文冠果壳苷抗阿尔茨海默病的炎症相关机制研究
|
摘要
目的：文冠果壳苷是一种从文冠果果壳中提取出的三萜皂苷类化合物,前期研究证实其对多种痴呆模型动物的学习记忆障碍具有改善作用。为进一步探讨文冠果壳苷对阿尔茨海默病(AD)防治作用及作用机制,本文依据AD的炎症假说,从整体水平及细胞分子水平考查了文冠果壳苷对β-淀粉样蛋白(Aβ)致AD模型的改善作用及炎症相关机制。方法：①以β淀粉样蛋白25-35肽段(Aβ25-35)/γ-干扰素(IFN-γ)诱导小胶质细胞活化后,考察文冠果壳苷对Aβ25-35/IFN-γ激活的小胶质细胞NO释放量的影响；通过ELISA实验检测IL-1β及TNF-α的含量；采用western blot方法检测iNOS、COX-2、NF-κB及MAPK通路相关蛋白表达的情况；采用免疫荧光方法检测NF-κB P65的核转移情况；采用RT-PCR方法检测IL-1β、TNF-α、 iNOS、COX-2及TLR2mRNA表达的情况；通过MTT法考察小胶质细胞条件培养液对SH-SY5Y神经元生存率的影响。②侧脑室注射Aβ1-42制备痴呆小鼠模型,通过Y迷宫、Morris水迷宫实验考察文冠果壳苷对模型小鼠学习记忆障碍的影响；通过免疫组织化学方法考察了小鼠海马及皮层区CD11b的表达情况；利用ELISA方法考察了小鼠海马组织中IL-6及IL-4表达情况；利用western blot方法考察了小鼠海马组织中iNOS、COX-2、NF-κB及MAPK通路相关蛋白表达的情况；利用RT-PCR方法考察了小鼠海马组织中iNOS、COX-2及TLR2mRNA表达的情况。结果：①文冠果壳苷可显著降低Aβ25-35/IFN-γ诱导的N9细胞及原代小胶质细胞培养液中NO、TNF-α、IL-1β的含量,抑制iNOS及COX-2蛋白的表达,抑制(?)TNF-α、 IL-1β、iNOS、COX-2及TLR2mRNA表达;显著抑制NF-κB、MAPK蛋白的激活及NF-κB P65的核转移,抑制活化的小胶质细胞条件培养液引起的SH-SY5Y神经元的死亡。②文冠果壳苷(0.08～0.32mg/kg)显著提高侧脑室注射Aβ1-42致痴呆模型小鼠Y迷宫实验中小鼠自发交替反应率；显著缩短水迷宫实验中小鼠到达安全台的逃避潜伏期及游泳路程,并显著增加小鼠在原安全台所在象限游泳时间和游泳路程百分比；文冠果壳苷可显著抑制模型小鼠海马促炎症因子IL-6含量的增加及炎症抑制因子IL-4含量的减少；抑制大脑皮层及海马CD11b蛋白的表达；Western blot结果显示,文冠果壳苷可显著降低iNOS、COX-2蛋白的表达；抑制NF-κB及MAPK蛋白的激活；RT-PCR结果显示,文冠果壳苷可显著抑制iNOS、 COX-2及TLR2mRNA表达。结论：文冠果壳苷下调小胶质细胞TLR2,抑制IKK表达、IκB蛋白的降解及NF-κB p50和p65亚单位的核转录,抑制MAPKs信号转导通路,进而抑制炎症因子释放的作用可能与其神经元保护作用及对侧脑室注射Ap1-42致痴呆模型小鼠的学习记忆障碍改善作用有关。本研究及前期试验结果提示,文冠果壳苷具有显著的改善学习记忆障碍及神经保护作用,作为AD防治候选化合物,具有进一步研究开发价值。
Aim:Xanthoceraside is a novel triterpenoid saponin extracted from the shell of the fruit of Xanthoceras sorbifolia Bunge. Our previous study showed that xanthoceraside could significantly improve learning and memory impairment in several Alzheimer's disease (AD) animal models. In this study, we further investigate the effect of xanthoceraside on AD model in vitro and in vivo according to inflammation hypothesis, which aims to explore its anti-AD effects and possible related mechanisms of action.
Methods:①We investigated the effect of xanthoceraside on Aβ25-35/IFN-γ-induced microglia activation. The NO production was measured by Griess regent. The levels of IL-1β and TNF-a protein expression were measured by ELISA assay according to the manufacturer's instructions; NF-κB P65nuclear translocation were measured with the immunofluorescence assay, the expression of iNOS、COX-2、 NF-κB and MAPKs were measured with western blot assay; iNOS、COX-2and TLR2mRNA expression were measured with RT-PCR.②We studied the effect of xanthoceraside on learning and memory impairments in mice induced by intracerebroventricular (i.c.v.) injection of the aggregated Aβ by using Y-maze and Morris water-maze test. The expression of CD11b in the hippocampus and cortex of mice were measured with immunohistochemistry assay; IL-6and IL-4protein expression were measured with ELISA assay according to the manufacturer's instructions; The expression of iNOS、COX-2、NF-κB and MAPKs were measured with western blot assay; iNOS、COX-2and TLR2mRNA expression were measured with RT-PCR.
Results:①Compared with model group, Pretreatment with xanthoceraside (0.01,0.1μM) significantly suppressed the increase of NO, TNF-α and IL-1β production inprimary microglia and N9microglia, respectively, down-regulated TNF-α and IL-1β mRNA expression, decreased Aβ25.35/IFN-γ-induced iNOS and COX-2protein and mRNA expression in a concentration-dependent manner; Xanthoceraside inhibited the AP25-35/IFN-γ-induced translocation of NF-κB p50and p65into the nucleus, blocked IκB degradation and increased IKK level. Pretreatment with xanthoceraside significantly attenuated the Aβ25-35/IFN-y-induced phosphorylation of ERK, JNK and p38, whereas their non-phosphorylated forms were not changed, and decreased TLR2gene expression. Xanthoceraside protected neuron damage by the inhibition of microglia activation.②Compared with model group, xanthoceraside (0.08～0.32mg/kg) significantly decreased the escape latency and swimming distance in Morris-water maze test, and increased the swimming time and percentage of the swimming distance in the fourth quadrant where the platform had been locatedin the probe test; Xanthoceraside increased the percentage of alternation behaviors in Y-maze test; Xanthoceraside suppressed the release of IL-6and increased the IL-4production, decrease in CD11b positive particles in both cerebral cortex and hippocampus, attenuated iNOS and COX-2protein and mRNA expression, inhibited the translocation of NF-κB p50and p65into the nucleus, attenuated the phosphorylation of ERK, JNK and p38; and decreased TLR2gene expression.
Conclusion:Xanthoceraside has the effect of improving learning and memory impairment in mice induced by i.c.v. of Aβ and inhibited pro-inflammation expression in Aβ25-35/IFN-γ-stimulated microglia via TLR2/MAPKs and NF-κB pathways. The neuroprotective effects of xanthoceraside may include the inhibition of pro-inflammation and TLR2expression, and attenuated the NF-κB and MAPKs activity. Therefore, xanthoceraside may provide a useful therapeutic strategy for the treatment of AD.
Aim:Xanthoceraside is a novel triterpenoid saponin extracted from the shell of the fruit of Xanthoceras sorbifolia Bunge. Our previous study showed that xanthoceraside could significantly improve learning and memory impairment in several Alzheimer's disease (AD) animal models. In this study, we further investigate the effect of xanthoceraside on AD model in vitro and in vivo according to inflammation hypothesis, which aims to explore its anti-AD effects and possible related mechanisms of action.
Methods:①We investigated the effect of xanthoceraside on Aβ25-35/IFN-γ-induced microglia activation. The NO production was measured by Griess regent. The levels of IL-1β and TNF-a protein expression were measured by ELISA assay according to the manufacturer's instructions; NF-κB P65nuclear translocation were measured with the immunofluorescence assay, the expression of iNOS、COX-2、 NF-κB and MAPKs were measured with western blot assay; iNOS、COX-2and TLR2mRNA expression were measured with RT-PCR.②We studied the effect of xanthoceraside on learning and memory impairments in mice induced by intracerebroventricular (i.c.v.) injection of the aggregated Aβ by using Y-maze and Morris water-maze test. The expression of CD11b in the hippocampus and cortex of mice were measured with immunohistochemistry assay; IL-6and IL-4protein expression were measured with ELISA assay according to the manufacturer's instructions; The expression of iNOS、COX-2、NF-κB and MAPKs were measured with western blot assay; iNOS、COX-2and TLR2mRNA expression were measured with RT-PCR.
Results:①Compared with model group, Pretreatment with xanthoceraside (0.01,0.1μM) significantly suppressed the increase of NO, TNF-α and IL-1β production inprimary microglia and N9microglia, respectively, down-regulated TNF-α and IL-1β mRNA expression, decreased Aβ25.35/IFN-γ-induced iNOS and COX-2protein and mRNA expression in a concentration-dependent manner; Xanthoceraside inhibited the AP25-35/IFN-γ-induced translocation of NF-κB p50and p65into the nucleus, blocked IκB degradation and increased IKK level. Pretreatment with xanthoceraside significantly attenuated the Aβ25-35/IFN-y-induced phosphorylation of ERK, JNK and p38, whereas their non-phosphorylated forms were not changed, and decreased TLR2gene expression. Xanthoceraside protected neuron damage by the inhibition of microglia activation.②Compared with model group, xanthoceraside (0.08～0.32mg/kg) significantly decreased the escape latency and swimming distance in Morris-water maze test, and increased the swimming time and percentage of the swimming distance in the fourth quadrant where the platform had been locatedin the probe test; Xanthoceraside increased the percentage of alternation behaviors in Y-maze test; Xanthoceraside suppressed the release of IL-6and increased the IL-4production, decrease in CD11b positive particles in both cerebral cortex and hippocampus, attenuated iNOS and COX-2protein and mRNA expression, inhibited the translocation of NF-κB p50and p65into the nucleus, attenuated the phosphorylation of ERK, JNK and p38; and decreased TLR2gene expression.
Conclusion:Xanthoceraside has the effect of improving learning and memory impairment in mice induced by i.c.v. of Aβ and inhibited pro-inflammation expression in Aβ25-35/IFN-γ-stimulated microglia via TLR2/MAPKs and NF-κB pathways. The neuroprotective effects of xanthoceraside may include the inhibition of pro-inflammation and TLR2expression, and attenuated the NF-κB and MAPKs activity. Therefore, xanthoceraside may provide a useful therapeutic strategy for the treatment of AD.
引文
[1]William T, Laura B. Alzheimer's Association Report 2011 Alzheimer's disease facts and figures. Alzheimer's & Dementia.2011;7:208-244.
[2]Davalos D, Grutzendler J, Yang G, Kim JV, Zuo Y, Jung S, et al. ATP mediates rapid microglial response to local brain injury in vivo. Nat Neurosci.2005;8(6):752-758.
[3]Wake H, Moorhouse AJ, Jinno S, Kohsaka S, Nabekura J. Resting microglia directly monitor the functional state of synapses in vivo and determine the fate of ischemic terminals. J Neurosci.2009; 29(13):3974-3980.
[4]Kettenmann H, Hanisch UK, Noda M, Verkhratsky A. Physiology of Microglia. Physiol Rev.2011;91:461-553.
[5]Bessis A, Bechade Bernard CD, Roumier A. Microglial control of neuronal death and synaptic properties. Glia.2007;55:233-238.
[6]McGeer PL, Itagaki S, Tago H, McGeer EG. Reactive microglia in patients with senile dementia of the Alzheimer type are positive for the histocompatibility glycoprotein HLA-DR. Neurosci Lett.1987;79:195-200.
[7]Bamberger ME, Harris ME, McDonald DR, Husemann J, Landreth GE. A cell surface receptor complex for fibrillar beta-amyloid mediates microglial activation. J Neurosci. 2003;23:2665-2674.
[8]Das P, Howard V, Loosbrock N, Dickson D, Murphy MP, Golde TE. Amyloid-beta immunization effectively reduces amyloid depositionin FcRgamma-/-knock-out mice. J Neurosci.2003;23:8532-8538.
[9]Schenk D, Barbour R, Dunn W, Gordon G, Grajeda H, Guido T,et al. Immunization with amyloid-beta attenuates Alzheimer-disease-like pathology in the PDAPP mouse. Nature. 1999;400:173-177.
[10]Senior K. Dosing in phase Ⅱtrial of Alzheimer's vaccine suspended.Lancet Neural. 2002;1:3.
[11]Furlan R, Brambilla E, Sanvito F, Roccatagliata L, Olivieri S, Bergami A, et al.Vaccination with amyloid-beta peptide induces autoimmune encephalomyelitis in C57/BL6 mice. Brain.2003; 126:285-291.
[12]Craft JM, Watterson DM, Frautschy SA, Van Eldik LJ. Aminopyridazines inhibit beta-amyloid-induced glial activation and neuronal damage in vivo. Neurobiol Aging.2004;25:1283-1292.
[13]Mehlhorn G, Hollborn M, Schilebs R. Induction of cytokines in glial cells surrounding cortical beta-amyloid plaques in transgenic Tg2576 mice with Alzheimer's pathology. Int J Dev Neurosci.2000; 18:423-431.
[14]Fan R, Xu F, Previti ML, Davis J, Grande AM, et al. Minocycycline reduces microglial activation and improves behavioral deficits in a transgenic model of cerebral microvascular amyloid. J Neurosci.2007;27:3057-3063.
[15]Cheng G, Whitehead SN, Hachinski V, Cechetto DF. Effects of pyrrolidine dithiocarbamate on beta-amyloid (25-35)-induced inflammatory responses and memory deficits in the rat. Neurobiol Dis.2006;23:140-151.
[16]Rojo LE, Fernandez JA, Maccioni AA, Jimenez JM, Maccioni RB. Neuroinflammation: implications for the pathogenesis and molecular diagnosis of Alzheimer's disease. Arch. Med. Res.2008;39:1-16.
[17]Hoozemans JJ, Veerhuis R, Rozemuller JM; Eikelenboom P. Neuroinflammation and regeneration in the early stages of Alzheimer's disease pathology. Int. J. Dev. Neurosci. 2006;24:157-165.
[18]Rogers J, Lue LF. Microglial chemotaxis, activation, and phagocytosis of amyloid beta-peptide as linked phenomena in Alzheimer's disease. Neurochem Int.2001;39:333-340.
[19]Yan Q, Zhang J, Liu H, Babu-Khan S, Vassar R, Biere AL, et al. Anti-inflammatory drug therapy alters betaamyloid processing and deposition in an animal model of Alzheimer's disease. J Neurosci.2003;23:7504-7509.
[20]He P, Zhong Z, Lindholm K, Berning L, Lee W, et al. Deletion of tumor necrosis factor death receptor inhibits amyloid beta generation and prevents learning and memory deficits in Alzheimer's mice. J Cell Biol.2007; 178:829-841.
[21]Di Bona D, Candore G, Franceschi C, Licastro F, Colonna-Romano G, Camma C, et al. Systematic review by meta-analyses on the possible role of TNF-alpha polymorphisms in association with Alzheimer's disease. Brain Res Rev.2009;61:60-68.
[22]Townsend KP, Pratico D. Novel therapeutic opportunities for Alzheimer's disease:focus on nonsteroidal anti-inflammatory drugs. FASEB J.2005; 19:1592-1601.
[23]Versijpt JJ, Dumont F, Van Laere KJ, Decoo D, Santens P, Audenaert K, et al. Assessment of neuroinflammation and microglial activation in Alzheimer's disease with radiolabelled PK11195 and single photon emission computed tomography:a pilot study. Eur. Neurol.2003;50:39-47.
[24]Edison P, Archer HA, Gerhard A, Hinz R, Pavese N, Turkheimer FE, et al. Microglia, amyloid, and cognition in Alzheimer's disease:An [11C](R)PK11195-PET and [11C] PIB PET study. Neurobiol. Dis.2008;32:412-419.
[25]Wiley CA, Lopresti BJ, Venneti S, Price J, Klunk WE, DeKosky ST. Carbon 11-labeled Pittsburgh Compound B and carbon 11-labeled (R)-PK11195 positron emission tomographic imaging in Alzheimer disease. Arch.Neurol.2009;66:60-67.
[26]Venneti S, Lopresti BJ, Wang G, Hamilton RL, Mathis CA, Klunk WE, et al. PK11195 labels activated microglia in Alzheimer's disease and in vivo in a mouse model using PET. Neurobiol. Aging.2009;30:1217-1226.
[27]Lucin KM, Wyss-Coray T. Immune activation in brain aging and neurodegeneration:too much or too little? Neuron.2009;64(1):110-122.
[28]Halle A, Hornung V, Petzold GC, Stewart CR, Monks BG, Reinheckel T, et al. The NALP3 inflammasome is involved in the innate immune response to amyloid-beta. Nat. Immunol.2008;9:857-865.
[29]Tuppo EE, Arias HR. The role of inflammation in Alzheimer's disease. Int J Biochem Cell Biol.2005;37:289-305.
[30]Sastre M, Klockgether T, Heneka MT. Contribution of inflammatory processes to Alzheimer's disease:molecular mechanisms. Int J Devl Neuroscience.2006;24:167-176
[31]Griffin WS.Inflammation and neurodegenerative disease.Am J Clin Nutr.2006; 83:470-474
[32]Weisman D, Hakimian E, Ho GJ, et al. Interleukins,Inflammation,and Mechanisms of Alzheimer's Disease. Vitam Horm.2006;74:505-530.
[33]Mark RE, GriffinWS. Glia and their cytokines in progression of neurodegeneration. Neurobiol Aging.2005;26:349-354.
[34]Bauer J, Strauss S, Schreiter-Gasser U, et al. Interleukin-6 and Phamacroglobulin indicate an acute-phase state in Alzheimers disease cortices. FEBS Lett.1991;285:111-114.
[35]Utsumi T, Take ST, Tanaka K, et al.Transmembrane TNF(pro-TNF) is palmitoylated. FEBS Lett.2001;500(1-2):1-6.
[36]Culpan D, MacGowan SH, Ford JM, et al. Tumournecrosis factor-a gene polymorphisms and Alzheimer's disease. Neurosci Lett.2003;350:61-65.
[37]Badie B, Schartner J, Vorpahl J, Preston K. Interferon-gamma induces apoptosis and augments the expression of Fas and Fas ligand by microglia in vitro. Exp Neurol. 2000; 162:290-296.
[38]Fassbender K, Walter S, Kuhl S, Landmann R, Ishii K, Bertsch T, et al. The LPS receptor (CD14) links innate immunity with Alzheimer's disease. FASEB J. 2004; 18:203-205.
[39]Liu Y, Walter S, Stagi M, Cherny D, Letiembre M, Schulz-Schaeffer W, et al. LPS receptor (CD 14):a receptor for phagocytosis of Alzheimer's amyloid peptide. Brain. 2005;128:1778-1789.
[40]Walter S, Letiembre M, Liu Y, Heine H, Penke B, Hao W, et al. Role of the toll like receptor 4 in neuroinflammation in Alzheimer's disease. Cell Physiol Biochem. 2007;20:947-956.
[41]Letiembre M, Liu Y, Walter S, Hao W, Pfander T, Wrede A, et al. Screening of innate immune receptors in neurodegenerative diseases:a similar pattern. Neurobiol Aging. 2009;30:759-768.
[42]Reed-Geaghan EG, Savage JC, Hise AG, Landreth GE. CD 14 and toll-like receptors 2 and 4 are required for fibrillar A{beta}-stimulated microglial activation. J Neurosci. 2009;29:11982-11989.
[43]Frank S, Copanaki E, Burbach GJ, Muller UC, Deller T. Differential regulation of toll-like receptor mRNAs in amyloid plaque-associated brain tissue of aged APP23 transgenic mice. Neurosci Lett.2009;453:41^44.
[44]Jana M, Palencia CA, Pahan K. Fibrillar amyloid-beta peptides activate microglia via TLR2:implications for Alzheimer's disease. J Immunol.2008; 181:7254-7262.
[45]Cameron B, Landreth GE. Inflammation, microglia, and Alzheimer's disease. Neurobiol Dis.2010;37:503-509.
[46]Carty M, Bowie AG. Evaluating the role of Toll-like receptors in diseases of the central nervous system. Biochem Pharmacol.2011;81:825-837.
[47]Chen K, Iribarren P, Hu J, Chen J, Gong W, Cho EH, et al. Activation of Toll-like receptor 2 onmicroglia promotes cell uptake of Alzheimer disease-associated amyloid beta peptide. J Biol Chem.2006;281:3651-3659.
[48]Tang SC, Lathia JD, Selvaraj PK, Jo DG, Mughal MR, Cheng A, et al. Toll-like receptor-4 mediates neuronal apoptosis induced by amyloid beta-peptide and the membrane lipid peroxidation product 4-hydroxynonenal. Exp Neurol.2008;213:114-121.
[49]Herrmann N, Li A,& Lanctot K. Memantine in dementia:A review of the current evidence. Expert Opin Pharmacother.2011; 12:787-800.
[50]Small G,& Bullock R... Defining optimal treatment with cholinesterase inhibitors in Alzheimer's disease. Alzheimers Dement.2011;7:177-184.
[51]王莉莉,马挺巴,巴俊杰.蒙药文冠木研究进展.内蒙古医学院学报.2008;30：153-155.
[52]Kim HS, Suh YH. Minocycline and neurodegenerative diseases. Behav Brain Res. 2009; 196:168-179.
[53]Choi Y, Kim HS, Shin KY, Kim EM, Kim M, Suh YH, et al. Minocycline attenuates neuronal cell death and improves cognitive impairment in Alzheimer's disease models. Neuropsychopharmacology.2007;32:2393-2404.
[54]Fuster-Matanzo A, Llorens-Martin M, Hernandez F and Avila J. Role of neuroinflammation in adult neurogenesis and Alzheimer disease:Therapeutic approaches. Mediat Inflamm.2013;1;1-9.
[55]Zipp F, Aktas O. The brain as a target of inflammation:common pathways link inflammatory and neurodegenerative diseases. Trends Neurosci.2006;29:518-527.
[56]Chi TY, Wang LH, Qu C, Yang BZ, Ji XF, Wang Y. Protective effects of xanthoceraside on learning and memory impairment induced by Aβ25-35 in mice. J Asian Nat Prod Res. 2009;11:1019-1027.
[57]Lu P, Mamiya T, Lu L, Mouri A, Ikejima T, Kim HC, et al. Xanthoceraside attenuates amyloid β peptide25-35-induced learning and memory impairments in mice. Psychopharmacology.2012;219:181-190.
[58]Hashioka S, Han YH, Fujii S, Kato T, Monji A, Utsumi H, et al. Phosphatidylserine and phosphatidylcholine-containing liposomes inhibit amyloid β and interferon-y-induced microglial activation. Free Radical Bio Med.2007;42:945-954.
[59]Yamamoto M, Kiyota T, Horiba M, Buescher, JL, Walsh SM, et al. Interferon-y and tumor necrosis factor-a regulate amyloid-β plaque deposition and β-secretase expression in Swedish mutant APP transgenic mice. Am J Pathol,2007; 170:680-692.
[60]Meda L, Cassatella MA, Szendrei Gl, Otvos L, Baron P, Villalba M, et al. Activation of microglial cells by β-amyloid protein and interferon-y. Nature,1995; 374:647-650.
[61]Neymotin A, Petri S, Calingasan NY, Wille E, Schafer P, Stewart C, et al. Lenalidomide (Revlimid(?)) administration at symptom onset is neuroprotective in a mouse model of amyotrophic lateral sclerosis. Exp Neurol.2009;220:191-197.
[62]Kim YJ, Hwang SY, Oh ES, Oh S, Han IO. IL-1β, an immediate early protein secreted by activated microglia, induces iNOS/NO in C6 astrocytoma cells through p38 MAPK and NF-κB pathways. J Neurosci Res.2006;84:1037-1046.
[63]McAlpine FE, Lee JK, Harms AS, Ruhn KA, Blurton-Jones M, Hong J, et al. Inhibition of soluble TNF signaling in a mouse model of Alzheimer's disease prevents pre-plaque amyloid-associated neuropathology. Neurobiol Dis.2009;34:163-177.
[64]Zhao Y, Calon F, Julien C, Winkler JW, Petasis NA, Lukiw WJ, et al. Docosahexaenoic acid-derived neuroprotectin dl induces neuronal survival via secretase and PPARy-mediated mechanisms in Alzheimer's disease models. PLoS ONE.2011;6:1-15.
[65]Surh YJ, Chun KS, Cha HH, Han SS, Keum YS, Park KK. Molecular mechanisms underlying chemopreventive activities of anti-inflammatory phytochemicals:down-regulation of COX-2 and iNOS through suppression of NF-κB activation. Mutat Res.2001; 480-481: 243-268.
[66]Morel SV, Park JY, Kim BW, Kumar H, Lim HW, Kang SM, et al. Anti-neuroinflamm-tory activity of a novel cannabinoid derivative by inhibiting the NF-κB signaling pathway in Lipopolysaccharide-induced BV-2 microglial cells. J Pharmacol Sci.2013;121:119-130.
[67]Jeon NR, Koppula S, Kim B-W, Park SH, Lee H-W, Choi D-K. MMHD[(s,e)-2-methyl-1-(2-methylthiazol-4-yl) hexa-1,5-dien-ol], a novel synthetic compound derived from epothilone, suppresses nuclear factor-kappa b-mediated cytokine expression in lipopolysaccharide-stimulated BV-2 microglia. J Pharmacol Sci.2010;112:158-166.
[68]Kim BW, Koppula S, Kim IS, Lim HW, Hong SM, Han SD, et al. Anti-neuroinflammatory activity of kamebakaurin from isodon japonicus via inhibition of c-Jun NH2-terminal kinase and p38 mitogen-activated protein kinase pathway in activated microglial cells. J Pharmacol Sci.2011; 116,296-308.
[69]Choi Y, Lee MK, Lim SY, Sung SH, Kim YC. Inhibition of inducible NO synthase, cyclooxygenase-2 and interleukin-1 beta by torilin is mediated by mitogen-activated protein kinases in microglial BV2 cells. Br J Phamrmacol.2009; 156:933-940.
[70]John M, Yriakis K and Avruch J. Mammalian Mitogen-activated protein kinase signal transduction pathways activated by stress and inflammation. Physiolo Rev.2001;81:807-869.
[71]Kim YH, Choi KH, Park JW, Kwon TK. LY294002 inhibits LPS-induced NO production through a inhibition of NF-κB activation:independent mechanism of phosphatidylinositol 3-kinase. Immunol Lett.2005;99:45-50.
[72]Rosenberger J, Petrovics G, Buzas B. Oxidative stress induces proorphanin FQ and proenkephalin gene expression in astrocytes through p38-and ERK-MAP kinases and NF-kappa B. J Neurochem.2001;79:35-44.
[73]Lal MA, Brismar H, Eklof AC, Aperia A. Role of oxidative stress in advanced glycation end product-induced mesangial cell activation. Kidney Int.2002;61:2006-2014.
[74]Chaturvedi P. Inhibitory response of Raphanus sativus on lipid peroxidation in albino rats. Evidence-Based Compl. Altern Med.2008;5:55-59.
[75]Newburger PE, Ezekowitz RA, Whitney C, Wright J, Orkin SH. Induction of phagocyte cytochrome b heavy chain gene expression by interferon-y. Proc. Natl. Acad. Sci. USA. 1988;85:5215-5219.
[76]Hanamsagar R, Hanke ML and Kielian T. Toll-like receptor (TLR) and inflammasome actions in the central nervous system. Trends Immunol.2012;33:333-342.
[77]Yirmiya R, Goshen I. Immune modulation of learning, memory, neural plasticity and neurogenesis. Brain Behav Immun.2011;25:181-213.
[78]Schroder K, Hertzog PJ, Ravasi T, Hume DA. Interferon-y:an overview of signals, mechanisms and functions. J Leukoc Biol.2004;75:163-189.
[79]Kim D, Kim MA, Cho IH, Kim MS, Lee S, Jo EK, et al. A critical role of toll-like receptor 2 in nerve injury-induced spinal cord glial cell activation and pain hypersensitivity. J Biol Chem.2007;282:14975-14983.
[80]Weitz TM, Town T. Microglia in Alzheimer disease:It's all about context. Int J Alzheimers Dis.2012; 1:1-11.
[81]Cameron B, Landreth GE. Inflammation, microglia, and Alzheimer's disease. Neurobiol Dis.2010;37:503-509.
[82]Laursen SE, and Belknap JK. Intranerebroventricular injections in mice:some methodological refinements. J pharmacol meth.1986; 16:335-357.
[83]Griffin WS, Sheng JG, Roberts GW, Mrak RE. Interleukin-1 expression in different plaque types in Alzheimer's disease:significance in plaque evolution. J Neuropathol Exp Neurol.1995;54:276-281.
[84]Griffin WS, Stanley LC, Ling C, White L, MacLeod V, Perrot LJ. Brain interleukin 1 and S-100 immunoreactivity are elevated in Down syndrome and Alzheimer disease. Proc Natl Acad Sci USA.1989;86:7611-7615.
[85]Tan ZS, Beiser AS, Vasan RS, Roubenoff R, Dinarello CA, Harris TB. Inflammatory markers and the risk of Alzheimer disease:the Framingham Study. Neurology.2007; 68:1902-1908.
[86]Kalman J, Juhasz A, Laird G, Dickens P, Jardanhazy T, Rimanoczy A. Serum interleukin-6 levels correlate with the severity of dementia in Down syndrome and in Alzheimer's disease. Acta Neurol Scand.1997;96:236-240.
[87]Yu XW, Chen Q, Kennedy RH, Liu SJ. Inhibition of sarcoplasmic reticular function by chronic interleukin-6 exposure via iNOS in adult ventricular myocytes. J Physiol.2005;566: 327-340.
[88]Mollie K. Meffert and David Baltimore. Physiological functions for brain NF-κB. TRENDS in Neuro.2005; 28:1-7.
[89]Scheubert P, Rudolphi K. Interfering with the pathologic activation of microglial cells and astrocyte in dementia. Alzheimer's Dis Assoc Disord.1988(suppl 2):821-828.
[90]Bales KR,Du Y, Dodel RC, et al. The NF-κB/Rel family of proteins mediates abeta induced neurotoxicity and glial activation. Brain Res Mol Brain Res.1998;57:63-72.
[91]Kim SH, Smith CJ, Van Eldik LJ. Importance of MAPK pathways for microglial pro-inflammatory cytokine IL-1h production. Neurobiol Aging.2004;25:431-439.
[92]Bach JH, Chae HS, Rah JC, Lee MW, Park CH, Choi SH. C-terminal fragment of amyloid precursor protein induces astrocytosis. J Neurochem.2001;78:109-120.
[93]Koistinaho M, Kettunen MI, Goldsteins G, Keinanen R, Salminen A, Ort M. β-amyloid precursor protein transgenic mice that harbor diffuse A beta deposits but do not form plaques show increased ischemic vulnerability:role of inflammation. Proc Natl Acad Sci USA. 2002;99:1610-1615.
[94]Hua LL, Zhao ML, Cosenza M, Kim MO, Huang H, Tanowitz HB. Role of mitogen-activated protein kinases in inducible nitric oxide synthase and TNFa expression in human fetal astrocytes, J Neuroimmunol.2002; 126:180-189.
[95]Guan Z, Buckman SY, Springer LD, Morrison AR. Both p38aMAPK and JNK/SAPK pathways are important for induction of nitric-oxide synthase by interleukin-1β in rat glomerular mesangial cells. J Biol Chem.1999;274:36200-36206.
[96]Cho MK, Suh SH, Kim SG. JunB/AP-1 and NF-jB-mediated induction of nitric oxide synthase by bovine type I collagen in serum-stimulated murine macrophages. Nitric Oxide. 2002;6:319-332.
[97]Kan H, Xie Z, Finkel MS. TNF-alpha enhances cardiac myocyte NO production through MAP kinase-mediated NF-kappaB activation. Am J Physiol.1999;277:1641-1646.
[98]Han IO, Kim HS, Kim HC, Joe EH, Kim WK. Synergistic expression of inducible nitric oxide synthase by phorbol ester and interferon-c is mediated through NF-κB and ERK in microglial cells. Neurosci Res.2003;73:659-669.
[99]Wang T, Lafuse WP, Zwilling BS. NFkappaB and Spl elements are necessary for maximal transcription of toll-like receptor 2 induced by Mycobacterium avium. J Immunol. 2001b; 167:6924-6932.
[2]Davalos D, Grutzendler J, Yang G, Kim JV, Zuo Y, Jung S, et al. ATP mediates rapid microglial response to local brain injury in vivo. Nat Neurosci.2005;8(6):752-758.
[3]Wake H, Moorhouse AJ, Jinno S, Kohsaka S, Nabekura J. Resting microglia directly monitor the functional state of synapses in vivo and determine the fate of ischemic terminals. J Neurosci.2009; 29(13):3974-3980.
[4]Kettenmann H, Hanisch UK, Noda M, Verkhratsky A. Physiology of Microglia. Physiol Rev.2011;91:461-553.
[5]Bessis A, Bechade Bernard CD, Roumier A. Microglial control of neuronal death and synaptic properties. Glia.2007;55:233-238.
[6]McGeer PL, Itagaki S, Tago H, McGeer EG. Reactive microglia in patients with senile dementia of the Alzheimer type are positive for the histocompatibility glycoprotein HLA-DR. Neurosci Lett.1987;79:195-200.
[7]Bamberger ME, Harris ME, McDonald DR, Husemann J, Landreth GE. A cell surface receptor complex for fibrillar beta-amyloid mediates microglial activation. J Neurosci. 2003;23:2665-2674.
[8]Das P, Howard V, Loosbrock N, Dickson D, Murphy MP, Golde TE. Amyloid-beta immunization effectively reduces amyloid depositionin FcRgamma-/-knock-out mice. J Neurosci.2003;23:8532-8538.
[9]Schenk D, Barbour R, Dunn W, Gordon G, Grajeda H, Guido T,et al. Immunization with amyloid-beta attenuates Alzheimer-disease-like pathology in the PDAPP mouse. Nature. 1999;400:173-177.
[10]Senior K. Dosing in phase Ⅱtrial of Alzheimer's vaccine suspended.Lancet Neural. 2002;1:3.
[11]Furlan R, Brambilla E, Sanvito F, Roccatagliata L, Olivieri S, Bergami A, et al.Vaccination with amyloid-beta peptide induces autoimmune encephalomyelitis in C57/BL6 mice. Brain.2003; 126:285-291.
[12]Craft JM, Watterson DM, Frautschy SA, Van Eldik LJ. Aminopyridazines inhibit beta-amyloid-induced glial activation and neuronal damage in vivo. Neurobiol Aging.2004;25:1283-1292.
[13]Mehlhorn G, Hollborn M, Schilebs R. Induction of cytokines in glial cells surrounding cortical beta-amyloid plaques in transgenic Tg2576 mice with Alzheimer's pathology. Int J Dev Neurosci.2000; 18:423-431.
[14]Fan R, Xu F, Previti ML, Davis J, Grande AM, et al. Minocycycline reduces microglial activation and improves behavioral deficits in a transgenic model of cerebral microvascular amyloid. J Neurosci.2007;27:3057-3063.
[15]Cheng G, Whitehead SN, Hachinski V, Cechetto DF. Effects of pyrrolidine dithiocarbamate on beta-amyloid (25-35)-induced inflammatory responses and memory deficits in the rat. Neurobiol Dis.2006;23:140-151.
[16]Rojo LE, Fernandez JA, Maccioni AA, Jimenez JM, Maccioni RB. Neuroinflammation: implications for the pathogenesis and molecular diagnosis of Alzheimer's disease. Arch. Med. Res.2008;39:1-16.
[17]Hoozemans JJ, Veerhuis R, Rozemuller JM; Eikelenboom P. Neuroinflammation and regeneration in the early stages of Alzheimer's disease pathology. Int. J. Dev. Neurosci. 2006;24:157-165.
[18]Rogers J, Lue LF. Microglial chemotaxis, activation, and phagocytosis of amyloid beta-peptide as linked phenomena in Alzheimer's disease. Neurochem Int.2001;39:333-340.
[19]Yan Q, Zhang J, Liu H, Babu-Khan S, Vassar R, Biere AL, et al. Anti-inflammatory drug therapy alters betaamyloid processing and deposition in an animal model of Alzheimer's disease. J Neurosci.2003;23:7504-7509.
[20]He P, Zhong Z, Lindholm K, Berning L, Lee W, et al. Deletion of tumor necrosis factor death receptor inhibits amyloid beta generation and prevents learning and memory deficits in Alzheimer's mice. J Cell Biol.2007; 178:829-841.
[21]Di Bona D, Candore G, Franceschi C, Licastro F, Colonna-Romano G, Camma C, et al. Systematic review by meta-analyses on the possible role of TNF-alpha polymorphisms in association with Alzheimer's disease. Brain Res Rev.2009;61:60-68.
[22]Townsend KP, Pratico D. Novel therapeutic opportunities for Alzheimer's disease:focus on nonsteroidal anti-inflammatory drugs. FASEB J.2005; 19:1592-1601.
[23]Versijpt JJ, Dumont F, Van Laere KJ, Decoo D, Santens P, Audenaert K, et al. Assessment of neuroinflammation and microglial activation in Alzheimer's disease with radiolabelled PK11195 and single photon emission computed tomography:a pilot study. Eur. Neurol.2003;50:39-47.
[24]Edison P, Archer HA, Gerhard A, Hinz R, Pavese N, Turkheimer FE, et al. Microglia, amyloid, and cognition in Alzheimer's disease:An [11C](R)PK11195-PET and [11C] PIB PET study. Neurobiol. Dis.2008;32:412-419.
[25]Wiley CA, Lopresti BJ, Venneti S, Price J, Klunk WE, DeKosky ST. Carbon 11-labeled Pittsburgh Compound B and carbon 11-labeled (R)-PK11195 positron emission tomographic imaging in Alzheimer disease. Arch.Neurol.2009;66:60-67.
[26]Venneti S, Lopresti BJ, Wang G, Hamilton RL, Mathis CA, Klunk WE, et al. PK11195 labels activated microglia in Alzheimer's disease and in vivo in a mouse model using PET. Neurobiol. Aging.2009;30:1217-1226.
[27]Lucin KM, Wyss-Coray T. Immune activation in brain aging and neurodegeneration:too much or too little? Neuron.2009;64(1):110-122.
[28]Halle A, Hornung V, Petzold GC, Stewart CR, Monks BG, Reinheckel T, et al. The NALP3 inflammasome is involved in the innate immune response to amyloid-beta. Nat. Immunol.2008;9:857-865.
[29]Tuppo EE, Arias HR. The role of inflammation in Alzheimer's disease. Int J Biochem Cell Biol.2005;37:289-305.
[30]Sastre M, Klockgether T, Heneka MT. Contribution of inflammatory processes to Alzheimer's disease:molecular mechanisms. Int J Devl Neuroscience.2006;24:167-176
[31]Griffin WS.Inflammation and neurodegenerative disease.Am J Clin Nutr.2006; 83:470-474
[32]Weisman D, Hakimian E, Ho GJ, et al. Interleukins,Inflammation,and Mechanisms of Alzheimer's Disease. Vitam Horm.2006;74:505-530.
[33]Mark RE, GriffinWS. Glia and their cytokines in progression of neurodegeneration. Neurobiol Aging.2005;26:349-354.
[34]Bauer J, Strauss S, Schreiter-Gasser U, et al. Interleukin-6 and Phamacroglobulin indicate an acute-phase state in Alzheimers disease cortices. FEBS Lett.1991;285:111-114.
[35]Utsumi T, Take ST, Tanaka K, et al.Transmembrane TNF(pro-TNF) is palmitoylated. FEBS Lett.2001;500(1-2):1-6.
[36]Culpan D, MacGowan SH, Ford JM, et al. Tumournecrosis factor-a gene polymorphisms and Alzheimer's disease. Neurosci Lett.2003;350:61-65.
[37]Badie B, Schartner J, Vorpahl J, Preston K. Interferon-gamma induces apoptosis and augments the expression of Fas and Fas ligand by microglia in vitro. Exp Neurol. 2000; 162:290-296.
[38]Fassbender K, Walter S, Kuhl S, Landmann R, Ishii K, Bertsch T, et al. The LPS receptor (CD14) links innate immunity with Alzheimer's disease. FASEB J. 2004; 18:203-205.
[39]Liu Y, Walter S, Stagi M, Cherny D, Letiembre M, Schulz-Schaeffer W, et al. LPS receptor (CD 14):a receptor for phagocytosis of Alzheimer's amyloid peptide. Brain. 2005;128:1778-1789.
[40]Walter S, Letiembre M, Liu Y, Heine H, Penke B, Hao W, et al. Role of the toll like receptor 4 in neuroinflammation in Alzheimer's disease. Cell Physiol Biochem. 2007;20:947-956.
[41]Letiembre M, Liu Y, Walter S, Hao W, Pfander T, Wrede A, et al. Screening of innate immune receptors in neurodegenerative diseases:a similar pattern. Neurobiol Aging. 2009;30:759-768.
[42]Reed-Geaghan EG, Savage JC, Hise AG, Landreth GE. CD 14 and toll-like receptors 2 and 4 are required for fibrillar A{beta}-stimulated microglial activation. J Neurosci. 2009;29:11982-11989.
[43]Frank S, Copanaki E, Burbach GJ, Muller UC, Deller T. Differential regulation of toll-like receptor mRNAs in amyloid plaque-associated brain tissue of aged APP23 transgenic mice. Neurosci Lett.2009;453:41^44.
[44]Jana M, Palencia CA, Pahan K. Fibrillar amyloid-beta peptides activate microglia via TLR2:implications for Alzheimer's disease. J Immunol.2008; 181:7254-7262.
[45]Cameron B, Landreth GE. Inflammation, microglia, and Alzheimer's disease. Neurobiol Dis.2010;37:503-509.
[46]Carty M, Bowie AG. Evaluating the role of Toll-like receptors in diseases of the central nervous system. Biochem Pharmacol.2011;81:825-837.
[47]Chen K, Iribarren P, Hu J, Chen J, Gong W, Cho EH, et al. Activation of Toll-like receptor 2 onmicroglia promotes cell uptake of Alzheimer disease-associated amyloid beta peptide. J Biol Chem.2006;281:3651-3659.
[48]Tang SC, Lathia JD, Selvaraj PK, Jo DG, Mughal MR, Cheng A, et al. Toll-like receptor-4 mediates neuronal apoptosis induced by amyloid beta-peptide and the membrane lipid peroxidation product 4-hydroxynonenal. Exp Neurol.2008;213:114-121.
[49]Herrmann N, Li A,& Lanctot K. Memantine in dementia:A review of the current evidence. Expert Opin Pharmacother.2011; 12:787-800.
[50]Small G,& Bullock R... Defining optimal treatment with cholinesterase inhibitors in Alzheimer's disease. Alzheimers Dement.2011;7:177-184.
[51]王莉莉,马挺巴,巴俊杰.蒙药文冠木研究进展.内蒙古医学院学报.2008;30：153-155.
[52]Kim HS, Suh YH. Minocycline and neurodegenerative diseases. Behav Brain Res. 2009; 196:168-179.
[53]Choi Y, Kim HS, Shin KY, Kim EM, Kim M, Suh YH, et al. Minocycline attenuates neuronal cell death and improves cognitive impairment in Alzheimer's disease models. Neuropsychopharmacology.2007;32:2393-2404.
[54]Fuster-Matanzo A, Llorens-Martin M, Hernandez F and Avila J. Role of neuroinflammation in adult neurogenesis and Alzheimer disease:Therapeutic approaches. Mediat Inflamm.2013;1;1-9.
[55]Zipp F, Aktas O. The brain as a target of inflammation:common pathways link inflammatory and neurodegenerative diseases. Trends Neurosci.2006;29:518-527.
[56]Chi TY, Wang LH, Qu C, Yang BZ, Ji XF, Wang Y. Protective effects of xanthoceraside on learning and memory impairment induced by Aβ25-35 in mice. J Asian Nat Prod Res. 2009;11:1019-1027.
[57]Lu P, Mamiya T, Lu L, Mouri A, Ikejima T, Kim HC, et al. Xanthoceraside attenuates amyloid β peptide25-35-induced learning and memory impairments in mice. Psychopharmacology.2012;219:181-190.
[58]Hashioka S, Han YH, Fujii S, Kato T, Monji A, Utsumi H, et al. Phosphatidylserine and phosphatidylcholine-containing liposomes inhibit amyloid β and interferon-y-induced microglial activation. Free Radical Bio Med.2007;42:945-954.
[59]Yamamoto M, Kiyota T, Horiba M, Buescher, JL, Walsh SM, et al. Interferon-y and tumor necrosis factor-a regulate amyloid-β plaque deposition and β-secretase expression in Swedish mutant APP transgenic mice. Am J Pathol,2007; 170:680-692.
[60]Meda L, Cassatella MA, Szendrei Gl, Otvos L, Baron P, Villalba M, et al. Activation of microglial cells by β-amyloid protein and interferon-y. Nature,1995; 374:647-650.
[61]Neymotin A, Petri S, Calingasan NY, Wille E, Schafer P, Stewart C, et al. Lenalidomide (Revlimid(?)) administration at symptom onset is neuroprotective in a mouse model of amyotrophic lateral sclerosis. Exp Neurol.2009;220:191-197.
[62]Kim YJ, Hwang SY, Oh ES, Oh S, Han IO. IL-1β, an immediate early protein secreted by activated microglia, induces iNOS/NO in C6 astrocytoma cells through p38 MAPK and NF-κB pathways. J Neurosci Res.2006;84:1037-1046.
[63]McAlpine FE, Lee JK, Harms AS, Ruhn KA, Blurton-Jones M, Hong J, et al. Inhibition of soluble TNF signaling in a mouse model of Alzheimer's disease prevents pre-plaque amyloid-associated neuropathology. Neurobiol Dis.2009;34:163-177.
[64]Zhao Y, Calon F, Julien C, Winkler JW, Petasis NA, Lukiw WJ, et al. Docosahexaenoic acid-derived neuroprotectin dl induces neuronal survival via secretase and PPARy-mediated mechanisms in Alzheimer's disease models. PLoS ONE.2011;6:1-15.
[65]Surh YJ, Chun KS, Cha HH, Han SS, Keum YS, Park KK. Molecular mechanisms underlying chemopreventive activities of anti-inflammatory phytochemicals:down-regulation of COX-2 and iNOS through suppression of NF-κB activation. Mutat Res.2001; 480-481: 243-268.
[66]Morel SV, Park JY, Kim BW, Kumar H, Lim HW, Kang SM, et al. Anti-neuroinflamm-tory activity of a novel cannabinoid derivative by inhibiting the NF-κB signaling pathway in Lipopolysaccharide-induced BV-2 microglial cells. J Pharmacol Sci.2013;121:119-130.
[67]Jeon NR, Koppula S, Kim B-W, Park SH, Lee H-W, Choi D-K. MMHD[(s,e)-2-methyl-1-(2-methylthiazol-4-yl) hexa-1,5-dien-ol], a novel synthetic compound derived from epothilone, suppresses nuclear factor-kappa b-mediated cytokine expression in lipopolysaccharide-stimulated BV-2 microglia. J Pharmacol Sci.2010;112:158-166.
[68]Kim BW, Koppula S, Kim IS, Lim HW, Hong SM, Han SD, et al. Anti-neuroinflammatory activity of kamebakaurin from isodon japonicus via inhibition of c-Jun NH2-terminal kinase and p38 mitogen-activated protein kinase pathway in activated microglial cells. J Pharmacol Sci.2011; 116,296-308.
[69]Choi Y, Lee MK, Lim SY, Sung SH, Kim YC. Inhibition of inducible NO synthase, cyclooxygenase-2 and interleukin-1 beta by torilin is mediated by mitogen-activated protein kinases in microglial BV2 cells. Br J Phamrmacol.2009; 156:933-940.
[70]John M, Yriakis K and Avruch J. Mammalian Mitogen-activated protein kinase signal transduction pathways activated by stress and inflammation. Physiolo Rev.2001;81:807-869.
[71]Kim YH, Choi KH, Park JW, Kwon TK. LY294002 inhibits LPS-induced NO production through a inhibition of NF-κB activation:independent mechanism of phosphatidylinositol 3-kinase. Immunol Lett.2005;99:45-50.
[72]Rosenberger J, Petrovics G, Buzas B. Oxidative stress induces proorphanin FQ and proenkephalin gene expression in astrocytes through p38-and ERK-MAP kinases and NF-kappa B. J Neurochem.2001;79:35-44.
[73]Lal MA, Brismar H, Eklof AC, Aperia A. Role of oxidative stress in advanced glycation end product-induced mesangial cell activation. Kidney Int.2002;61:2006-2014.
[74]Chaturvedi P. Inhibitory response of Raphanus sativus on lipid peroxidation in albino rats. Evidence-Based Compl. Altern Med.2008;5:55-59.
[75]Newburger PE, Ezekowitz RA, Whitney C, Wright J, Orkin SH. Induction of phagocyte cytochrome b heavy chain gene expression by interferon-y. Proc. Natl. Acad. Sci. USA. 1988;85:5215-5219.
[76]Hanamsagar R, Hanke ML and Kielian T. Toll-like receptor (TLR) and inflammasome actions in the central nervous system. Trends Immunol.2012;33:333-342.
[77]Yirmiya R, Goshen I. Immune modulation of learning, memory, neural plasticity and neurogenesis. Brain Behav Immun.2011;25:181-213.
[78]Schroder K, Hertzog PJ, Ravasi T, Hume DA. Interferon-y:an overview of signals, mechanisms and functions. J Leukoc Biol.2004;75:163-189.
[79]Kim D, Kim MA, Cho IH, Kim MS, Lee S, Jo EK, et al. A critical role of toll-like receptor 2 in nerve injury-induced spinal cord glial cell activation and pain hypersensitivity. J Biol Chem.2007;282:14975-14983.
[80]Weitz TM, Town T. Microglia in Alzheimer disease:It's all about context. Int J Alzheimers Dis.2012; 1:1-11.
[81]Cameron B, Landreth GE. Inflammation, microglia, and Alzheimer's disease. Neurobiol Dis.2010;37:503-509.
[82]Laursen SE, and Belknap JK. Intranerebroventricular injections in mice:some methodological refinements. J pharmacol meth.1986; 16:335-357.
[83]Griffin WS, Sheng JG, Roberts GW, Mrak RE. Interleukin-1 expression in different plaque types in Alzheimer's disease:significance in plaque evolution. J Neuropathol Exp Neurol.1995;54:276-281.
[84]Griffin WS, Stanley LC, Ling C, White L, MacLeod V, Perrot LJ. Brain interleukin 1 and S-100 immunoreactivity are elevated in Down syndrome and Alzheimer disease. Proc Natl Acad Sci USA.1989;86:7611-7615.
[85]Tan ZS, Beiser AS, Vasan RS, Roubenoff R, Dinarello CA, Harris TB. Inflammatory markers and the risk of Alzheimer disease:the Framingham Study. Neurology.2007; 68:1902-1908.
[86]Kalman J, Juhasz A, Laird G, Dickens P, Jardanhazy T, Rimanoczy A. Serum interleukin-6 levels correlate with the severity of dementia in Down syndrome and in Alzheimer's disease. Acta Neurol Scand.1997;96:236-240.
[87]Yu XW, Chen Q, Kennedy RH, Liu SJ. Inhibition of sarcoplasmic reticular function by chronic interleukin-6 exposure via iNOS in adult ventricular myocytes. J Physiol.2005;566: 327-340.
[88]Mollie K. Meffert and David Baltimore. Physiological functions for brain NF-κB. TRENDS in Neuro.2005; 28:1-7.
[89]Scheubert P, Rudolphi K. Interfering with the pathologic activation of microglial cells and astrocyte in dementia. Alzheimer's Dis Assoc Disord.1988(suppl 2):821-828.
[90]Bales KR,Du Y, Dodel RC, et al. The NF-κB/Rel family of proteins mediates abeta induced neurotoxicity and glial activation. Brain Res Mol Brain Res.1998;57:63-72.
[91]Kim SH, Smith CJ, Van Eldik LJ. Importance of MAPK pathways for microglial pro-inflammatory cytokine IL-1h production. Neurobiol Aging.2004;25:431-439.
[92]Bach JH, Chae HS, Rah JC, Lee MW, Park CH, Choi SH. C-terminal fragment of amyloid precursor protein induces astrocytosis. J Neurochem.2001;78:109-120.
[93]Koistinaho M, Kettunen MI, Goldsteins G, Keinanen R, Salminen A, Ort M. β-amyloid precursor protein transgenic mice that harbor diffuse A beta deposits but do not form plaques show increased ischemic vulnerability:role of inflammation. Proc Natl Acad Sci USA. 2002;99:1610-1615.
[94]Hua LL, Zhao ML, Cosenza M, Kim MO, Huang H, Tanowitz HB. Role of mitogen-activated protein kinases in inducible nitric oxide synthase and TNFa expression in human fetal astrocytes, J Neuroimmunol.2002; 126:180-189.
[95]Guan Z, Buckman SY, Springer LD, Morrison AR. Both p38aMAPK and JNK/SAPK pathways are important for induction of nitric-oxide synthase by interleukin-1β in rat glomerular mesangial cells. J Biol Chem.1999;274:36200-36206.
[96]Cho MK, Suh SH, Kim SG. JunB/AP-1 and NF-jB-mediated induction of nitric oxide synthase by bovine type I collagen in serum-stimulated murine macrophages. Nitric Oxide. 2002;6:319-332.
[97]Kan H, Xie Z, Finkel MS. TNF-alpha enhances cardiac myocyte NO production through MAP kinase-mediated NF-kappaB activation. Am J Physiol.1999;277:1641-1646.
[98]Han IO, Kim HS, Kim HC, Joe EH, Kim WK. Synergistic expression of inducible nitric oxide synthase by phorbol ester and interferon-c is mediated through NF-κB and ERK in microglial cells. Neurosci Res.2003;73:659-669.
[99]Wang T, Lafuse WP, Zwilling BS. NFkappaB and Spl elements are necessary for maximal transcription of toll-like receptor 2 induced by Mycobacterium avium. J Immunol. 2001b; 167:6924-6932.