缺血性脑卒中后星形胶质细胞信号通路变化及潜在治疗靶点研究
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摘要
星形胶质细胞是中枢神经系统中含量最丰富的神经胶质细胞,对维持大脑正常生理功能起着重要作用。此外,星形胶质细胞还参与多种中枢神经系统疾病的发病过程,如局灶性脑缺血。局灶性脑缺血是导致患者脑损伤和死亡的主要原因,其主要病理特征之一是星形胶质细胞增生以及胶质疤痕的形成。本文针对缺血性脑卒中后星形胶质细胞中分子水平的动态变化以及信号通路进行综述,探讨基于星形胶质细胞的治疗局灶性脑缺血的潜在治疗靶点。
Astrocytes are a specialized and the most abundant cell type in the central nervous system( CNS). They play important roles in physiology of the brain. Astrocytes are also critically involved in many CNS disorders including focal ischemic stroke,the leading cause of brain injury and death in patients. One of the prominent pathological features of focal ischemic stroke is reactive astrogliosis and glial scar formation. In this article,we provided an overview of the most recent advances based on the experimental results obtained from different animal models,including dynamic changes of different molecular levels in astrocytes and signaling pathways involved in glial cell proliferation after ischemic stroke. Besides,we also discussed about therapeutic potential of reactive astrocytes during ischemic stroke from molecular perspective.
Astrocytes are a specialized and the most abundant cell type in the central nervous system( CNS). They play important roles in physiology of the brain. Astrocytes are also critically involved in many CNS disorders including focal ischemic stroke,the leading cause of brain injury and death in patients. One of the prominent pathological features of focal ischemic stroke is reactive astrogliosis and glial scar formation. In this article,we provided an overview of the most recent advances based on the experimental results obtained from different animal models,including dynamic changes of different molecular levels in astrocytes and signaling pathways involved in glial cell proliferation after ischemic stroke. Besides,we also discussed about therapeutic potential of reactive astrocytes during ischemic stroke from molecular perspective.
引文
[1]COLANGELO AM,ALBERGHINA L,PAPA M.Astrogliosis as a therapeutic target for neurodegenerative diseases[J].Neurosci Lett,2014,565:59-64.
[2]FEIGIN VL,NORRVING B.A new paradigm for primary prevention strategy in people with elevated risk of stroke[J].Int J Stroke,2014,9(5):624-626.
[3]KOYAMA Y.Signaling molecules regulating phenotypic conversions of astrocytes and glial scar formation in damaged nerve tissues[J].Neurochem Int,2014,78:35-42.
[4]BROWN AM.Brain glycogen re-awakened[J].J Neurochem,2004,89(3):537-552.
[5]MAGISTRETTI PJ.Neuron-glia metabolic coupling and plasticity[J].J Exp Biol,2006,209(12):2304-2311.
[6]WU X,ZHOU C,DU F,et al.Ginkgolide B preconditioning on astrocytes promotes neuronal survival in ischemic injury via upregulating erythropoietin secretion[J].Neurochem Int,2013,62(2):157-164.
[7]WANG HY,WANG GL,YU YH,et al.The role of phosphoinositide-3-kinase/Akt pathway in propofol-induced postconditioning against focal cerebral ischemia-reperfusion injury in rats[J].Brain Res,2009,1297:177-184.
[8]QU WS,WANG YH,WANG JP,et al.Galectin-1 enhances astrocytic BDNF production and improves functional outcome in rats following ischemia[J].Neurochem Res,2010,35(11):1716-1724.
[9]LI PC,JIAO Y,DING J,et al.Cystamine improves functional recovery via axon remodeling and neuroprotection after stroke in mice[J].CNS Neurosci Ther,2015,21(3):231-240.
[10]ACKER T,BECK H,PLATE KH.Cell type specific expression of vascular endothelial growth factor and angiopoietin-1 and-2suggests an important role of astrocytes in cerebellar vascularization[J].Mech Dev,2001,108(1-2):45-57.
[11]WEST H,RICHARDSON WD,FRUTTIGER M.Stabilization of the retinal vascular network by reciprocal feedback between blood vessels and astrocytes[J].Development,2005,132(8):1855-1862.
[12]SUN Y,JIN K,XIE L,et al.VEGF-induced neuroprotection,neurogenesis,and angiogenesis after focal cerebral ischemia[J].J Clin Invest,2003,111(12):1843-1851.
[13]MONTANA V,MALARKEY EB,VERDERIO C,et al.Vesicular transmitter release from astrocytes[J].Glia,2006,54(7):700-715.
[14]FELLIN T,PASCUAL O,GOBBO S,et al.Neuronal synchrony mediated by astrocytic glutamate through activation of extrasynaptic NMDA receptors[J].Neuron,2004,43(5):729-743.
[15]CONTRERAS JE,SANCHEZ HA,VELIZ LP,et al.Role of connexin-based gap junction channels and hemichannels in ischemia-induced cell death in nervous tissue[J].Brain Res,2004,47(1-3):290-303.
[16]THOMPSON RJ,ZHOU N,MACVICAR BA.Ischemia opens neuronal gap junction hemichannels[J].Science,2006,312(5775):924-927.
[17]PARPURA V,SCEMES E,SPRAY DC.Mechanisms of gluta-mate release from astrocytes:gap junction“hemichannels”,purinergic receptors and exocytotic release[J].Neurochem Int,2004,45(2-3):259-264.
[18]RANA S,DRINGEN R.Gap junction hemichannel-mediated release of glutathione from cultured rat astrocytes[J].Neurosci Lett,2007,415(1):45-48.
[19]DING S,WANG T,CUI W,et al.Photothrombosis ischemia stimulates a sustained astrocytic Ca2+signaling in vivo[J].Glia,2009,57(7):767-776.
[20]SHIMADA IS,BORDERS A,ARONSHTAM A,et al.Proliferating reactive astrocytes are regulated by Notch-1 in the peri-infarct area after stroke[J].Stroke,2011,42(11):3231-3237.
[21]BAO Y,QIN L,KIM E,et al.CD36 is involved in astrocyte activation and astroglial scar formation[J].J Cereb Blood Flow Metab,2012,32(8):1567-1577.
[22]CUADRADO A,NEBREDA AR.Mechanisms and functions of p38 MAPK signalling[J].J Biochem,2010,429(3):403-417.
[23]RALAY RANAIVO H,HODGE JN,CHOI N,et al.Albumin induces upregulation of matrix metalloproteinase-9 in astrocytes via MAPK and reactive oxygen species-dependent pathways[J].J Neuroinflammation,2012,9:68.
[24]ROY CHOUDHURY G,RYOU MG,POTEET E,et al.Involvement of p38 MAPK in reactive astrogliosis induced by ischemic stroke[J].Brain Res,2014,1551:45-58.
[25]ZHANG Y,HW K,WANG F,et al.Notch-1 signaling regulates astrocytic proliferation and activation after hypoxia exposure[J].Neurosci Lett,2015,603:12-18.
[26]NICOLAS CS,AMICI M,BORTOLOTTO ZA,et al.The role of JAK-STAT signaling within the CNS[J].JAKSTAT,2013,2(1):e22925.
[27]HERRMANN JE,IMURA T,SONG B,et al.STAT3 is a critical regulator of astrogliosis and scar formation after spinal cord injury[J].J Neurosci,2008,28(28):7231-7243.
[28]ZELENINA M.Regulation of brain aquaporins[J].Neurochem Int,2010,57(4):468-488.
[29]孟文婷,李东翔,佟玲.缺血性脑卒中的治疗研究进展[J].中国新药杂志,2016,25(10):1114-1120.
[30]GUNNARSON E,SONG Y,KOWALEWSKI JM,et al.Erythropoietin modulation of astrocyte water permeability as a component of neuroprotection[J].Proc Natl Acad Sci USA,2009,106(5):1602-1607.
[31]RODRIGUES RJ,TOME AR,CUNHA RA.ATP as a multi-target danger signal in the brain[J].Front Neurosci,2015,9:148.
[32]OUYANG YB,VOLOBOUEVA LA,XU LJ,et al.Selective dysfunction of hippocampal CA1 astrocytes contributes to delayed neuronal damage after transient forebrain ischemia[J].J Neurosci,2007,27(16):4253-4260.
[33]WELLER ML,STONE IM,GOSS A,et al.Selective overexpression of excitatory amino acid transporter 2(EAAT2)in astrocytes enhances neuroprotection from moderate but not severe hypoxia-ischemia[J].Neurosci,2008,155(4):1204-1211.
[34]MIAO Y,QIU Y,LIN Y,et al.Protection by pyruvate against glutamate neurotoxicity is mediated by astrocytes through a glutathione-dependent mechanism[J].Mol Biol Rep,2011,38(5):3235-3242.
[35]HILL JJ,JIN K,MAO XO,et al.Intracerebral chondroitinase ABC and heparan sulfate proteoglycan glypican improve outcome from chronic stroke in rats[J].Proc Natl Acad Sci USA,2012,109(23):9155-9160.
[36]GUO Z,ZHANG L,WU Z,et al.In vivo direct reprogramming of reactive glial cells into functional neurons after brain injury and in an Alzheimer's disease model[J].Cell Stem Cell,2014,14(2):188-202.
[37]ZHANG ZG,CHOPP M.Neurorestorative therapies for stroke:underlying mechanisms and translation to the clinic[J].Lancet Neurol,2009,8(5):491-500.
[38]HOSSEINI SM,FARAHMANDNIA M,KAZEMI S,et al.A novel cell therapy method for recovering after brain stroke in rats[J].Int J Stem Cells,2015,8(2):191-199.
[2]FEIGIN VL,NORRVING B.A new paradigm for primary prevention strategy in people with elevated risk of stroke[J].Int J Stroke,2014,9(5):624-626.
[3]KOYAMA Y.Signaling molecules regulating phenotypic conversions of astrocytes and glial scar formation in damaged nerve tissues[J].Neurochem Int,2014,78:35-42.
[4]BROWN AM.Brain glycogen re-awakened[J].J Neurochem,2004,89(3):537-552.
[5]MAGISTRETTI PJ.Neuron-glia metabolic coupling and plasticity[J].J Exp Biol,2006,209(12):2304-2311.
[6]WU X,ZHOU C,DU F,et al.Ginkgolide B preconditioning on astrocytes promotes neuronal survival in ischemic injury via upregulating erythropoietin secretion[J].Neurochem Int,2013,62(2):157-164.
[7]WANG HY,WANG GL,YU YH,et al.The role of phosphoinositide-3-kinase/Akt pathway in propofol-induced postconditioning against focal cerebral ischemia-reperfusion injury in rats[J].Brain Res,2009,1297:177-184.
[8]QU WS,WANG YH,WANG JP,et al.Galectin-1 enhances astrocytic BDNF production and improves functional outcome in rats following ischemia[J].Neurochem Res,2010,35(11):1716-1724.
[9]LI PC,JIAO Y,DING J,et al.Cystamine improves functional recovery via axon remodeling and neuroprotection after stroke in mice[J].CNS Neurosci Ther,2015,21(3):231-240.
[10]ACKER T,BECK H,PLATE KH.Cell type specific expression of vascular endothelial growth factor and angiopoietin-1 and-2suggests an important role of astrocytes in cerebellar vascularization[J].Mech Dev,2001,108(1-2):45-57.
[11]WEST H,RICHARDSON WD,FRUTTIGER M.Stabilization of the retinal vascular network by reciprocal feedback between blood vessels and astrocytes[J].Development,2005,132(8):1855-1862.
[12]SUN Y,JIN K,XIE L,et al.VEGF-induced neuroprotection,neurogenesis,and angiogenesis after focal cerebral ischemia[J].J Clin Invest,2003,111(12):1843-1851.
[13]MONTANA V,MALARKEY EB,VERDERIO C,et al.Vesicular transmitter release from astrocytes[J].Glia,2006,54(7):700-715.
[14]FELLIN T,PASCUAL O,GOBBO S,et al.Neuronal synchrony mediated by astrocytic glutamate through activation of extrasynaptic NMDA receptors[J].Neuron,2004,43(5):729-743.
[15]CONTRERAS JE,SANCHEZ HA,VELIZ LP,et al.Role of connexin-based gap junction channels and hemichannels in ischemia-induced cell death in nervous tissue[J].Brain Res,2004,47(1-3):290-303.
[16]THOMPSON RJ,ZHOU N,MACVICAR BA.Ischemia opens neuronal gap junction hemichannels[J].Science,2006,312(5775):924-927.
[17]PARPURA V,SCEMES E,SPRAY DC.Mechanisms of gluta-mate release from astrocytes:gap junction“hemichannels”,purinergic receptors and exocytotic release[J].Neurochem Int,2004,45(2-3):259-264.
[18]RANA S,DRINGEN R.Gap junction hemichannel-mediated release of glutathione from cultured rat astrocytes[J].Neurosci Lett,2007,415(1):45-48.
[19]DING S,WANG T,CUI W,et al.Photothrombosis ischemia stimulates a sustained astrocytic Ca2+signaling in vivo[J].Glia,2009,57(7):767-776.
[20]SHIMADA IS,BORDERS A,ARONSHTAM A,et al.Proliferating reactive astrocytes are regulated by Notch-1 in the peri-infarct area after stroke[J].Stroke,2011,42(11):3231-3237.
[21]BAO Y,QIN L,KIM E,et al.CD36 is involved in astrocyte activation and astroglial scar formation[J].J Cereb Blood Flow Metab,2012,32(8):1567-1577.
[22]CUADRADO A,NEBREDA AR.Mechanisms and functions of p38 MAPK signalling[J].J Biochem,2010,429(3):403-417.
[23]RALAY RANAIVO H,HODGE JN,CHOI N,et al.Albumin induces upregulation of matrix metalloproteinase-9 in astrocytes via MAPK and reactive oxygen species-dependent pathways[J].J Neuroinflammation,2012,9:68.
[24]ROY CHOUDHURY G,RYOU MG,POTEET E,et al.Involvement of p38 MAPK in reactive astrogliosis induced by ischemic stroke[J].Brain Res,2014,1551:45-58.
[25]ZHANG Y,HW K,WANG F,et al.Notch-1 signaling regulates astrocytic proliferation and activation after hypoxia exposure[J].Neurosci Lett,2015,603:12-18.
[26]NICOLAS CS,AMICI M,BORTOLOTTO ZA,et al.The role of JAK-STAT signaling within the CNS[J].JAKSTAT,2013,2(1):e22925.
[27]HERRMANN JE,IMURA T,SONG B,et al.STAT3 is a critical regulator of astrogliosis and scar formation after spinal cord injury[J].J Neurosci,2008,28(28):7231-7243.
[28]ZELENINA M.Regulation of brain aquaporins[J].Neurochem Int,2010,57(4):468-488.
[29]孟文婷,李东翔,佟玲.缺血性脑卒中的治疗研究进展[J].中国新药杂志,2016,25(10):1114-1120.
[30]GUNNARSON E,SONG Y,KOWALEWSKI JM,et al.Erythropoietin modulation of astrocyte water permeability as a component of neuroprotection[J].Proc Natl Acad Sci USA,2009,106(5):1602-1607.
[31]RODRIGUES RJ,TOME AR,CUNHA RA.ATP as a multi-target danger signal in the brain[J].Front Neurosci,2015,9:148.
[32]OUYANG YB,VOLOBOUEVA LA,XU LJ,et al.Selective dysfunction of hippocampal CA1 astrocytes contributes to delayed neuronal damage after transient forebrain ischemia[J].J Neurosci,2007,27(16):4253-4260.
[33]WELLER ML,STONE IM,GOSS A,et al.Selective overexpression of excitatory amino acid transporter 2(EAAT2)in astrocytes enhances neuroprotection from moderate but not severe hypoxia-ischemia[J].Neurosci,2008,155(4):1204-1211.
[34]MIAO Y,QIU Y,LIN Y,et al.Protection by pyruvate against glutamate neurotoxicity is mediated by astrocytes through a glutathione-dependent mechanism[J].Mol Biol Rep,2011,38(5):3235-3242.
[35]HILL JJ,JIN K,MAO XO,et al.Intracerebral chondroitinase ABC and heparan sulfate proteoglycan glypican improve outcome from chronic stroke in rats[J].Proc Natl Acad Sci USA,2012,109(23):9155-9160.
[36]GUO Z,ZHANG L,WU Z,et al.In vivo direct reprogramming of reactive glial cells into functional neurons after brain injury and in an Alzheimer's disease model[J].Cell Stem Cell,2014,14(2):188-202.
[37]ZHANG ZG,CHOPP M.Neurorestorative therapies for stroke:underlying mechanisms and translation to the clinic[J].Lancet Neurol,2009,8(5):491-500.
[38]HOSSEINI SM,FARAHMANDNIA M,KAZEMI S,et al.A novel cell therapy method for recovering after brain stroke in rats[J].Int J Stem Cells,2015,8(2):191-199.