileuton may be a potential therapeutic strategy for temporal lobe epilepsy by blocking Notchl signaling.展开更多
Glial scarring following severe tissue damage and inflammation after spinal cord injury （SCI） is due to an extreme, uncontrolled form of reactive astrogliosis that typically occurs around the injury site. The scarri...Glial scarring following severe tissue damage and inflammation after spinal cord injury （SCI） is due to an extreme, uncontrolled form of reactive astrogliosis that typically occurs around the injury site. The scarring process includes the misalignment of activated astrocytes and the deposition of inhibitory chondroitin sulfate proteoglycans. Here, we first discuss recent developments in the molecular and cellular features of glial scar formation, with special focus on the potential cellular origin of scar-forming cells and the molecular mechanisms underlying glial scar formation after SCI. Second, we discuss the role of glial scar formation in the regulation of axonal regeneration and the cascades of neuro-inflammation. Last, we summarize the physical and pharmacological approaches targeting the modulation of glial scarring to better understand the role of glial scar formation in the repair of SCI.展开更多
Severe traumatic spinal cord injury(SCI)results in a devastating and permanent loss of function,and is currently an incurable condition.It is generally accepted that future intervention strategies will require combina...Severe traumatic spinal cord injury(SCI)results in a devastating and permanent loss of function,and is currently an incurable condition.It is generally accepted that future intervention strategies will require combinational approaches,including bioengineered scaffolds,to support axon growth across tissue scarring and cystic cavitation.Previously,we demonstrated that implantation of a microporous type-I collagen scaffold into an experimental model of SCI was capable of supporting functional recovery in the absence of extensive implant–host neural tissue integration.Here,we demonstrate the reactive host cellular responses that may be detrimental to neural tissue integration after implantation of collagen scaffolds into unilateral resection injuries of the adult rat spinal cord.Immunohistochemistry demonstrated scattered fibroblast-like cell infiltration throughout the scaffolds as well as the presence of variable layers of densely packed cells,the fine processes of which extended along the graft–host interface.Few reactive astroglial or regenerating axonal profiles could be seen traversing this layer.Such encapsulation-type behaviour around bioengineered scaffolds impedes the integration of host neural tissues and reduces the intended bridging role of the implant.Characterization of the cellular and molecular mechanisms underpinning this behaviour will be pivotal in the future design of collagen-based bridging scaffolds intended for regenerative medicine.展开更多
Previous studies have suggested that thrombospondin-1(TSP-1) regulates the transforming growth factor beta 1(TGF-b1)/phosphorylated Smad2/3(p Smad2/3) pathway. Moreover, TSP-1 is closely associated with epilepsy. Howe...Previous studies have suggested that thrombospondin-1(TSP-1) regulates the transforming growth factor beta 1(TGF-b1)/phosphorylated Smad2/3(p Smad2/3) pathway. Moreover, TSP-1 is closely associated with epilepsy. However, the role of the TSP-1-regulated TGFb1/p Smad2/3 pathway in seizures remains unclear. In this study, changes in this pathway were assessed following kainic acid(KA)-induced status epilepticus(SE) in rats.The results showed that increases in the TSP-1/TGF-b1/p Smad2/3 levels spatially and temporally matched the increases in glial fibrillary acidic protein(GFAP)/chondroitin sulfate(CS56) levels following KA administration.Inhibition of TSP-1 expression by small interfering RNA or inhibition of TGF-b1 activation with a Leu-Ser-Lys-Leu peptide significantly reduced the severity of KA-induced acute seizures. These anti-seizure effects were accompanied by decreased GFAP/CS56 expression and Smad2/3 phosphorylation. Moreover, inhibiting Smad2/3 phosphorylation with ponatinib or SIS3 also significantly reduced seizure severity, alongside reducing GFAP/CS56 immunoreactivity. These results suggest that the TSP-1-regulated TGF-b1/p Smad2/3 pathway plays a key role in KA-induced SE and astrogliosis, and that inhibiting this pathway may be a potential anti-seizure strategy.展开更多
Spinal cord injury(SCI)affects approximately 200,000 individuals per year worldwide.There are more than 27 million people worldwide living with long-term disability due to SCI.Historically,it was thought that the cent...Spinal cord injury(SCI)affects approximately 200,000 individuals per year worldwide.There are more than 27 million people worldwide living with long-term disability due to SCI.Historically,it was thought that the central nervous system(CNS)had little ability for regeneration;however,more recent studies have demonstrated potential for repair within the CNS.Because of this,there exists a renewed interest in the discovery of novel approaches to promote regeneration in the CNS including the spinal cord.It is important to know the roles of the microRNAs(miRNAs)in modulation of pathogenesis in SCI and the potentials of the miRNA-based clinical interventions for controlling post-injury symptoms and improving functional recovery.The miRNAs,which are non-coding RNAs with an average of 22 nucleotides in length,are post-transcriptional gene regulators that cause degradation of the target mRNAs and thus negatively control their translation.This review article focuses on current research related to miRNAs and their roles in modulating SCI symptoms,asserting that miRNAs contribute to critical post-SCI molecular processes including neuroplasticity,functional recovery,astrogliosis,neuropathic pain,inflammation,and apoptosis.In particular,miR-96 provides a promising therapeutic opportunity to improve the outcomes of clinical interventions,including the way SCI injuries are evaluated and treated.展开更多
The effect of ciliary neurotrophic factor (CNTF) on reactive astrogliosis was studied on a mechanical scratch model of the confluent astrocytic cultures from newborn rat brain. Following injury, the astrocytes at the ...The effect of ciliary neurotrophic factor (CNTF) on reactive astrogliosis was studied on a mechanical scratch model of the confluent astrocytic cultures from newborn rat brain. Following injury, the astrocytes at the edge of the injured area displayed a typical process of the reactive astrogliosis. This process included apparently hyperplastic change and significantly increased GFAP expression of the flat astrocytes, and migration to the injured area of the O-2A progenitor cells and their differentiation into process-bearing astrocytes. Exogenous CNTF applied to the cell cultures significantly promoted the hyperplasia and GFAP expression of the flat astrocytes. The results suggest that CNTF can enhance the reactive astrogliosis in the injured area.展开更多
基金financially supported by the Koln Fortune Programmthe Jean-Uhrmacher FoundationAkdeniz University Research Fund
文摘Recently,we have shown that manual stimulation of paralyzed vibrissal muscles after facial-facial anastomosis reduced the poly-innervation of neuromuscular junctions and restored vibrissal whisking.Using gene knock outs,we found a differential dependence of manual stimulation effects on growth factors.Thus,insulin-like growth factor-1 and brain-derived neurotrophic factor are required to underpin manual stimulation-mediated improvements,whereas FGF-2 is not.The lack of dependence on FGF-2 in mediating these peripheral effects prompted us to look centrally,i.e.within the facial nucleus where increased astrogliosis after facial-facial anastomosis follows ＂synaptic stripping＂.We measured the intensity of Cy3-fluorescence after immunostaining for glial fibrillary acidic protein（GFAP） as an indirect indicator of synaptic coverage of axotomized neurons in the facial nucleus of mice lacking FGF-2（FGF-2^（-/-） mice）.There was no difference in GFAP-Cy3-fluorescence（pixel number,gray value range17-103） between intact wildtype mice（2.12± 0.37×10~7） and their intact FGF-2^（-/-） counterparts（2.12±0.27×10~7） nor after facial-facial anastomosis ＋handling（wildtype：4.06±0.32×10~7;FGF-2^（-/-）：4.39±0.17×10~7）.However,after facial-facial anastomosis,GFAP-Cy3-fluorescence remained elevated in FGF-2^（-/-）-animals（4.54±0.12×10~7）,whereas manual otimulation reduced the intensity of GFAP-immunofluorescence in wild type mice to values that were not significantly different from intact mice（2.63±0.39×10）.We conclude that FGF-2 is not required to underpin the beneficial effects of manual stimulation at the neuro-muscular junction,but it is required to minimize astrogliosis in the brainstem and,by implication,restore synaptic coverage of recovering facial motoneurons.
文摘Background:Exposure to ethanol in utero leads to several brain development disorders including retinal abnormalities whose underlying cellular pathogenesis remains elusive.We have previously reported changes in electroretinogram recordings in moderate fetal alcohol exposure(MFAE)vervet monkeys.The goal of this study is to characterize the anatomical effects of moderate MFAE during the third trimester in the vervet monkey retina.Methods:Using immunohistochemistry and Western blots,we analyzed changes in the expression of cell-type specific proteins that may occur in the MFAE retina compared to the normal retina.We also compared the basic retinal anatomy across groups by examining retinal layering and thickness.Results:Our main result indicates that GFAP(a potent marker of astrocytes)immunoreactivity was increased in the MFAE retina indicating strong astrogliosis.There was no obvious change in the overall anatomy in the MFAE retina and no significant differences in the mean thickness of each retinal layer.Furthermore,no significant changes in the morphology of the photoreceptors,horizontal cells,bipolar cells,and amacrines cells was observed.Conclusions:These data indicate that astrogliosis is a consequence of prenatal alcohol exposure and might explain the reported changes in the electroretinographic responses.
基金supported by the Key Project of the National Natural Science Foundation of China,No.81930070(to SF)the National Natural Science Foundation of China,No.81972074(to XY)the Key Program of Natural Science Foundation of Tianjin,No.19JCZDJC34900(to XY)。
文摘Argatroban is a synthetic thrombin inhibitor approved by U.S.Food and Drug Administration for the treatment of thrombosis.However,whether it plays a role in the repair of spinal cord injury is unknown.In this study,we established a rat model of T10 moderate spinal cord injury using an NYU Impactor ModerⅢand performed intraperitoneal injection of argatroban for 3 consecutive days.Our results showed that argatroban effectively promoted neurological function recovery after spinal cord injury and decreased thrombin expression and activity in the local injured spinal cord.RNA sequencing transcriptomic analysis revealed that the differentially expressed genes in the argatroban-treated group were enriched in the JAK2/STAT3 pathway,which is involved in astrogliosis and glial scar formation.Western blotting and immunofluorescence results showed that argatroban downregulated the expression of the thrombin receptor PAR1 in the injured spinal cord and the JAK2/STAT3 signal pathway.Argatroban also inhibited the activation and proliferation of astrocytes and reduced glial scar formation in the spinal cord.Taken together,these findings suggest that argatroban may inhibit astrogliosis by inhibiting the thrombin-mediated PAR1/JAK2/STAT3 signal pathway,thereby promoting the recovery of neurological function after spinal cord injury.
基金supported by the Heart and Stroke Foundation and Ontario Institute of Regenerative Medicine (New Ideas Grant)Canada First Research Excellence Fund(Medicine by Design)+2 种基金the National Sciences and Engineering Research Councilthe Jurgen Manchot Foundationthe Christiane and Claudia Hempel Foundation for Clinical Stem Cell Research and the James and Elisabeth Cloppenburg,Peek and Cloppenburg Düsseldorf Stiftung (to PK)
文摘Astrocytes are indispensable for central nervous system development and homeostasis.In response to injury and disease,astrocytes are integral to the immunological-and the,albeit limited,repair response.In this review,we will examine some of the functions reactive astrocytes play in the context of multiple sclerosis and related animal models.We will consider the heterogeneity or plasticity of astrocytes and the mechanisms by which they promote or mitigate demyelination.Finally,we will discuss a set of biomedical strategies that can stimulate astrocytes in their promyelinating response.
文摘Neuronal damage, glial inflammation, and astrogliosis/astroglial scar formation are major secondary injury mechanisms that are significant contributors to functional deficits after spinal cord injury （SCI）. The objectives of the study were to evaluate the distinct roles of ERK2 vs. ERK1/2 and ERK1/2-calpain 1 -NF-r,B signal transduction in the tissue damage and astrogliosis/astroglial scar formation following SCI in rats. RNAi approaches, pharmacological intervention （U0126）, Western blot analysis, immunofluorescence analysis, and histological assessment were used to target ERK1/2-calpain 1-NF-KB signal transduction pathway for neuroprotection. Histological staining analysis demonstrated that selectively reducing pERK2 using ERK2 siRNA, but not inhibition of pERK1/2 with U0126, significantly reduced lesion volume and improved total tissue sparing, white matter sparing, and gray matter sparing in spinal cord two weeks after contusive SCI. An ERK1/2-calpain 1-NF-KB signal transduction pathway was involved in the astroglial scar formation after SCI. Blockade of ERK1/2 by U0126 decreased calpain 1 expression 4 h following SCI. Selective calpain 1 reduction by lentiviral shRNA attenuated astroglial NF-κB activity and astroglial scar formation after SCI in rats. Taken together, these results demonstrate the involvement of individual ERK2 and caipain 1 signaling pathways in tissue damage and astrogliosis/astroglial scar formation in animal models of SCI. Therefore, targeting individual ERK and its downstream signal transduction of calpain 1-NF-κB may provide greater potential as novel therapeutics for minimizing tissue damage and astroglial scar formation following SCI.
基金supported by the National Natural Science Foundation of China,No.81672171(to XY),81330042(to SQF),81620108018(to SQF),81772342the State Key Laboratory of Medicinal Chemical Biology(Nankai University),China,No.2017027
文摘Ferroptosis is an iron-dependent novel cell death pathway. Deferoxamine, a ferroptosis inhibitor, has been reported to promote spinal cord injury repair. It has yet to be clarified whether ferroptosis inhibition represents the mechanism of action of Deferoxamine on spinal cord injury recovery. A rat model of Deferoxamine at thoracic 10 segment was established using a modified Allen's method. Ninety 8-week-old female Wistar rats were used. Rats in the Deferoxamine group were intraperitoneally injected with 100 mg/kg Deferoxamine 30 minutes before injury. Simultaneously, the Sham and Deferoxamine groups served as controls. Drug administration was conducted for 7 consecutive days. The results were as follows:(1) Electron microscopy revealed shrunken mitochondria in the spinal cord injury group.(2) The Basso, Beattie and Bresnahan locomotor rating score showed that recovery of the hindlimb was remarkably better in the Deferoxamine group than in the spinal cord injury group.(3) The iron concentration was lower in the Deferoxamine group than in the spinal cord injury group after injury.(4) Western blot assay revealed that, compared with the spinal cord injury group, GPX4, xCT, and glutathione expression was markedly increased in the Deferoxamine group.(5) Real-time polymerase chain reaction revealed that, compared with the Deferoxamine group, mRNA levels of ferroptosis-related genes Acyl-CoA synthetase family member 2(ACSF2) and iron-responsive element-binding protein 2(IREB2) were up-regulated in the Deferoxamine group.(6) Deferoxamine increased survival of neurons and inhibited gliosis. These findings confirm that Deferoxamine can repair spinal cord injury by inhibiting ferroptosis. Targeting ferroptosis is therefore a promising therapeutic approach for spinal cord injury.
基金supported by research grants to SL from NIH(1R01NS079432 and 1R01EY024575)Shriners Research Foundation(SHC-86300-PHI,SHC-86200-PHI-16 and SHC-85100)
文摘Reactive astrogliosis occurs after central nervous system（CNS） injuries whereby resident astrocytes form rapid responses along a graded continuum. Following CNS lesions, na？ve astrocytes are converted into reactive astrocytes and eventually into scar-forming astrocytes that block axon regeneration and neural repair. It has been known for decades that scarring development and its related extracellular matrix molecules interfere with regeneration of injured axons after CNS injury, but the cellular and molecular mechanisms for controlling astrocytic scar formation and maintenance are not well known. Recent use of various genetic tools has made tremendous progress in better understanding genesis of reactive astrogliosis. Especially, the latest experiments demonstrate environment-dependent plasticity of reactive astrogliosis because reactive astrocytes isolated from injured spinal cord form scarring astrocytes when transplanted into injured spinal cord, but revert in retrograde to naive astrocytes when transplanted into naive spinal cord. The interactions between upregulated type I collagen and its receptor integrin β1 and the N-cadherin-mediated cell adhesion appear to play major roles for local astrogliosis around the lesion. This review centers on the environment-dependent plasticity of reactive astrogliosis after spinal cord injury and its potential as a therapeutic target.
文摘Parkinson’s disease（PD） is an age-related neurodegenerative disease for which the characteristic motor symptoms emerge after an extensive loss of dopamine containing neurons.The cell bodies of these neurons are present in the substantia nigra,with the nerve terminals being in the striatum.Both innate and adaptive immune responses may contribute to dopaminergic neurodegeneration and disease progression is potentially linked to these.Studies in the last twenty years have indicated an important role for neuroinflammation in PD through degeneration of the nigrostriatal dopaminergic pathway.Characteristic of neuroinflammation is the activation of brain glial cells,principally microglia and astrocytes that release various soluble factors.Many of these factors are proinflammatory and neurotoxic and harmful to nigral dopaminergic neurons.Recent studies have identified several different agents with immunomodulatory properties that protected dopaminergic neurons from degeneration and death in animal models of PD.All of the agents were effective in reducing the motor deficit and alleviating dopaminergic neurotoxicity and,when measured,preventing the decrease of dopamine upon being administered therapeutically after 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine,6-hydroxydopamine,rotenone-lesioning or delivery of adeno-associated virus-α-synuclein to the ventral midbrain of animals.Some of these agents were shown to exert an anti-inflammatory action,decrease oxidative stress,and reduce lipid peroxidation products.Activation of microglia and astrocytes was also decreased,as well as infiltration of T cells into the substantia nigra.Pretreatment with fingolimod,tanshinoine I,dimethyl fumarate,thalidomide,or cocaine-and amphetamine-regulated transcript peptide as a preventive strategy ameliorated motor deficits and nigral dopaminergic neurotoxicity in brain-lesioned animals.Immunomodulatory agents could be used to treat patients with early clinical signs of the disease or potentially even prior to disease onset in those identified as having pre-disposing risk,including genetic factors.
基金supported by grants from the National Natural Science Foundation of China,No. 30971633 and 31171045the Program for Changjiang Scholars and Innovative Research Team in University,No. IRT0935the New Jersey Commission on Spinal Cord Research
文摘MicroRNAs are a class of recently discovered, small non-coding RNAs that have been shown to play essential roles in a vast majority of biological processes. Very little is known about the role of microRNAs during spinal cord injury. This review summarizes the changes in expression levels of microRNAs after spinal cord injury. These aberrant changes suggest that microRNAs play an important role in inflammation, oxidative stress, apoptosis, glial scar formation and axonal regeneration. Given their small size and specificity of action, microRNAs could be potential therapeutics for treating spinal cord injury in the future. There are rapidly developing techniques for manipulating microRNA levels in animals; we review different chemical modification and delivery strategies. These may provide platforms for designing efficient microRNA delivery protocols for use in the clinic.
基金funded by the Natural Science Foundation of Hubei Province in China,No.02.02.040458
文摘Temporal lobe epilepsy is associated with astrogliosis. Notchl signaling can induce astrogliosis in glioma. However, it remains unknown whether Notchl signaling is involved in the pathogenesis of epilepsy. This study investigated the presence of Notchl, hairy and enhancer of split-l, and glial fibrillary acidic protein in the temporal neocortex and hippocampus of lithium-pilocar- pine-treated rats. The presence of Notchl and hairy and enhancer of split-1 was also explored in brain tissues of patients with intractable temporal lobe epilepsy. Quantitative electroencephalo- gram analysis and behavioral observations were used as auxiliary measures. Results revealed that the presence of Notchl, hairy and enhancer of split-l, and glial fibriUary acidic protein were en- hanced in status epilepticus and vehicle-treated spontaneous recurrent seizures rats, but remain unchanged in the following groups： control, absence of either status epilepticus or spontaneous recurrent seizures, and zileuton-treated spontaneous recurrent seizures. Compared with patient control cases, the presences of Notch1 and hairy and enhancer of split- 1 were upregulated in the temporal neocortex of patients with intractable temporal lobe epilepsy. Therefore, these results suggest that Notchl signaling may play an important role in the onset of temporal lobe epilepsy via astrogliosis. Furthermore, zileuton may be a potential therapeutic strategy for temporal lobe epilepsy by blocking Notchl signaling.
基金supported by grants from the National Basic Research Development Program of China (2011CB504401)the National Natural Science Foundation of China (31130024,31070922 and 81261130313)
文摘Glial scarring following severe tissue damage and inflammation after spinal cord injury （SCI） is due to an extreme, uncontrolled form of reactive astrogliosis that typically occurs around the injury site. The scarring process includes the misalignment of activated astrocytes and the deposition of inhibitory chondroitin sulfate proteoglycans. Here, we first discuss recent developments in the molecular and cellular features of glial scar formation, with special focus on the potential cellular origin of scar-forming cells and the molecular mechanisms underlying glial scar formation after SCI. Second, we discuss the role of glial scar formation in the regulation of axonal regeneration and the cascades of neuro-inflammation. Last, we summarize the physical and pharmacological approaches targeting the modulation of glial scarring to better understand the role of glial scar formation in the repair of SCI.
基金supported by the START-Program of the Faculty of Medicine,RWTH Aachen.
文摘Severe traumatic spinal cord injury(SCI)results in a devastating and permanent loss of function,and is currently an incurable condition.It is generally accepted that future intervention strategies will require combinational approaches,including bioengineered scaffolds,to support axon growth across tissue scarring and cystic cavitation.Previously,we demonstrated that implantation of a microporous type-I collagen scaffold into an experimental model of SCI was capable of supporting functional recovery in the absence of extensive implant–host neural tissue integration.Here,we demonstrate the reactive host cellular responses that may be detrimental to neural tissue integration after implantation of collagen scaffolds into unilateral resection injuries of the adult rat spinal cord.Immunohistochemistry demonstrated scattered fibroblast-like cell infiltration throughout the scaffolds as well as the presence of variable layers of densely packed cells,the fine processes of which extended along the graft–host interface.Few reactive astroglial or regenerating axonal profiles could be seen traversing this layer.Such encapsulation-type behaviour around bioengineered scaffolds impedes the integration of host neural tissues and reduces the intended bridging role of the implant.Characterization of the cellular and molecular mechanisms underpinning this behaviour will be pivotal in the future design of collagen-based bridging scaffolds intended for regenerative medicine.
基金the National Natural Science Foundation of China(81573412)the Key Research and Development Plan(2018GSF121004)the Natural Science Foundation of Shandong Province,China(ZR2014JL055).
文摘Previous studies have suggested that thrombospondin-1(TSP-1) regulates the transforming growth factor beta 1(TGF-b1)/phosphorylated Smad2/3(p Smad2/3) pathway. Moreover, TSP-1 is closely associated with epilepsy. However, the role of the TSP-1-regulated TGFb1/p Smad2/3 pathway in seizures remains unclear. In this study, changes in this pathway were assessed following kainic acid(KA)-induced status epilepticus(SE) in rats.The results showed that increases in the TSP-1/TGF-b1/p Smad2/3 levels spatially and temporally matched the increases in glial fibrillary acidic protein(GFAP)/chondroitin sulfate(CS56) levels following KA administration.Inhibition of TSP-1 expression by small interfering RNA or inhibition of TGF-b1 activation with a Leu-Ser-Lys-Leu peptide significantly reduced the severity of KA-induced acute seizures. These anti-seizure effects were accompanied by decreased GFAP/CS56 expression and Smad2/3 phosphorylation. Moreover, inhibiting Smad2/3 phosphorylation with ponatinib or SIS3 also significantly reduced seizure severity, alongside reducing GFAP/CS56 immunoreactivity. These results suggest that the TSP-1-regulated TGF-b1/p Smad2/3 pathway plays a key role in KA-induced SE and astrogliosis, and that inhibiting this pathway may be a potential anti-seizure strategy.
基金The work was supported in part by an investigator-initiated research grant(SCIRF-2015-1-01)from South Carolina Spinal Cord Injury Research Fund(Columbia,SC,USA)an award from the Soy Health Research Program(SHRP,United Soybean Board,Chesterfield,MO,USA)and earlier R01 grants(CA-091460 and NS-057811)from the National Institutes of Health(Bethesda,MD,USA).
文摘Spinal cord injury(SCI)affects approximately 200,000 individuals per year worldwide.There are more than 27 million people worldwide living with long-term disability due to SCI.Historically,it was thought that the central nervous system(CNS)had little ability for regeneration;however,more recent studies have demonstrated potential for repair within the CNS.Because of this,there exists a renewed interest in the discovery of novel approaches to promote regeneration in the CNS including the spinal cord.It is important to know the roles of the microRNAs(miRNAs)in modulation of pathogenesis in SCI and the potentials of the miRNA-based clinical interventions for controlling post-injury symptoms and improving functional recovery.The miRNAs,which are non-coding RNAs with an average of 22 nucleotides in length,are post-transcriptional gene regulators that cause degradation of the target mRNAs and thus negatively control their translation.This review article focuses on current research related to miRNAs and their roles in modulating SCI symptoms,asserting that miRNAs contribute to critical post-SCI molecular processes including neuroplasticity,functional recovery,astrogliosis,neuropathic pain,inflammation,and apoptosis.In particular,miR-96 provides a promising therapeutic opportunity to improve the outcomes of clinical interventions,including the way SCI injuries are evaluated and treated.
文摘The effect of ciliary neurotrophic factor (CNTF) on reactive astrogliosis was studied on a mechanical scratch model of the confluent astrocytic cultures from newborn rat brain. Following injury, the astrocytes at the edge of the injured area displayed a typical process of the reactive astrogliosis. This process included apparently hyperplastic change and significantly increased GFAP expression of the flat astrocytes, and migration to the injured area of the O-2A progenitor cells and their differentiation into process-bearing astrocytes. Exogenous CNTF applied to the cell cultures significantly promoted the hyperplasia and GFAP expression of the flat astrocytes. The results suggest that CNTF can enhance the reactive astrogliosis in the injured area.
