Corilagin抑制照射后BV-2细胞炎症因子表达的体外研究
摘要
【目的】研究抗炎药物Corilagin抑制放射引起小胶质细胞(BV-2)炎症反应的作用及其防护的分子机制。
【方法】细胞抑制实验(MTT)检测Corilagin对BV-2细胞抑制率;Corilagin预处理小胶质细胞,12 h后以0和32Gy 2个放射剂量照射BV-2细胞,Real-time PCR检测小胶质细胞照射后不同时间点炎症因子IL-1β、TNF-α表达水平;硝酸还原酶法检测细胞上清液中一氧化氮(NO)的含量;Western-blot检测各组细胞核转录因子NF-κB p65蛋白表达;激光共聚焦显微镜观察各组细胞标志物Iba-1的表达、NF-κB p65核转位及Nemo的表达。
【结果】1~10μg/mL浓度范围内Corilagin对BV-2细胞增殖几乎无影响;照射后小胶质细胞表面标志物Iba-1表达明显,提示小胶质细胞激活,且炎症因子NO、TNF-α、IL-1β表达上调,而Corilagin(5μg/mL)可以显著抑制上述炎症因子的表达(tIL-1β=6.341,P<0.001;tTNF-α=3.411,P<0.007;tNO=3.134,P<0.015);照射后BV-2细胞内核转录因子NF-κB p65从胞浆转入胞核,免疫细胞化学进一步提示照射后细胞内活化蛋白Nemo表达增加,而IκB表达减少。Corilagin可抑制NF-κB活化蛋白Nemo,并显著抑制NF-κB p65的转位。
【结论】Corilagin可能通过抑制途径照射后小胶质细胞NF-κB信号转导的活化,从而下调炎症因子表达,保护神经元。
【Objective】The aim of this work was to explore the inhibitory effects of Corilagin on the production of pro-inflammatory cytokines in microglia stimulated by radiation.
【Methods】The cytotoxicity of Corilagin was measured by MTT assay. Microglia BV-2 cells were stimulated by radiation(0, 32Gy)after pretreated with Corilagin for 12 hours. Realtime-PCR was used to detect the inflammatory cytokines such as IL-1β, TNF-αwhich were expressed by radiation-stimulated microglia BV cells on several time point. The production of Nitric Oxide (NO) was determined with nitrate reductase. The translocation of NF-κB p65 was measured by western-blot and immunocyto- chemical stain. Confocal microscopy was used to detected the expression of Iba-1, Nemo , IκB and the translocation of NF-κB p65.
【Results】Corilagin showed no cytotoxicity for BV-2 cells within 1-10μg/mL. Irradiation was able to activate microglia cell with expression of Iba-1, and elevated the expression of inflammatory cytokines such as IL-1β, TNF-αand NO. Whereas, 5μg/mL Corilagin was significantly able to inhibit the production of IL-1β, TNF-αin activated microglia cells (tIL-1β=6.341,p<0.001;tTNF-α=3.411,p<0.007;tNO=3.134,p<0.015). Given a 32Gy of irradiation, NF-κB p65 in BV-2 translocate from cytoplasm to nuclear, correspondence with a increased Nemo and a inhibition of IκB, Corilagin significantly inhibited the expression of Nemo and the translocation and activation of NF-κB p65.
【Conclusions】Corilagin could inhibit the activation of radiated microglia cells and down-regulate the expression of inflammatory cytokines, via inhibition of NF-κB signaling pathway.
【方法】细胞抑制实验(MTT)检测Corilagin对BV-2细胞抑制率;Corilagin预处理小胶质细胞,12 h后以0和32Gy 2个放射剂量照射BV-2细胞,Real-time PCR检测小胶质细胞照射后不同时间点炎症因子IL-1β、TNF-α表达水平;硝酸还原酶法检测细胞上清液中一氧化氮(NO)的含量;Western-blot检测各组细胞核转录因子NF-κB p65蛋白表达;激光共聚焦显微镜观察各组细胞标志物Iba-1的表达、NF-κB p65核转位及Nemo的表达。
【结果】1~10μg/mL浓度范围内Corilagin对BV-2细胞增殖几乎无影响;照射后小胶质细胞表面标志物Iba-1表达明显,提示小胶质细胞激活,且炎症因子NO、TNF-α、IL-1β表达上调,而Corilagin(5μg/mL)可以显著抑制上述炎症因子的表达(tIL-1β=6.341,P<0.001;tTNF-α=3.411,P<0.007;tNO=3.134,P<0.015);照射后BV-2细胞内核转录因子NF-κB p65从胞浆转入胞核,免疫细胞化学进一步提示照射后细胞内活化蛋白Nemo表达增加,而IκB表达减少。Corilagin可抑制NF-κB活化蛋白Nemo,并显著抑制NF-κB p65的转位。
【结论】Corilagin可能通过抑制途径照射后小胶质细胞NF-κB信号转导的活化,从而下调炎症因子表达,保护神经元。
【Objective】The aim of this work was to explore the inhibitory effects of Corilagin on the production of pro-inflammatory cytokines in microglia stimulated by radiation.
【Methods】The cytotoxicity of Corilagin was measured by MTT assay. Microglia BV-2 cells were stimulated by radiation(0, 32Gy)after pretreated with Corilagin for 12 hours. Realtime-PCR was used to detect the inflammatory cytokines such as IL-1β, TNF-αwhich were expressed by radiation-stimulated microglia BV cells on several time point. The production of Nitric Oxide (NO) was determined with nitrate reductase. The translocation of NF-κB p65 was measured by western-blot and immunocyto- chemical stain. Confocal microscopy was used to detected the expression of Iba-1, Nemo , IκB and the translocation of NF-κB p65.
【Results】Corilagin showed no cytotoxicity for BV-2 cells within 1-10μg/mL. Irradiation was able to activate microglia cell with expression of Iba-1, and elevated the expression of inflammatory cytokines such as IL-1β, TNF-αand NO. Whereas, 5μg/mL Corilagin was significantly able to inhibit the production of IL-1β, TNF-αin activated microglia cells (tIL-1β=6.341,p<0.001;tTNF-α=3.411,p<0.007;tNO=3.134,p<0.015). Given a 32Gy of irradiation, NF-κB p65 in BV-2 translocate from cytoplasm to nuclear, correspondence with a increased Nemo and a inhibition of IκB, Corilagin significantly inhibited the expression of Nemo and the translocation and activation of NF-κB p65.
【Conclusions】Corilagin could inhibit the activation of radiated microglia cells and down-regulate the expression of inflammatory cytokines, via inhibition of NF-κB signaling pathway.
引文
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2. Mizumatsu S,Monje ML, Morhardt DR, et a1.Extreme sensitivity of adult neurogenesis to low doses of X-irradiation[J]. Cancer Res, 2003, 63(14): 4021-4027
3. Monje ML, Palmer T. Radiation injury and neurogenesis. Curr Opin Neurol. 2003. 16: 129– 134
4. Monje ML, Mizumatsu S, Fike JR, et al. Irradiation induces neural precursor-cell dysfunction[J]. Nat Med. 2002. 8: 955–962
5. L?brich M, Rief N, Kühne M, et al. In vivo formation and repair of DNA double strand breaks after computed tomography examinations. PNAS, 2005, 102(25): 8984-8989.
6. Rübe CE, Dong XR, Kühne M, et al. DNA double-strand break rejoining in complex normal tissues. Radiat Oncol Biol Phys, 2008, 72(4): 1180-1187.
7.陈玉武,等.蜜柑草抗癌有效成份研究Ⅱ.多酚类成分的分离与鉴定[J].中草药, 1997, 28(4): 198-202.
8. Zhao S L, et al. Preliminary exploration on anti-inflammatory mechanism of Corilagin [beta-1-O-galloyl-3,6-(R)-hexahydroxydiphenoyl-d-glucose] in Vitro[J]. Int Immunophamac- ol, 2008, 8(7): 1 059-1 064.
9.刘朝阳,等.柯里拉京抗肿瘤和致突变作用实验研究[J].肿瘤防治杂志, 2003,10(5): 469-472.
10. Kumaran A, et al. Nitric oxide radical scavenging active components from Phyllanthus emblica L.[J]. Plant Foods Hum Nutr. 2006, 61(1): 1-5.
11. S Kinoshita. et al. Free radical scavenging action of medicinal herbs from Mongolia[J]. Phytomedicine. 2007. 14(11): 755-762.
12. Sheline GE, Wara WM, Smith V. Therapeutic irradiation and brain injury[J]. Int JRadiat Oncol Biol Phys. 1980. 6: 1215-1228.
13. Schultheiss TE, Kun LE, Ang KK, et al. Radiation response of the central nervous system. Int J Radiat Oncol Biol Phys. 1995. 31: 1093-1112
14. Ammstrong CL, Gyato K, Awadalla AW,et a1. A critical review of the clinical effects of therapeutic irradiation damage to the brain : the roots of controversy[J].Nettropsychol Rev, 2004, 14(1):65-86.
15. Mizumatsu S, Monje ML, Morhardt DR, et al. Extreme sensitivity of adult neurogenesis to low doses of X-irradiation. Cancer Res[J]. 2003. 63: 4021–4027
16. Calvo W. Experimental radiation damage of the central nervous system.Recent Result Cancer Res, 1993, 130: 175-188.
17. Badan I, Buchhold B, Hamm A, et al. Accelerated glial reactivity to stroke in aged rats correlates with reduced functional recovery. Cereb Blood Flow Metab, 2003. 23(7): 845-854.
18. Franklin A,Parmentier-Batteur S,Walter L, et al.Palmitoylethanolamide increases after focal cerebral ischemia and potentiates microglial cell motility. Neurosci, 2003, 23(21): 7767-7775
19. Yin L, Ohtaki H, Nakamachi T, et al. Delayed expressed TNFRl co-localize with ICAM-1 in astrocyte in mice brain after transient focal ischemia. Neurosci Lett, 2004. 370(1): 30-35.
20. Bbetz A L, Schiellee G P, Yang G Y, Interleukin-1 in cerebral ischemia[J]. Keio J Med, 1996. 45: 230-238
21.刘辉,陈俊抛.一氧化氮、一氧化氮合酶与脑缺血损伤[J].国外医学?生理病理科学与临床分册. 1999. 19(2):12-23.
22. Harper JW, Elledge SJ. The DNA damage response: ten years after . Mol Cell. 2007. 28(5): 739-745.
23. Wang Y,Meng Z.Expression of NF-κB, caspase-3 and cell apoptosis after focal cerebral ischemia and reperfusion injury in rats[J].Journal of Apoplexy and erous Diseases. 2004. 21(3):208—210.
24. Madrid LV, Wang CY, Guttridge DC, et al. Akt suppress apoptosis by stimulating the transactivation potential of the RelA/P65 subnit of NF-Κb[J]. Mol cell boil. 2000. 20(5): 1626-1638
25.张树蜂,明艳林,林毅等.叶下株属植物活性成分柯里拉京研究进展(综述).亚热带植物科学. 2010. 39(4): 79-83
26.沈志强,等.叶下珠有效部位的溶栓作用及其对PAI-1和tPA活性的影响[J].天然产物研究与开发, 2003,15: 441-445.
27.呙爱秀,等.天然产物柯里拉京防治心血管疾病的药理效用概述[J].湖南环境生物职业技术学院学报. 2007. 13(2):11-14.
28. An J, Huang YC, Xu QZ, et al. DNA-PKcs plays a dominant role in the regulation of H2AX phosphorylatin in response to DNA damage and cell cycle progression. BMC Mol Biol. 2010. 11:18.
29. Banath JP, MacPhail SH, Olive PL. (2004) Radiation sensitivity, H2AX phosphorylation, and kinetics of repair of DNA strand breaks in irradiated cervical cancer cell lines. Cancer Res. 64: 7144–7149
1. New P. Radiation injury to the nervous system[J]. Curr Opin Neurol, 2001. 14(6): 725-734
2. Pena LA, Fuks Z, Kolesnick RN. Radiation-induced apoptosisi of endothelial cells in the murine central nervous system: protection by fibroblast growth factor and sphingomyelinase deficiency[J]. Cancer Res, 2000. 60(2): 321-327
3. Tofilon PJ,Fike JR.The mdioresponse of the central nerous system:a dynamic process. Radiat Res, 2000. 153(3): 357-370
4.刘强.放射性脑损伤研究现状[J].国外医学?放射医学核医学分册, 2004, 28(4): 178-181
5. Chan PH. Oxygen radicals in focal cerebral isehemia[J].Brain Pathol, 1994. 4(1): 59-65
6. Romero AA, Gross SR, Cheng KY, et a1. An age-related increase in resistance to DNA damaged-induced apopotic cell death is associated with development of DNA repair mechanisms[J]. Neurochem, 2003. 84(6): 1275-1287
7. Nieder C, Andratschke N, Price RE, et a1. Innovative prevention strategies for radiation necrosis of the central nervous system[J]. Antieancer Res, 2002. 22(2A): 1017—1023
8. Anderson VA, Godber T, Smibert E, et al. Cognitive and academic outcome following cranial irradiation and chemotherapy in children:a longitudinal study[J]. Br J Cancer. 2000. 82: 255–262
9. Crossen JR, Garwood D, Glatstein E, et al. Neurobehavioral sequelae of cranial irradiation in adults: a review of radiationinduced encephalopathy[J]. J Clin Oncol. 1994. 12: 627-642
10. Rola R, Raber J, Rizk A, et al. Radiationinduced impairment of hippocampalneurogenesis is associated with cognitive deficits in young mice[J]. Exp Neurol. 2004. 188: 316–330
11. Shors TJ, Miesegaes G, Beylin A, et al. Neurogenesis in the adult is involved in the formation of trace memories[J]. 2001. Nature. 410: 372–376.
12. Mizumatsu S, Monje ML, Morhardt DR, et al. Extreme sensitivity of adult neurogenesis to low doses of X-irradiation. Cancer Res[J]. 2003. 63: 4021–4027.
13. Mirescu C, Gould E. Stress and adult neurogenesis[J]. Hippocampus. 2006. 16: 233–238.
14. Monje ML, Toda H, Palmer TD. Inflammatory blockade restores adult hippocampal neurogenesis[J]. Science. 2003. 302: 1760–1765
15. Monje ML, Mizumatsu S, Fike JR, et al. Irradiation induces neural precursor-cell dysfunction[J]. Nat Med. 2002. 8: 955–962.
16. Palmer TD, Willhoite AR, Gage FH. Vascular niche for adult hippocampal neurogenesis[J]. Comp Neurol. 2000. 425: 479–494.
17. Yin L, Ohtaki H, Nakamachi T, et al. Delayed expressed TNFRl co-localize with ICAM-1 in astrocyte in mice brain after transient focal ischemia. Neurosci Lett, 2004. 370(1): 30-35.
18. Bbetz A L, Schiellee G P, Yang G Y, Interleukin-1 in cerebral ischemia[J]. Keio J Med, 1996. 45: 230-238
19. Badan I, Buchhold B, Hamm A, et al. Accelerated glial reactivity to stroke in aged rats correlates with reduced functional recovery. Cereb Blood Flow Metab, 2003. 23(7): 845-854.
20. Franklin A,Parmentier-Batteur S,Walter L, et al.Palmitoylethanolamide increases after focal cerebral ischemia and potentiates microglial cell motility. Neurosci, 2003, 23(21): 7767-7775
21. Monje ML, Palmer T. Radiation injury and neurogenesis. Curr Opin Neurol. 2003. 16: 129– 134.
22. heikh AY, Gibson JJ, Rollins MD, et a1. Effect of hyperoxia on vascularendothelial growth factor levels in a wound model[J]. Arch Surg, 2000. 135(11): 1293-1297.
23. Sminia P, van der Kleij AJ, Carl UM, et a1. Prophylactic hyperbaric oxygen treatment and rat spinal cord reirradiation[J]. Cancer Lett, 2003. 191(1): 59-65
24. Sriram Ramanan,Mitra Kooshki,Mike E. Robbins. PPARαligands inhibit radiation-induced microglial inflammatory responses by negatively regulating NF-κB and AP-1 pathways. Free Radical Biology & Medicine. 2008. 45(12): 1695-1704
25.丁维军,王建华,汪洋,等.静脉注射骨髓基质干细胞对放射性脑损伤模型大鼠认知障碍的影响.中华放射肿瘤学杂志.2007. 2-143.
26. Esen F, Erdem T, Aktan D, et a1. Efects of magnesium administration on brain edema and blood-brain barrier breakdown after experimental traumatic brain injury in rats[J]. J Neurosurg Anesthesiol, 2003, 15(2): 119-125.
27.涂彧,周菊英,千利利. MgSO4对大鼠急性放射性脑损伤后钙超载的抑制作用[J].中华放射医学与防护杂志,2005,25(4):339-341.
2. Mizumatsu S,Monje ML, Morhardt DR, et a1.Extreme sensitivity of adult neurogenesis to low doses of X-irradiation[J]. Cancer Res, 2003, 63(14): 4021-4027
3. Monje ML, Palmer T. Radiation injury and neurogenesis. Curr Opin Neurol. 2003. 16: 129– 134
4. Monje ML, Mizumatsu S, Fike JR, et al. Irradiation induces neural precursor-cell dysfunction[J]. Nat Med. 2002. 8: 955–962
5. L?brich M, Rief N, Kühne M, et al. In vivo formation and repair of DNA double strand breaks after computed tomography examinations. PNAS, 2005, 102(25): 8984-8989.
6. Rübe CE, Dong XR, Kühne M, et al. DNA double-strand break rejoining in complex normal tissues. Radiat Oncol Biol Phys, 2008, 72(4): 1180-1187.
7.陈玉武,等.蜜柑草抗癌有效成份研究Ⅱ.多酚类成分的分离与鉴定[J].中草药, 1997, 28(4): 198-202.
8. Zhao S L, et al. Preliminary exploration on anti-inflammatory mechanism of Corilagin [beta-1-O-galloyl-3,6-(R)-hexahydroxydiphenoyl-d-glucose] in Vitro[J]. Int Immunophamac- ol, 2008, 8(7): 1 059-1 064.
9.刘朝阳,等.柯里拉京抗肿瘤和致突变作用实验研究[J].肿瘤防治杂志, 2003,10(5): 469-472.
10. Kumaran A, et al. Nitric oxide radical scavenging active components from Phyllanthus emblica L.[J]. Plant Foods Hum Nutr. 2006, 61(1): 1-5.
11. S Kinoshita. et al. Free radical scavenging action of medicinal herbs from Mongolia[J]. Phytomedicine. 2007. 14(11): 755-762.
12. Sheline GE, Wara WM, Smith V. Therapeutic irradiation and brain injury[J]. Int JRadiat Oncol Biol Phys. 1980. 6: 1215-1228.
13. Schultheiss TE, Kun LE, Ang KK, et al. Radiation response of the central nervous system. Int J Radiat Oncol Biol Phys. 1995. 31: 1093-1112
14. Ammstrong CL, Gyato K, Awadalla AW,et a1. A critical review of the clinical effects of therapeutic irradiation damage to the brain : the roots of controversy[J].Nettropsychol Rev, 2004, 14(1):65-86.
15. Mizumatsu S, Monje ML, Morhardt DR, et al. Extreme sensitivity of adult neurogenesis to low doses of X-irradiation. Cancer Res[J]. 2003. 63: 4021–4027
16. Calvo W. Experimental radiation damage of the central nervous system.Recent Result Cancer Res, 1993, 130: 175-188.
17. Badan I, Buchhold B, Hamm A, et al. Accelerated glial reactivity to stroke in aged rats correlates with reduced functional recovery. Cereb Blood Flow Metab, 2003. 23(7): 845-854.
18. Franklin A,Parmentier-Batteur S,Walter L, et al.Palmitoylethanolamide increases after focal cerebral ischemia and potentiates microglial cell motility. Neurosci, 2003, 23(21): 7767-7775
19. Yin L, Ohtaki H, Nakamachi T, et al. Delayed expressed TNFRl co-localize with ICAM-1 in astrocyte in mice brain after transient focal ischemia. Neurosci Lett, 2004. 370(1): 30-35.
20. Bbetz A L, Schiellee G P, Yang G Y, Interleukin-1 in cerebral ischemia[J]. Keio J Med, 1996. 45: 230-238
21.刘辉,陈俊抛.一氧化氮、一氧化氮合酶与脑缺血损伤[J].国外医学?生理病理科学与临床分册. 1999. 19(2):12-23.
22. Harper JW, Elledge SJ. The DNA damage response: ten years after . Mol Cell. 2007. 28(5): 739-745.
23. Wang Y,Meng Z.Expression of NF-κB, caspase-3 and cell apoptosis after focal cerebral ischemia and reperfusion injury in rats[J].Journal of Apoplexy and erous Diseases. 2004. 21(3):208—210.
24. Madrid LV, Wang CY, Guttridge DC, et al. Akt suppress apoptosis by stimulating the transactivation potential of the RelA/P65 subnit of NF-Κb[J]. Mol cell boil. 2000. 20(5): 1626-1638
25.张树蜂,明艳林,林毅等.叶下株属植物活性成分柯里拉京研究进展(综述).亚热带植物科学. 2010. 39(4): 79-83
26.沈志强,等.叶下珠有效部位的溶栓作用及其对PAI-1和tPA活性的影响[J].天然产物研究与开发, 2003,15: 441-445.
27.呙爱秀,等.天然产物柯里拉京防治心血管疾病的药理效用概述[J].湖南环境生物职业技术学院学报. 2007. 13(2):11-14.
28. An J, Huang YC, Xu QZ, et al. DNA-PKcs plays a dominant role in the regulation of H2AX phosphorylatin in response to DNA damage and cell cycle progression. BMC Mol Biol. 2010. 11:18.
29. Banath JP, MacPhail SH, Olive PL. (2004) Radiation sensitivity, H2AX phosphorylation, and kinetics of repair of DNA strand breaks in irradiated cervical cancer cell lines. Cancer Res. 64: 7144–7149
1. New P. Radiation injury to the nervous system[J]. Curr Opin Neurol, 2001. 14(6): 725-734
2. Pena LA, Fuks Z, Kolesnick RN. Radiation-induced apoptosisi of endothelial cells in the murine central nervous system: protection by fibroblast growth factor and sphingomyelinase deficiency[J]. Cancer Res, 2000. 60(2): 321-327
3. Tofilon PJ,Fike JR.The mdioresponse of the central nerous system:a dynamic process. Radiat Res, 2000. 153(3): 357-370
4.刘强.放射性脑损伤研究现状[J].国外医学?放射医学核医学分册, 2004, 28(4): 178-181
5. Chan PH. Oxygen radicals in focal cerebral isehemia[J].Brain Pathol, 1994. 4(1): 59-65
6. Romero AA, Gross SR, Cheng KY, et a1. An age-related increase in resistance to DNA damaged-induced apopotic cell death is associated with development of DNA repair mechanisms[J]. Neurochem, 2003. 84(6): 1275-1287
7. Nieder C, Andratschke N, Price RE, et a1. Innovative prevention strategies for radiation necrosis of the central nervous system[J]. Antieancer Res, 2002. 22(2A): 1017—1023
8. Anderson VA, Godber T, Smibert E, et al. Cognitive and academic outcome following cranial irradiation and chemotherapy in children:a longitudinal study[J]. Br J Cancer. 2000. 82: 255–262
9. Crossen JR, Garwood D, Glatstein E, et al. Neurobehavioral sequelae of cranial irradiation in adults: a review of radiationinduced encephalopathy[J]. J Clin Oncol. 1994. 12: 627-642
10. Rola R, Raber J, Rizk A, et al. Radiationinduced impairment of hippocampalneurogenesis is associated with cognitive deficits in young mice[J]. Exp Neurol. 2004. 188: 316–330
11. Shors TJ, Miesegaes G, Beylin A, et al. Neurogenesis in the adult is involved in the formation of trace memories[J]. 2001. Nature. 410: 372–376.
12. Mizumatsu S, Monje ML, Morhardt DR, et al. Extreme sensitivity of adult neurogenesis to low doses of X-irradiation. Cancer Res[J]. 2003. 63: 4021–4027.
13. Mirescu C, Gould E. Stress and adult neurogenesis[J]. Hippocampus. 2006. 16: 233–238.
14. Monje ML, Toda H, Palmer TD. Inflammatory blockade restores adult hippocampal neurogenesis[J]. Science. 2003. 302: 1760–1765
15. Monje ML, Mizumatsu S, Fike JR, et al. Irradiation induces neural precursor-cell dysfunction[J]. Nat Med. 2002. 8: 955–962.
16. Palmer TD, Willhoite AR, Gage FH. Vascular niche for adult hippocampal neurogenesis[J]. Comp Neurol. 2000. 425: 479–494.
17. Yin L, Ohtaki H, Nakamachi T, et al. Delayed expressed TNFRl co-localize with ICAM-1 in astrocyte in mice brain after transient focal ischemia. Neurosci Lett, 2004. 370(1): 30-35.
18. Bbetz A L, Schiellee G P, Yang G Y, Interleukin-1 in cerebral ischemia[J]. Keio J Med, 1996. 45: 230-238
19. Badan I, Buchhold B, Hamm A, et al. Accelerated glial reactivity to stroke in aged rats correlates with reduced functional recovery. Cereb Blood Flow Metab, 2003. 23(7): 845-854.
20. Franklin A,Parmentier-Batteur S,Walter L, et al.Palmitoylethanolamide increases after focal cerebral ischemia and potentiates microglial cell motility. Neurosci, 2003, 23(21): 7767-7775
21. Monje ML, Palmer T. Radiation injury and neurogenesis. Curr Opin Neurol. 2003. 16: 129– 134.
22. heikh AY, Gibson JJ, Rollins MD, et a1. Effect of hyperoxia on vascularendothelial growth factor levels in a wound model[J]. Arch Surg, 2000. 135(11): 1293-1297.
23. Sminia P, van der Kleij AJ, Carl UM, et a1. Prophylactic hyperbaric oxygen treatment and rat spinal cord reirradiation[J]. Cancer Lett, 2003. 191(1): 59-65
24. Sriram Ramanan,Mitra Kooshki,Mike E. Robbins. PPARαligands inhibit radiation-induced microglial inflammatory responses by negatively regulating NF-κB and AP-1 pathways. Free Radical Biology & Medicine. 2008. 45(12): 1695-1704
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