CX3CR1在缺血性白质损伤中的意义及机制研究
摘要
缺血性白质损伤可以引起认知功能障碍，严重损害人类健康，其主要的发生机制有免疫炎性损害、氧化应激损伤、突触结构及功能异常等。目前研究的较多的为免疫炎性损伤机制。小胶质细胞作为中枢神经系统免疫吞噬细胞发挥着双重作用，少量被激活时，可以释放神经营养因子、吞噬废弃的组织碎片发挥保护性作用；大量被激活则产生炎性损害作用。CX3CR1作为小胶质细胞表面的一种受体分子，在生理条件下，使小胶质细胞保持静息状态、维持内环境的稳定状态；在急性缺血、变性疾病、神经创伤时发挥着损害性作用。在缺血性白质损伤时，如何变化、起什么样的作用尚未有研究。p38MAPK是MAPK家族中重要成员，主要参与炎性应激反应。p38MAPK是否参与CX3CR1介导的缺血性白质损伤的发病过程目前还不清楚。
目的：观察CX3CR1是否参与了慢性缺血性白质损伤发病过程；CX3CR1对慢性缺血性白质损伤是否通过p38MAPK途经实现。方法：雄性Wistar大鼠320只，随机分为正常组、假手术组、缺血组、阴性对照组、干预组，Morris水迷宫观察造模后28d学习记忆功能。造模后不同时间点（1d、3d、7d、14d、28d），HE染色及Luxol Fast Blue（LFB）染色法评价胼胝体、内囊、视神经纤维变化；Western Blot观察CX3CR1、P-p38/p38蛋白表达；免疫荧光双标技术观察CX3CR1与小胶质细胞关系；免疫组织化学染色评价小胶质细胞变化规律；侧脑室内注射不同浓度CX3CR1中和抗体、p38抑制剂进一步观察缺血后上述指标的变化。结果：（1）造模后28d，缺血组逃避潜伏期、空间探索路径较正常组延长，跨越平台次数显著减少（P<0.01）。（2）随着缺血时间的延长，HE染色观察到胼胝体、内囊及视神经区域白质纤维疏松，排列紊乱且空泡样改变；LFB染色可见上述区域髓鞘崩解范围扩大，分层明显，部分髓鞘出现空泡状；CX3CR1表达量持续增加，与CD11b标记的小胶质细胞数目持续增多相一致且高于假手术组和正常组（P<0.01）。（3）随着缺血时间的延长，P-p38/p38比值在缺血3d时出现明显变化，与CX3CR1变化具有相关性。（4）不同浓度CX3CR1中和抗体对缺血性白质损伤的认知功能、纤维损伤程度、CD11b小胶质细胞数目及P-p38/p38比值均有改善作用，且呈现剂量依赖性。应用p38抑制剂后，缺血性白质的纤维损伤程度及小胶质细胞数目均有不同程度改善。结论：（1）CX3CR1过表达通过介导小胶质细胞的变化对缺血性白质产生损伤作用，进而影响空间学习记忆功能。（2）CX3CR1/p38MAPK信号通路是缺血性白质损伤发生机制之一。
White matter lesions (WMLs) induced by chronic cerebral hypoperfusion (CCH) havebeen suggested to contribute to cognition impairment, which causes serious damage to humanhealth. Inflammation, oxidative stress and dysfuction of synatic structure are involved in thepathologic progress. For many years, increasing evidence indicates that inflammation plays acritical role in the pathogenesis of WMLs. In WMLs, microglia plays a dual role in diseaseprogression, being essential for clearing necrotic tissues and releasing of neurotrophic factors.Once the number of actived microglia is high, it can damge the normal tissue by producingsome inflammatory factors. CX3CR1, exclusively expressed by microglia in the brain,contributes to the ability of microglia to maintain a resting phenotype. CX3CR1has an effecton some disorders, such as acute ischemia, degenarative diseases and nerve damages.However, there is no study conferring to CX3CR1involved in the WMLs after CCH.p38MAPK, one of the important members in the MAPK families, is mainly involved ininflammation. It is unclear whether p38MAPK is involved in the process of WMLs inducedby CX3CR1after CCH.
Objective: The purpose of our study was to examine the relationship of CX3CR1withWMLs in CCH; to further study p38MAPK in the pathogenesis of CX3CR1invovled inWMLs. Methods: CCH was induced by permanent occlusion of bilateral common carotidarteries (BCCA) in male Wistar rats.320rats were randomly divided into five groups asfollows:(i)normal;(ii)sham-operation group;(iii)rats exposed to BCCA contribute to CCH;(iv)rats received control anti-IgG antibody or DMSO then exposed to BCCA;(v) rats receivedlateral ventricle stereotaxic injection of anti-CX3CR1neutralizing antibody or a p38inhibitorthen exposed to BCCA. Performance of Morris water maze task and the relationship ofCX3CR1with CD11b are analyzed at28d after CCH. Hematein Eosin(HE) and Luxol FastBlue(LFB) for white matters(corpus callosum, internal capsule and optic nerve), Western Blotfor CX3CR1and p38MAPK, immunohistochemistry for the progress of microglia areanalyzed at different times(1d,3d,7d,14d,28d) after post-hypoperfusion. All of above objectives were measured after post-hypoperfusion with lateral intraventricular injection ofdifferent concentration CX3CR1neutralizing antibodies or a p38inhibitor. Results：(1) Onthe28thafter surgery, compared with the control group, BCCA group significantly increasedthe mean escape latency, path length and reduced the numbers that the rats crossed over theposition where the platform located(P<0.01).(2) HE staining showed fibers lossen,disorganization and vacuolus in the corpus callosum, internal capsule and optic nerve. LFBstaining showed that increased number of vacuoles and demyelinated fibers in the abovewhite matters. A gradual increase in CX3CR1protein levels was observed in white mattersand CD11b marked activated microglia was almost at similar levels in these areas(P<0.01).(3)The ratio of P-p38/p38in white matters was significantly higher at the3rdafterpost-hypoperfusion, which had relationship with the alternation of CX3CR1.(4)Theadministration of anti-CX3CR1neutralizing antibodies, in which therer is an optismconcentrtion, alleviated behavior, white matters, microglia activation and the alternation ofP-p38/p38in rats with CCH. The administration of a p38inhibitor alleviated white mattersand microglia activation. Conclusion：(1) CX3CR1over expression has a bad effect byaffecting microglia on white matters after CCH, which plays an important role in learning andmemory.(2) CX3CR1/p38MAPK signaling is one of the pathogenesis in the WMLs afterCCH.
目的：观察CX3CR1是否参与了慢性缺血性白质损伤发病过程；CX3CR1对慢性缺血性白质损伤是否通过p38MAPK途经实现。方法：雄性Wistar大鼠320只，随机分为正常组、假手术组、缺血组、阴性对照组、干预组，Morris水迷宫观察造模后28d学习记忆功能。造模后不同时间点（1d、3d、7d、14d、28d），HE染色及Luxol Fast Blue（LFB）染色法评价胼胝体、内囊、视神经纤维变化；Western Blot观察CX3CR1、P-p38/p38蛋白表达；免疫荧光双标技术观察CX3CR1与小胶质细胞关系；免疫组织化学染色评价小胶质细胞变化规律；侧脑室内注射不同浓度CX3CR1中和抗体、p38抑制剂进一步观察缺血后上述指标的变化。结果：（1）造模后28d，缺血组逃避潜伏期、空间探索路径较正常组延长，跨越平台次数显著减少（P<0.01）。（2）随着缺血时间的延长，HE染色观察到胼胝体、内囊及视神经区域白质纤维疏松，排列紊乱且空泡样改变；LFB染色可见上述区域髓鞘崩解范围扩大，分层明显，部分髓鞘出现空泡状；CX3CR1表达量持续增加，与CD11b标记的小胶质细胞数目持续增多相一致且高于假手术组和正常组（P<0.01）。（3）随着缺血时间的延长，P-p38/p38比值在缺血3d时出现明显变化，与CX3CR1变化具有相关性。（4）不同浓度CX3CR1中和抗体对缺血性白质损伤的认知功能、纤维损伤程度、CD11b小胶质细胞数目及P-p38/p38比值均有改善作用，且呈现剂量依赖性。应用p38抑制剂后，缺血性白质的纤维损伤程度及小胶质细胞数目均有不同程度改善。结论：（1）CX3CR1过表达通过介导小胶质细胞的变化对缺血性白质产生损伤作用，进而影响空间学习记忆功能。（2）CX3CR1/p38MAPK信号通路是缺血性白质损伤发生机制之一。
White matter lesions (WMLs) induced by chronic cerebral hypoperfusion (CCH) havebeen suggested to contribute to cognition impairment, which causes serious damage to humanhealth. Inflammation, oxidative stress and dysfuction of synatic structure are involved in thepathologic progress. For many years, increasing evidence indicates that inflammation plays acritical role in the pathogenesis of WMLs. In WMLs, microglia plays a dual role in diseaseprogression, being essential for clearing necrotic tissues and releasing of neurotrophic factors.Once the number of actived microglia is high, it can damge the normal tissue by producingsome inflammatory factors. CX3CR1, exclusively expressed by microglia in the brain,contributes to the ability of microglia to maintain a resting phenotype. CX3CR1has an effecton some disorders, such as acute ischemia, degenarative diseases and nerve damages.However, there is no study conferring to CX3CR1involved in the WMLs after CCH.p38MAPK, one of the important members in the MAPK families, is mainly involved ininflammation. It is unclear whether p38MAPK is involved in the process of WMLs inducedby CX3CR1after CCH.
Objective: The purpose of our study was to examine the relationship of CX3CR1withWMLs in CCH; to further study p38MAPK in the pathogenesis of CX3CR1invovled inWMLs. Methods: CCH was induced by permanent occlusion of bilateral common carotidarteries (BCCA) in male Wistar rats.320rats were randomly divided into five groups asfollows:(i)normal;(ii)sham-operation group;(iii)rats exposed to BCCA contribute to CCH;(iv)rats received control anti-IgG antibody or DMSO then exposed to BCCA;(v) rats receivedlateral ventricle stereotaxic injection of anti-CX3CR1neutralizing antibody or a p38inhibitorthen exposed to BCCA. Performance of Morris water maze task and the relationship ofCX3CR1with CD11b are analyzed at28d after CCH. Hematein Eosin(HE) and Luxol FastBlue(LFB) for white matters(corpus callosum, internal capsule and optic nerve), Western Blotfor CX3CR1and p38MAPK, immunohistochemistry for the progress of microglia areanalyzed at different times(1d,3d,7d,14d,28d) after post-hypoperfusion. All of above objectives were measured after post-hypoperfusion with lateral intraventricular injection ofdifferent concentration CX3CR1neutralizing antibodies or a p38inhibitor. Results：(1) Onthe28thafter surgery, compared with the control group, BCCA group significantly increasedthe mean escape latency, path length and reduced the numbers that the rats crossed over theposition where the platform located(P<0.01).(2) HE staining showed fibers lossen,disorganization and vacuolus in the corpus callosum, internal capsule and optic nerve. LFBstaining showed that increased number of vacuoles and demyelinated fibers in the abovewhite matters. A gradual increase in CX3CR1protein levels was observed in white mattersand CD11b marked activated microglia was almost at similar levels in these areas(P<0.01).(3)The ratio of P-p38/p38in white matters was significantly higher at the3rdafterpost-hypoperfusion, which had relationship with the alternation of CX3CR1.(4)Theadministration of anti-CX3CR1neutralizing antibodies, in which therer is an optismconcentrtion, alleviated behavior, white matters, microglia activation and the alternation ofP-p38/p38in rats with CCH. The administration of a p38inhibitor alleviated white mattersand microglia activation. Conclusion：(1) CX3CR1over expression has a bad effect byaffecting microglia on white matters after CCH, which plays an important role in learning andmemory.(2) CX3CR1/p38MAPK signaling is one of the pathogenesis in the WMLs afterCCH.
引文
[1] Gemma C, Bachstetter AD.The role of microglia in adult hippocampal neurogenesis[J].Front Cell Neurosci,2013;7:229.
[2] Rostène W, Kitabgi P, Parsadaniantz SM.Chemokines: a new class of neuromodulator[J]? Nat Rev Neurosci,2007,8(11):895-903.
[3] Lagane B, Ballet S, Planchenault T, et al.Mutation of the DRY motif reveals differentstructural requirements for the CC chemokine receptor5-mediated signaling andreceptor endocytosis[J].Mol Pharmacol.2005,67(6):1966-76.
[4] Berchiche YA, Chow KY, Lagane B, et al.Direct assessment of CXCR4mutantconformations reveals complex link between receptor structure and G(alpha)(i)activation[J].J Biol Chem.2007,282(8):5111-5.
[5] Murdoch C, Finn A.Chemokine receptors and their role in inflammation and infectiousdiseases[J].Blood.2000,95(10):3032-43.
[6] Samstag Y, Eibert SM, Klemke M,et al.Actin cytoskeletal dynamics in T lymphocyteactivation and migration[J].J Leukoc Biol.2003,73(1):30-48.
[7] Slice LW, Wong HC, Sternini C, et al.The conserved NPXnY motif present in thegastrin-releasing peptide receptor is not a general sequestration sequence[J].J BiolChem.1994,269(34):21755-61.
[8] Barak LS, Tiberi M, Freedman NJ, et al.A highly conserved tyrosine residue in Gprotein-coupled receptors is required for agonist-mediated beta2-adrenergic receptorsequestration[J].J Biol Chem.1994,269(4):2790-5.
[9] Ribas C, Penela P, Murga C, et al.The G protein-coupled receptor kinase (GRK)interactome: role of GRKs in GPCR regulation and signaling[J].Biochim Biophys Acta.2007,1768(4):913-22.
[10] Clark AK, Yip PK, Grist J, et al.Inhibition of spinal microglial cathepsin S for thereversal of neuropathic pain[J].Proc Natl Acad Sci U S A.2007,104(25):10655-60.
[11] Hermand P, Pincet F, Carvalho S, et al.Functional adhesiveness of the CX3CL1chemokine requires its aggregation. Role of the transmembrane domain[J].J Biol Chem.2008,283(44):30225-34.
[12] Songyang Z, Lu KP, Kwon YT, et al.A structural basis for substrate specificities ofprotein Ser/Thr kinases: primary sequence preference of casein kinases I and II, NIMA,phosphorylase kinase, calmodulin-dependent kinase II, CDK5, and Erk1[J].Mol CellBiol.1996,16(11):6486-93.
[13] Cargnello M, Roux PP.Activation and function of the MAPKs and their substrates, theMAPK-activated protein kinases[J].Microbiol Mol Biol Rev.2011,75(1):50-83.
[14]张奇,白晓东,付小兵. p38MAPK信号通路研究进展.感染、炎症、修复[J],2005,6(2):121-123.
[15]张涛,杨承祥,王汉兵. p38MAPK信号通路与疼痛的关系[J].中国疼痛医学杂志,2012,18(3):177-180.
[16] Ji RR, Suter MR.p38MAPK, microglial signaling, and neuropathic pain[J].Mol Pain.2007,1(3):33.
[17] Julia V.CX3CL1in allergic diseases: not just a chemotactic molecule[J].Allergy.2012,67(9):1106-10.
[18] Giunti D, Parodi B, Usai C, et al.Mesenchymal stem cells shape microglia effectorfunctions through the release of CX3CL1[J].Stem Cells.2012,30(9):2044-53.
[19] Wang C, Liu F, Liu YY, et al.Identification and characterization of neuroblasts in thesubventricular zone and rostral migratory stream of the adult human brain[J].Cell Res.2011,21(11):1534-50.
[20] Gage FH.Mammalian neural stem cells[J].Science.2000,287(5457):1433-8.
[21] Gemma C, Bachstetter AD.The role of microglia in adult hippocampal neurogenesis[J].Front Cell Neurosci.2013,22(7):229.
[22] Ziv Y, Schwartz M.Immune-based regulation of adult neurogenesis: implications forlearning and memory[J].Brain Behav Immun.2008,22(2):167-76.
[23] Bachstetter AD, Morganti JM, Jernberg J, et al.Fractalkine and CX3CR1regulatehippocampal neurogenesis in adult and aged rats[J].Neurobiol Aging.2011,32(11):2030-44.
[24] Paolicelli RC, Bolasco G, Pagani F, et al.Synaptic pruning by microglia is necessary fornormal brain development[J].Science.2011,333(6048):1456-8.
[25] Hoshiko M, Arnoux I, Avignone E, et al.Deficiency of the microglial receptor CX3CR1impairs postnatal functional development of thalamocortical synapses in the barrelcortex[J].J Neurosci.2012,32(43):15106-11.
[26] Ross FM, Allan SM, Rothwell NJ, et al.A dual role for interleukin-1in LTP in mousehippocampal slices[J].J Neuroimmunol.2003,144(1-2):61-7.
[27] Fumagalli S, Perego C, Ortolano F, et al.CX3CR1deficiency induces an earlyprotective inflammatory environment in ischemic mice[J].Glia.2013,61(6):827-42.
[28] Williamson LL, Sholar PW, Mistry RS, et al.Microglia and memory: modulation byearly-life infection[J].J Neurosci.2011,31(43):15511-21.
[29] Rogers JT, Morganti JM, Bachstetter AD, et al.CX3CR1deficiency leads to impairmentof hippocampal cognitive function and synaptic plasticity[J].J Neurosci.2011,31(45):16241-50.
[30] Parkhurst CN, Yang G, Ninan I, et al.Microglia promote learning-dependent synapseformation through brain-derived neurotrophic factor[J].Cell.2013,155(7):1596-609.
[31] Cardona AE, Pioro EP, Sasse ME, et al.Control of microglial neurotoxicity by thefractalkine receptor[J].Nat Neurosci.2006,9(7):917-24.
[32] Zujovic V, Benavides J, Vigé X, et al.Fractalkine modulates TNF-alpha secretion andneurotoxicity induced by microglial activation[J].Glia.2000,29(4):305-15.
[33] Ji RR, Berta T, Nedergaard M.Glia and pain: Is chronic pain a gliopathy[J]?Pain.2013,154(Suppl1):S10-28.
[34] Staniland AA, Clark AK, Wodarski R, et al.Reduced inflammatory and neuropathic painand decreased spinal microglial response in fractalkine receptor (CX3CR1) knockoutmice[J].J Neurochem.2010,114(4):1143-57.
[35] Clark AK, Staniland AA, Marchand F,et al.P2X7-dependent release of interleukin-1betaand nociception in the spinal cord following lipopolysaccharide[J].J Neurosci.2010,30(2):573-82.
[36] Bian C, Wang ZC, Yang JL, et al.Up-regulation of interleukin-23induces persistentallodynia via CX3CL1and interleukin-18signaling in the rat spinal cord after tetanicsciatic stimulation[J].Brain Behav Immun.2014,37:220-30.
[37] Old EA, Malcangio M.Chemokine mediated neuron-glia communication and aberrantsignalling in neuropathic pain states[J].Curr Opin Pharmacol.2012,12(1):67-73.
[38] Hu JH, Yang JP, Liu L, et al.Involvement of CX3CR1in bone cancer pain through theactivation of microglia p38MAPK pathway in the spinal cord[J].Brain Res.2012,1465:1-9.
[39] Sun JL, Xiao C, Lu B,et al.CX3CL1/CX3CR1regulates nerve injury-induced painhypersensitivity through the ERK5signaling pathway[J].J Neurosci Res.2013,91(4):545-53.
[40] Yang JL, Xu B, Li SS, et al.Gabapentin reduces CX3CL1signaling and blocks spinalmicroglial activation in monoarthritic rats[J].Mol Brain.2012,5:18.
[41] McColl BW, Allan SM, Rothwell NJ.Systemic inflammation and stroke: aetiology,pathology and targets for therapy[J].Biochem Soc Trans.2007,35(Pt5):1163-5.
[42] Muir KW, Tyrrell P, Sattar N, et al.Inflammation and ischaemic stroke[J].Curr OpinNeurol.2007,20(3):334-42.
[43] Yenari MA, Xu L, Tang XN, et al.Microglia potentiate damage to blood-brain barrierconstituents: improvement by minocycline in vivo and in vitro[J].Stroke.2006,37(4):1087-93.
[44] Lalancette-Hébert M, Gowing G, Simard A, et al.Selective ablation of proliferatingmicroglial cells exacerbates ischemic injury in the brain[J].J Neurosci.2007,27(10):2596-605.
[45] Dénes A, Ferenczi S, Halász J, K rnyei Z, Kovács KJ.Role of CX3CR1(fractalkinereceptor) in brain damage and inflammation induced by focal cerebral ischemia inmouse[J].J Cereb Blood Flow Metab.2008,28(10):1707-21.
[46] Yrj nheikki J, Kein nen R, Pellikka M, et al.Tetracyclines inhibit microglial activationand are neuroprotective in global brain ischemia[J].Proc Natl Acad Sci U S A.1998,95(26):15769-74.
[47] David S, Kroner A.Repertoire of microglial and macrophage responses after spinal cordinjury[J].Nat Rev Neurosci.2011,12(7):388-99.
[48] Michelucci A, Heurtaux T, Grandbarbe L, et al.Characterization of the microglialphenotype under specific pro-inflammatory and anti-inflammatory conditions: Effectsof oligomeric and fibrillar amyloid-beta[J].J Neuroimmunol.2009,210(1-2):3-12.
[49] Fumagalli S, Perego C, Ortolano F, et al.CX3CR1deficiency induces an earlyprotective inflammatory environment in ischemic mice[J].Glia.2013,61(6):827-42.
[50] Cipriani R, Villa P, Chece G, et al.CX3CL1is neuroprotective in permanent focalcerebral ischemia in rodents[J].J Neurosci.2011,31(45):16327-35.
[51] Mandrekar-Colucci S, Landreth GE.Microglia and inflammation in Alzheimer'sdisease[J].CNS Neurol Disord Drug Targets.2010,9(2):156-67.
[52] Fuhrmann M, Bittner T, Jung CK, et al. Microglial Cx3cr1knockout prevents neuronloss in a mouse model of Alzheimer's disease[J].Nat Neurosci.2010,13(4):411-3.
[53] Wu J, Bie B, Yang H, et al.Suppression of central chemokine fractalkine receptorsignaling alleviates amyloid-induced memory deficiency[J].Neurobiol Aging.2013,34(12):2843-52.
[54] Liu Z, Condello C, Schain A, et al.CX3CR1in microglia regulates brain amyloiddeposition through selective protofibrillar amyloid-β phagocytosis[J].J Neurosci.2010,30(50):17091-101.
[55] Cho SH, Sun B, Zhou Y, et al.CX3CR1protein signaling modulates microglialactivation and protects against plaque-independent cognitive deficits in a mouse modelof Alzheimer disease[J].J Biol Chem.2011,286(37):32713-22.
[56] McGeer PL, Itagaki S, Boyes BE,et al.Reactive microglia are positive for HLA-DR inthe substantia nigra of Parkinson's and Alzheimer's disease brains[J].Neurology.1988,38(8):1285-91.
[57] Tansey MG, Goldberg MS.Neuroinflammation in Parkinson's disease: its role inneuronal death and implications for therapeutic intervention[J].Neurobiol Dis.2010,37(3):510-8.
[58] Shan S, Hong-Min T, Yi F, et al.New evidences for fractalkine/CX3CL1involved insubstantia nigral microglial activation and behavioral changes in a rat model ofParkinson's disease[J].Neurobiol Aging.2011,32(3):443-58.
[59] Pabon MM, Jernberg JN, Morganti J,et al.A spirulina-enhanced diet providesneuroprotection in an α-synuclein model of Parkinson's disease[J].PLoS One.2012,7(9):e45256.
[60] Compston A, Coles A.Multiple sclerosis[J].Lancet.2008,372(9648):1502-17.
[61] Jiang Y, Salafranca MN, Adhikari S, et al.Chemokine receptor expression in culturedglia and rat experimental allergic encephalomyelitis[J].J Neuroimmunol.1998,86(1):1-12.
[62] Sunnemark D, Eltayeb S, Nilsson M, et al.CX3CL1(fractalkine) and CX3CR1expression in myelin oligodendrocyte glycoprotein-induced experimental autoimmuneencephalomyelitis: kinetics and cellular origin[J].J Neuroinflammation.2005,2:17.
[63] Zhu W, Acosta C, MacNeil B,et al.Elevated expression of fractalkine (CX3CL1) andfractalkine receptor (CX3CR1) in the dorsal root ganglia and spinal cord inexperimental autoimmune encephalomyelitis: implications in multiple sclerosis-inducedneuropathic pain[J].Biomed Res Int.2013,2013:480702.
[64] Staniland AA, Clark AK, Wodarski R, et al.Reduced inflammatory and neuropathic painand decreased spinal microglial response in fractalkine receptor (CX3CR1) knockoutmice[J].J Neurochem.2010,114(4):1143-57.
[65] Boillée S, Vande Velde C, Cleveland DW.ALS: a disease of motor neurons and theirnonneuronal neighbors[J].Neuron.2006,52(1):39-59.
[66] Shapiro LA, Wang L, Ribak CE.Rapid astrocyte and microglial activation followingpilocarpine-induced seizures in rats[J].Epilepsia.2008,49(Suppl2):33-41.
[67] Kang TC, Kim DS, Kwak SE, et al.Epileptogenic roles of astroglial death andregeneration in the dentate gyrus of experimental temporal lobe epilepsy[J].Glia.2006,54(4):258-71.
[68] Yeo SI, Kim JE, Ryu HJ, et al.The roles of fractalkine/CX3CR1system in neuronaldeath following pilocarpine-induced status epilepticus[J].J Neuroimmunol.2011,234(1-2):93-102.
[69] Shechter R, London A, Varol C, et al.Infiltrating blood-derived macrophages are vitalcells playing an anti-inflammatory role in recovery from spinal cord injury in mice[J].PLoS Med.2009,6(7):e1000113.
[70] Donnelly DJ, Longbrake EE, Shawler TM, et al.Deficient CX3CR1signaling promotesrecovery after mouse spinal cord injury by limiting the recruitment and activation ofLy6Clo/iNOS+macrophages[J].J Neurosci.2011,31(27):9910-22.
[71] Targosz-Gajniak M1, Siuda J, Ochud o S, et al.Cerebral white matter lesions in patientswith dementia-from MCI to severe Alzheimer's disease[J].J Neurol Sci.2009,283(1-2):79-82.
[72] Hentschel F, Damian M, Krumm B, et al.White matter lesions-age-adjusted values forcognitively healthy and demented subjects[J].Acta Neurol Scand.2007,115(3):174-80.
[73] Bink DI, Ritz K, Aronica E, et al.Mouse models to study the effect of cardiovascularrisk factors on brain structure and cognition[J].J Cereb Blood Flow Metab.2013,33(11):1666-84.
[74]韩济生.神经科学原理.2版.北京:北京医科大学出版社, l999:1062.
[75]谢明.雌激素对脑梗塞的神经保护作用及机制[D].中南大学,2013.
[76] de la Torre JC, Fortin T.A chronic physiological rat model of dementia[J].Behav BrainRes.1994,63(1):35-40.
[77]伍强军,赵文元,刘建民.慢性血管源性脑缺血动物模型[J].中华脑血管病杂志(电子版),2011,5(3):216-223.
[78] Li YH, Hsieh CY, Wang DL, et al.Remodeling of carotid arteries is associated withincreased expression of thrombomodulin in a mouse transverse aortic constrictionmodel[J].Thromb Haemost.2007,97(4):658-64.
[79] Li YH, Reddy AK, Taffet GE, et al.Doppler evaluation of peripheral vascularadaptations to transverse aortic banding in mice[J].Ultrasound Med Biol.2003,29(9):1281-9.
[80] Carnevale D, Mascio G, Ajmone-Cat MA, et al.Role of neuroinflammation inhypertension-induced brain amyloid pathology[J].Neurobiol Aging.2012,33(1):205.e19-29.
[81]高阳.缺血性脑白质病变[J].脑与神经疾病杂志,2011,19(6):473-476.
[82] Stevens WD, Fortin T, Pappas BA.Retinal and optic nerve degeneration after chroniccarotid ligation: time course and role of light exposure[J].Stroke.2002,33(4):1107-12.
[83] Farkas E, Donka G, de Vos RA, et al.Experimental cerebral hypoperfusion induceswhite matter injury and microglial activation in the rat brain[J].Acta Neuropathol.2004,108(1):57-64.
[84] Scremin OU, Cerebral Vascular System. In: Paxinos G,ed, The rat nervous system[M],2nd edn, Academic Press, NewYork, pp3–35,1995.
[85] Zeman W, Innes JRM, Craigie’s Neuroanatomy of the Rat,[M]Academic Press, NewYork,1963.
[86] Targosz-Gajniak M, Siuda J, Ochud o S, et al.Cerebral white matter lesions in patientswith dementia-from MCI to severe Alzheimer's disease[J]. J Neurol Sci.2009,283(1-2):79-82.
[87] Hentschel F, Damian M, Krumm B, et al. White matter lesions-age-adjusted values forcognitively healthy and demented subjects[J].Acta Neurol Scand.2007,115(3):174-80.
[88] Farkas E, Donka G, de-Vos RA, et al.Experimental cerebral hypoperfusion induceswhite matter injury and microglia activation in the rat brain[J].Acta Neuropathol,2004,108(1):57-64.
[89] Harrison JK, Jiang Y, Chen S, et al. Role for neuronally derived fractalkine in mediatinginteractions between neurons and CX3CR1-expressing microglia[J]. Proc Natl Acad SciUSA.1998,95(18):10896-901.
[90]张营,吉训明,罗玉敏.脑缺血与白质损伤的研究进展[J].中国脑血管病杂志,2011,8(9):497-500.
[91]詹增土,叶钦勇.慢性脑缺血白质损伤的实验研究进展[J].医学综述,2010,16(14):2095-2098.
[92] Imai T, Hieshima K, Haskell C, et al. Identification and molecular characterization offractalkine receptor CX3CR1, which mediates both leukocyte migration and adhesion[J]. Cell.1997,91(4):521-530.
[93] Shan S, Hong-Min T, Yi F, et al.New evidences for fractalkine/CX3CL1involved insubstantia nigral microglial activation and behavioral changes in a rat model ofParkinson's disease[J].Neurobiol Aging.2011,32(3):443-58.
[94] Mitrasinovic OM, Robinson CC, Tenen DG, et al. Biolistic expression of themacrophage colony stimulating factor receptor in organotypic cultures induces aninflammatory response[J].J Neurosci Res.2004,77(3):420-9.
[95]赵琦.小胶质细胞不同功能状态下MAPK信号通路变化及梓醇对其影响[D].大连医科大学.2011.
[96] Choi BR, Kwon KJ, Park SH,et al.Alternations of Septal-hippocampal System in theAdult Wistar Rat with Spatial Memory Impairments Induced by Chronic CerebralHypoperfusion[J].Exp Neurobiol.2011,20(2):92-9.
[97] Lee KM, Bang JH, Han JS, et al.Cardiotonic pill attenuates white matter andhippocampal damage via inhibiting microglial activation and downregulating ERK andp38MAPK signaling in chronic cerebral hypoperfused rat[J].BMC Complement AlternMed.2013,13:33.
[98] Li Z, Jiang Y, Ulevitch RJ, et al.The primary structure of p38gamma: a new member ofp38group of MAP kinases[J].Biochem Biophys Res Commun.1996,228(2):334-40.
[99] Jiang Y, Chen C, Li Z, et al.Characterization of the structure and function of a newmitogen-activated protein kinase (p38beta)[J].J Biol Chem.1996,271(30):17920-6.
[100] Kumar S, McDonnell PC, Gum RJ, et al.Novel homologues of CSBP/p38MAP kinase:activation, substrate specificity and sensitivity to inhibition by pyridinyl imidazoles[J].Biochem Biophys Res Commun.1997,235(3):533-8.
[101] Gu L, Huang B, Shen W, et al.Early activation of nSMase2/ceramide pathway inastrocytes is involved in ischemia-associated neuronal damage via inflammation in rathippocampi[J]. J Neuroinflammation.2013,10:109.
[102] Han Q, Liu S, Li Z, et al. DCPIB, a potent volume-regulated anion channel antagonist,attenuates microglia-mediated inflammatory response and neuronal injury followingfocal cerebral ischemia[J].Brain Res.2014,1542:176-85.
[103] Genovese T, Impellizzeri D, Ahmad A, et al.Post-ischaemic thyroid hormone treatmentin a rat model of acute stroke[J].Brain Res.2013,1513:92-102.
[104] Choi BR, Kwon KJ, Park SH, et al.Alternations of Septal-hippocampal System in theAdult Wistar Rat with Spatial Memory Impairments Induced by Chronic CerebralHypoperfusion[J].Exp Neurobiol.2011,20(2):92-9.
[105] Walton KM, DiRocco R, Bartlett BA, et al.Activation of p38MAPK in microglia afterischemia[J]. J Neurochem.1998,70(4):1764-7.
[106] Zhao T, Gao S, Wang X, et al.Hypoxia-inducible factor-1regulates chemotacticmigration of pancreatic ductal adenocarcinoma cells through directly transactivating theCX3CR1gene[J].PLoS One.2012,7(8):e43399.
[107] Cipriani R, Villa P, Chece G, et al.CX3CL1is neuroprotective in permanent focalcerebral ischemia in rodents[J].J Neurosci.2011,31(45):16327-35.
[108] Sun JL, Xiao C, Lu B, et al.CX3CL1/CX3CR1regulates nerve injury-induced painhypersensitivity through the ERK5signaling pathway[J].J Neurosci Res.2013,91(4):545-53.
[109] Zhuang ZY, Kawasaki Y, Tan PH, et al.Role of the CX3CR1/p38MAPK pathway inspinal microglia for the development of neuropathic pain following nerveinjury-induced cleavage of fractalkine[J].Brain Behav Immun.2007,21(5):642-51.
[110] Hu JH, Yang JP, Liu L, et al.Involvement of CX3CR1in bone cancer pain through theactivation of microglia p38MAPK pathway in the spinal cord[J].Brain Res.2012J,1465:1-9.
[2] Rostène W, Kitabgi P, Parsadaniantz SM.Chemokines: a new class of neuromodulator[J]? Nat Rev Neurosci,2007,8(11):895-903.
[3] Lagane B, Ballet S, Planchenault T, et al.Mutation of the DRY motif reveals differentstructural requirements for the CC chemokine receptor5-mediated signaling andreceptor endocytosis[J].Mol Pharmacol.2005,67(6):1966-76.
[4] Berchiche YA, Chow KY, Lagane B, et al.Direct assessment of CXCR4mutantconformations reveals complex link between receptor structure and G(alpha)(i)activation[J].J Biol Chem.2007,282(8):5111-5.
[5] Murdoch C, Finn A.Chemokine receptors and their role in inflammation and infectiousdiseases[J].Blood.2000,95(10):3032-43.
[6] Samstag Y, Eibert SM, Klemke M,et al.Actin cytoskeletal dynamics in T lymphocyteactivation and migration[J].J Leukoc Biol.2003,73(1):30-48.
[7] Slice LW, Wong HC, Sternini C, et al.The conserved NPXnY motif present in thegastrin-releasing peptide receptor is not a general sequestration sequence[J].J BiolChem.1994,269(34):21755-61.
[8] Barak LS, Tiberi M, Freedman NJ, et al.A highly conserved tyrosine residue in Gprotein-coupled receptors is required for agonist-mediated beta2-adrenergic receptorsequestration[J].J Biol Chem.1994,269(4):2790-5.
[9] Ribas C, Penela P, Murga C, et al.The G protein-coupled receptor kinase (GRK)interactome: role of GRKs in GPCR regulation and signaling[J].Biochim Biophys Acta.2007,1768(4):913-22.
[10] Clark AK, Yip PK, Grist J, et al.Inhibition of spinal microglial cathepsin S for thereversal of neuropathic pain[J].Proc Natl Acad Sci U S A.2007,104(25):10655-60.
[11] Hermand P, Pincet F, Carvalho S, et al.Functional adhesiveness of the CX3CL1chemokine requires its aggregation. Role of the transmembrane domain[J].J Biol Chem.2008,283(44):30225-34.
[12] Songyang Z, Lu KP, Kwon YT, et al.A structural basis for substrate specificities ofprotein Ser/Thr kinases: primary sequence preference of casein kinases I and II, NIMA,phosphorylase kinase, calmodulin-dependent kinase II, CDK5, and Erk1[J].Mol CellBiol.1996,16(11):6486-93.
[13] Cargnello M, Roux PP.Activation and function of the MAPKs and their substrates, theMAPK-activated protein kinases[J].Microbiol Mol Biol Rev.2011,75(1):50-83.
[14]张奇,白晓东,付小兵. p38MAPK信号通路研究进展.感染、炎症、修复[J],2005,6(2):121-123.
[15]张涛,杨承祥,王汉兵. p38MAPK信号通路与疼痛的关系[J].中国疼痛医学杂志,2012,18(3):177-180.
[16] Ji RR, Suter MR.p38MAPK, microglial signaling, and neuropathic pain[J].Mol Pain.2007,1(3):33.
[17] Julia V.CX3CL1in allergic diseases: not just a chemotactic molecule[J].Allergy.2012,67(9):1106-10.
[18] Giunti D, Parodi B, Usai C, et al.Mesenchymal stem cells shape microglia effectorfunctions through the release of CX3CL1[J].Stem Cells.2012,30(9):2044-53.
[19] Wang C, Liu F, Liu YY, et al.Identification and characterization of neuroblasts in thesubventricular zone and rostral migratory stream of the adult human brain[J].Cell Res.2011,21(11):1534-50.
[20] Gage FH.Mammalian neural stem cells[J].Science.2000,287(5457):1433-8.
[21] Gemma C, Bachstetter AD.The role of microglia in adult hippocampal neurogenesis[J].Front Cell Neurosci.2013,22(7):229.
[22] Ziv Y, Schwartz M.Immune-based regulation of adult neurogenesis: implications forlearning and memory[J].Brain Behav Immun.2008,22(2):167-76.
[23] Bachstetter AD, Morganti JM, Jernberg J, et al.Fractalkine and CX3CR1regulatehippocampal neurogenesis in adult and aged rats[J].Neurobiol Aging.2011,32(11):2030-44.
[24] Paolicelli RC, Bolasco G, Pagani F, et al.Synaptic pruning by microglia is necessary fornormal brain development[J].Science.2011,333(6048):1456-8.
[25] Hoshiko M, Arnoux I, Avignone E, et al.Deficiency of the microglial receptor CX3CR1impairs postnatal functional development of thalamocortical synapses in the barrelcortex[J].J Neurosci.2012,32(43):15106-11.
[26] Ross FM, Allan SM, Rothwell NJ, et al.A dual role for interleukin-1in LTP in mousehippocampal slices[J].J Neuroimmunol.2003,144(1-2):61-7.
[27] Fumagalli S, Perego C, Ortolano F, et al.CX3CR1deficiency induces an earlyprotective inflammatory environment in ischemic mice[J].Glia.2013,61(6):827-42.
[28] Williamson LL, Sholar PW, Mistry RS, et al.Microglia and memory: modulation byearly-life infection[J].J Neurosci.2011,31(43):15511-21.
[29] Rogers JT, Morganti JM, Bachstetter AD, et al.CX3CR1deficiency leads to impairmentof hippocampal cognitive function and synaptic plasticity[J].J Neurosci.2011,31(45):16241-50.
[30] Parkhurst CN, Yang G, Ninan I, et al.Microglia promote learning-dependent synapseformation through brain-derived neurotrophic factor[J].Cell.2013,155(7):1596-609.
[31] Cardona AE, Pioro EP, Sasse ME, et al.Control of microglial neurotoxicity by thefractalkine receptor[J].Nat Neurosci.2006,9(7):917-24.
[32] Zujovic V, Benavides J, Vigé X, et al.Fractalkine modulates TNF-alpha secretion andneurotoxicity induced by microglial activation[J].Glia.2000,29(4):305-15.
[33] Ji RR, Berta T, Nedergaard M.Glia and pain: Is chronic pain a gliopathy[J]?Pain.2013,154(Suppl1):S10-28.
[34] Staniland AA, Clark AK, Wodarski R, et al.Reduced inflammatory and neuropathic painand decreased spinal microglial response in fractalkine receptor (CX3CR1) knockoutmice[J].J Neurochem.2010,114(4):1143-57.
[35] Clark AK, Staniland AA, Marchand F,et al.P2X7-dependent release of interleukin-1betaand nociception in the spinal cord following lipopolysaccharide[J].J Neurosci.2010,30(2):573-82.
[36] Bian C, Wang ZC, Yang JL, et al.Up-regulation of interleukin-23induces persistentallodynia via CX3CL1and interleukin-18signaling in the rat spinal cord after tetanicsciatic stimulation[J].Brain Behav Immun.2014,37:220-30.
[37] Old EA, Malcangio M.Chemokine mediated neuron-glia communication and aberrantsignalling in neuropathic pain states[J].Curr Opin Pharmacol.2012,12(1):67-73.
[38] Hu JH, Yang JP, Liu L, et al.Involvement of CX3CR1in bone cancer pain through theactivation of microglia p38MAPK pathway in the spinal cord[J].Brain Res.2012,1465:1-9.
[39] Sun JL, Xiao C, Lu B,et al.CX3CL1/CX3CR1regulates nerve injury-induced painhypersensitivity through the ERK5signaling pathway[J].J Neurosci Res.2013,91(4):545-53.
[40] Yang JL, Xu B, Li SS, et al.Gabapentin reduces CX3CL1signaling and blocks spinalmicroglial activation in monoarthritic rats[J].Mol Brain.2012,5:18.
[41] McColl BW, Allan SM, Rothwell NJ.Systemic inflammation and stroke: aetiology,pathology and targets for therapy[J].Biochem Soc Trans.2007,35(Pt5):1163-5.
[42] Muir KW, Tyrrell P, Sattar N, et al.Inflammation and ischaemic stroke[J].Curr OpinNeurol.2007,20(3):334-42.
[43] Yenari MA, Xu L, Tang XN, et al.Microglia potentiate damage to blood-brain barrierconstituents: improvement by minocycline in vivo and in vitro[J].Stroke.2006,37(4):1087-93.
[44] Lalancette-Hébert M, Gowing G, Simard A, et al.Selective ablation of proliferatingmicroglial cells exacerbates ischemic injury in the brain[J].J Neurosci.2007,27(10):2596-605.
[45] Dénes A, Ferenczi S, Halász J, K rnyei Z, Kovács KJ.Role of CX3CR1(fractalkinereceptor) in brain damage and inflammation induced by focal cerebral ischemia inmouse[J].J Cereb Blood Flow Metab.2008,28(10):1707-21.
[46] Yrj nheikki J, Kein nen R, Pellikka M, et al.Tetracyclines inhibit microglial activationand are neuroprotective in global brain ischemia[J].Proc Natl Acad Sci U S A.1998,95(26):15769-74.
[47] David S, Kroner A.Repertoire of microglial and macrophage responses after spinal cordinjury[J].Nat Rev Neurosci.2011,12(7):388-99.
[48] Michelucci A, Heurtaux T, Grandbarbe L, et al.Characterization of the microglialphenotype under specific pro-inflammatory and anti-inflammatory conditions: Effectsof oligomeric and fibrillar amyloid-beta[J].J Neuroimmunol.2009,210(1-2):3-12.
[49] Fumagalli S, Perego C, Ortolano F, et al.CX3CR1deficiency induces an earlyprotective inflammatory environment in ischemic mice[J].Glia.2013,61(6):827-42.
[50] Cipriani R, Villa P, Chece G, et al.CX3CL1is neuroprotective in permanent focalcerebral ischemia in rodents[J].J Neurosci.2011,31(45):16327-35.
[51] Mandrekar-Colucci S, Landreth GE.Microglia and inflammation in Alzheimer'sdisease[J].CNS Neurol Disord Drug Targets.2010,9(2):156-67.
[52] Fuhrmann M, Bittner T, Jung CK, et al. Microglial Cx3cr1knockout prevents neuronloss in a mouse model of Alzheimer's disease[J].Nat Neurosci.2010,13(4):411-3.
[53] Wu J, Bie B, Yang H, et al.Suppression of central chemokine fractalkine receptorsignaling alleviates amyloid-induced memory deficiency[J].Neurobiol Aging.2013,34(12):2843-52.
[54] Liu Z, Condello C, Schain A, et al.CX3CR1in microglia regulates brain amyloiddeposition through selective protofibrillar amyloid-β phagocytosis[J].J Neurosci.2010,30(50):17091-101.
[55] Cho SH, Sun B, Zhou Y, et al.CX3CR1protein signaling modulates microglialactivation and protects against plaque-independent cognitive deficits in a mouse modelof Alzheimer disease[J].J Biol Chem.2011,286(37):32713-22.
[56] McGeer PL, Itagaki S, Boyes BE,et al.Reactive microglia are positive for HLA-DR inthe substantia nigra of Parkinson's and Alzheimer's disease brains[J].Neurology.1988,38(8):1285-91.
[57] Tansey MG, Goldberg MS.Neuroinflammation in Parkinson's disease: its role inneuronal death and implications for therapeutic intervention[J].Neurobiol Dis.2010,37(3):510-8.
[58] Shan S, Hong-Min T, Yi F, et al.New evidences for fractalkine/CX3CL1involved insubstantia nigral microglial activation and behavioral changes in a rat model ofParkinson's disease[J].Neurobiol Aging.2011,32(3):443-58.
[59] Pabon MM, Jernberg JN, Morganti J,et al.A spirulina-enhanced diet providesneuroprotection in an α-synuclein model of Parkinson's disease[J].PLoS One.2012,7(9):e45256.
[60] Compston A, Coles A.Multiple sclerosis[J].Lancet.2008,372(9648):1502-17.
[61] Jiang Y, Salafranca MN, Adhikari S, et al.Chemokine receptor expression in culturedglia and rat experimental allergic encephalomyelitis[J].J Neuroimmunol.1998,86(1):1-12.
[62] Sunnemark D, Eltayeb S, Nilsson M, et al.CX3CL1(fractalkine) and CX3CR1expression in myelin oligodendrocyte glycoprotein-induced experimental autoimmuneencephalomyelitis: kinetics and cellular origin[J].J Neuroinflammation.2005,2:17.
[63] Zhu W, Acosta C, MacNeil B,et al.Elevated expression of fractalkine (CX3CL1) andfractalkine receptor (CX3CR1) in the dorsal root ganglia and spinal cord inexperimental autoimmune encephalomyelitis: implications in multiple sclerosis-inducedneuropathic pain[J].Biomed Res Int.2013,2013:480702.
[64] Staniland AA, Clark AK, Wodarski R, et al.Reduced inflammatory and neuropathic painand decreased spinal microglial response in fractalkine receptor (CX3CR1) knockoutmice[J].J Neurochem.2010,114(4):1143-57.
[65] Boillée S, Vande Velde C, Cleveland DW.ALS: a disease of motor neurons and theirnonneuronal neighbors[J].Neuron.2006,52(1):39-59.
[66] Shapiro LA, Wang L, Ribak CE.Rapid astrocyte and microglial activation followingpilocarpine-induced seizures in rats[J].Epilepsia.2008,49(Suppl2):33-41.
[67] Kang TC, Kim DS, Kwak SE, et al.Epileptogenic roles of astroglial death andregeneration in the dentate gyrus of experimental temporal lobe epilepsy[J].Glia.2006,54(4):258-71.
[68] Yeo SI, Kim JE, Ryu HJ, et al.The roles of fractalkine/CX3CR1system in neuronaldeath following pilocarpine-induced status epilepticus[J].J Neuroimmunol.2011,234(1-2):93-102.
[69] Shechter R, London A, Varol C, et al.Infiltrating blood-derived macrophages are vitalcells playing an anti-inflammatory role in recovery from spinal cord injury in mice[J].PLoS Med.2009,6(7):e1000113.
[70] Donnelly DJ, Longbrake EE, Shawler TM, et al.Deficient CX3CR1signaling promotesrecovery after mouse spinal cord injury by limiting the recruitment and activation ofLy6Clo/iNOS+macrophages[J].J Neurosci.2011,31(27):9910-22.
[71] Targosz-Gajniak M1, Siuda J, Ochud o S, et al.Cerebral white matter lesions in patientswith dementia-from MCI to severe Alzheimer's disease[J].J Neurol Sci.2009,283(1-2):79-82.
[72] Hentschel F, Damian M, Krumm B, et al.White matter lesions-age-adjusted values forcognitively healthy and demented subjects[J].Acta Neurol Scand.2007,115(3):174-80.
[73] Bink DI, Ritz K, Aronica E, et al.Mouse models to study the effect of cardiovascularrisk factors on brain structure and cognition[J].J Cereb Blood Flow Metab.2013,33(11):1666-84.
[74]韩济生.神经科学原理.2版.北京:北京医科大学出版社, l999:1062.
[75]谢明.雌激素对脑梗塞的神经保护作用及机制[D].中南大学,2013.
[76] de la Torre JC, Fortin T.A chronic physiological rat model of dementia[J].Behav BrainRes.1994,63(1):35-40.
[77]伍强军,赵文元,刘建民.慢性血管源性脑缺血动物模型[J].中华脑血管病杂志(电子版),2011,5(3):216-223.
[78] Li YH, Hsieh CY, Wang DL, et al.Remodeling of carotid arteries is associated withincreased expression of thrombomodulin in a mouse transverse aortic constrictionmodel[J].Thromb Haemost.2007,97(4):658-64.
[79] Li YH, Reddy AK, Taffet GE, et al.Doppler evaluation of peripheral vascularadaptations to transverse aortic banding in mice[J].Ultrasound Med Biol.2003,29(9):1281-9.
[80] Carnevale D, Mascio G, Ajmone-Cat MA, et al.Role of neuroinflammation inhypertension-induced brain amyloid pathology[J].Neurobiol Aging.2012,33(1):205.e19-29.
[81]高阳.缺血性脑白质病变[J].脑与神经疾病杂志,2011,19(6):473-476.
[82] Stevens WD, Fortin T, Pappas BA.Retinal and optic nerve degeneration after chroniccarotid ligation: time course and role of light exposure[J].Stroke.2002,33(4):1107-12.
[83] Farkas E, Donka G, de Vos RA, et al.Experimental cerebral hypoperfusion induceswhite matter injury and microglial activation in the rat brain[J].Acta Neuropathol.2004,108(1):57-64.
[84] Scremin OU, Cerebral Vascular System. In: Paxinos G,ed, The rat nervous system[M],2nd edn, Academic Press, NewYork, pp3–35,1995.
[85] Zeman W, Innes JRM, Craigie’s Neuroanatomy of the Rat,[M]Academic Press, NewYork,1963.
[86] Targosz-Gajniak M, Siuda J, Ochud o S, et al.Cerebral white matter lesions in patientswith dementia-from MCI to severe Alzheimer's disease[J]. J Neurol Sci.2009,283(1-2):79-82.
[87] Hentschel F, Damian M, Krumm B, et al. White matter lesions-age-adjusted values forcognitively healthy and demented subjects[J].Acta Neurol Scand.2007,115(3):174-80.
[88] Farkas E, Donka G, de-Vos RA, et al.Experimental cerebral hypoperfusion induceswhite matter injury and microglia activation in the rat brain[J].Acta Neuropathol,2004,108(1):57-64.
[89] Harrison JK, Jiang Y, Chen S, et al. Role for neuronally derived fractalkine in mediatinginteractions between neurons and CX3CR1-expressing microglia[J]. Proc Natl Acad SciUSA.1998,95(18):10896-901.
[90]张营,吉训明,罗玉敏.脑缺血与白质损伤的研究进展[J].中国脑血管病杂志,2011,8(9):497-500.
[91]詹增土,叶钦勇.慢性脑缺血白质损伤的实验研究进展[J].医学综述,2010,16(14):2095-2098.
[92] Imai T, Hieshima K, Haskell C, et al. Identification and molecular characterization offractalkine receptor CX3CR1, which mediates both leukocyte migration and adhesion[J]. Cell.1997,91(4):521-530.
[93] Shan S, Hong-Min T, Yi F, et al.New evidences for fractalkine/CX3CL1involved insubstantia nigral microglial activation and behavioral changes in a rat model ofParkinson's disease[J].Neurobiol Aging.2011,32(3):443-58.
[94] Mitrasinovic OM, Robinson CC, Tenen DG, et al. Biolistic expression of themacrophage colony stimulating factor receptor in organotypic cultures induces aninflammatory response[J].J Neurosci Res.2004,77(3):420-9.
[95]赵琦.小胶质细胞不同功能状态下MAPK信号通路变化及梓醇对其影响[D].大连医科大学.2011.
[96] Choi BR, Kwon KJ, Park SH,et al.Alternations of Septal-hippocampal System in theAdult Wistar Rat with Spatial Memory Impairments Induced by Chronic CerebralHypoperfusion[J].Exp Neurobiol.2011,20(2):92-9.
[97] Lee KM, Bang JH, Han JS, et al.Cardiotonic pill attenuates white matter andhippocampal damage via inhibiting microglial activation and downregulating ERK andp38MAPK signaling in chronic cerebral hypoperfused rat[J].BMC Complement AlternMed.2013,13:33.
[98] Li Z, Jiang Y, Ulevitch RJ, et al.The primary structure of p38gamma: a new member ofp38group of MAP kinases[J].Biochem Biophys Res Commun.1996,228(2):334-40.
[99] Jiang Y, Chen C, Li Z, et al.Characterization of the structure and function of a newmitogen-activated protein kinase (p38beta)[J].J Biol Chem.1996,271(30):17920-6.
[100] Kumar S, McDonnell PC, Gum RJ, et al.Novel homologues of CSBP/p38MAP kinase:activation, substrate specificity and sensitivity to inhibition by pyridinyl imidazoles[J].Biochem Biophys Res Commun.1997,235(3):533-8.
[101] Gu L, Huang B, Shen W, et al.Early activation of nSMase2/ceramide pathway inastrocytes is involved in ischemia-associated neuronal damage via inflammation in rathippocampi[J]. J Neuroinflammation.2013,10:109.
[102] Han Q, Liu S, Li Z, et al. DCPIB, a potent volume-regulated anion channel antagonist,attenuates microglia-mediated inflammatory response and neuronal injury followingfocal cerebral ischemia[J].Brain Res.2014,1542:176-85.
[103] Genovese T, Impellizzeri D, Ahmad A, et al.Post-ischaemic thyroid hormone treatmentin a rat model of acute stroke[J].Brain Res.2013,1513:92-102.
[104] Choi BR, Kwon KJ, Park SH, et al.Alternations of Septal-hippocampal System in theAdult Wistar Rat with Spatial Memory Impairments Induced by Chronic CerebralHypoperfusion[J].Exp Neurobiol.2011,20(2):92-9.
[105] Walton KM, DiRocco R, Bartlett BA, et al.Activation of p38MAPK in microglia afterischemia[J]. J Neurochem.1998,70(4):1764-7.
[106] Zhao T, Gao S, Wang X, et al.Hypoxia-inducible factor-1regulates chemotacticmigration of pancreatic ductal adenocarcinoma cells through directly transactivating theCX3CR1gene[J].PLoS One.2012,7(8):e43399.
[107] Cipriani R, Villa P, Chece G, et al.CX3CL1is neuroprotective in permanent focalcerebral ischemia in rodents[J].J Neurosci.2011,31(45):16327-35.
[108] Sun JL, Xiao C, Lu B, et al.CX3CL1/CX3CR1regulates nerve injury-induced painhypersensitivity through the ERK5signaling pathway[J].J Neurosci Res.2013,91(4):545-53.
[109] Zhuang ZY, Kawasaki Y, Tan PH, et al.Role of the CX3CR1/p38MAPK pathway inspinal microglia for the development of neuropathic pain following nerveinjury-induced cleavage of fractalkine[J].Brain Behav Immun.2007,21(5):642-51.
[110] Hu JH, Yang JP, Liu L, et al.Involvement of CX3CR1in bone cancer pain through theactivation of microglia p38MAPK pathway in the spinal cord[J].Brain Res.2012J,1465:1-9.