厄贝沙坦对大鼠局灶性脑缺血再灌注后炎症反应的影响
摘要
目的:研究厄贝沙坦预处理对缺血再灌注大鼠脑和血清ICAM-1与VCAM-1水平的动态变化,探讨厄贝沙坦对脑缺血再灌注损伤后炎症反应的影响和脑保护作用。
方法:健康雄性SD大鼠随机分为假手术组、缺血再灌注组和厄贝沙坦缺血再灌注组。线栓法建立大鼠大脑中动脉闭塞(MCAO)模型,厄贝沙坦缺血再灌注组动物于MCAO前3周给予灌胃新鲜配置成的厄贝沙坦混悬液(6mg/ml,30mg/kg),同时缺血再灌注组以及假手术组给予安慰剂(生理盐水,5ml/kg)灌胃3周。缺血再灌注24h和72h进行神经功能评分,后处死动物,TTC染色测梗死体积百分比。用免疫组化法半定量检测梗死半球缺血带的ICAM-1和VCAM-1的表达。用ELISA法测定血清中sICAM-1和sVCAM-1的表达。
结果:
(1)厄贝沙坦缺血再灌注组神经行为学评分为1.30±0.48(24h)和1.40±0.52(72h),与缺血再灌注组比较,厄贝沙坦能够显著的改善大鼠局灶性脑缺血再灌注后24h和72h的神经功能(均p＜0.01)。
(2)厄贝沙坦缺血再灌注组梗死体积百分比为31.7±8.47%(24h)和45.48±5.93%(72h),与缺血再灌注组相比,无论缺血再灌注24h还是72h,其梗死面积均明显小于缺血再灌注组(均p＜0.01)。
(3)厄贝沙坦缺血再灌注组再灌注后214h和72h后的脑内ICAM-1、VCAM-1蛋白的表达和缺血再灌注组相比,缺血再灌注24h和72h均显著降低(p＜0.05)。
(4)厄贝沙坦缺血再灌注组再灌注后:24h和72h后sICAM-1水平、sVCAM-1水平均明显低于缺血再灌注(p＜0.05)。缺血再灌注组和厄贝沙坦缺血再灌注组sICAM-1、sVCAM-1表达水平均明显高于假手术组的表达水平(p＜0.01)。
(5)Pearson相关性显示ICAM-1和sICAM-1有显著正相关性的(p＜0.05),VCAM-1、sVCAM-1也具有显著的正相关性(p＜0.05)。sICAM-1、sVCAM-1与梗死面积也具有正相关性(p＜0.05)。sICAM-1、sVCAM-1水平反映了缺血再灌注的损伤程度。
结论:厄贝沙坦可以降低中枢及外周粘附分子的表达,减少梗死体积,改善神经功能,对脑缺血再灌注起保护作用。
Objective:To investigate the anti-inflammatory effect of pretreatment with AT1 receptor antagonist,Irbesartan on brain and peripheral blood of the rats in focal brain ischemia-reperfusioln injury.
Methods:Male SD rats were randomly assigned to sham operated group、ischemia/reperfusion group and Irbesartan ischemia-reperfusion group. Pretreatment with Irbesartan(6mg/ml,30mg/kg)for 3 weeks in Irbesartan ischemia-reperfusion group and pretreatment with saline (5ml/kg)for 3 weeks in both ischemia-reperfusion group and sham operated group before operation,we applied MCAO model of Longa, after 24 hours and 72 hours reperfusion following 90 minutes of cerebral ischemia,cerebral infarct size was measured by TTC,adhesion molecules in brain and peripheral blood were detected by ELISA and immunohistochemical technique.
Result:
(1)The scores of the Irbesartan ischemia-reperfusion group were 1.30±0.48(24h)and 1.40±0.52(72h).There were significant differences on the neurological impairment scores between the Irbesartan ischemia-reperfusion group and the ischemia-reperfusion group at 24h and 72h(all p＜0.01).
(2)The infarct volume percentage of the Irbesartan ischemia-reperfusion group were 31.7±8.47%(24h)and 45.48±5.93%(72h).The infarct volume was significantly reduced in the Irbesartan ischemia-reperfusion group compared with the ischemia-reperfusion group(all p＜0.01).
(3)The level of ICAM-1 and VCAM-1 were significantly decreased in the Irbesartan ischemia-reperfusion group compared with the ischemia/reperfusion group(p＜0.05).
(4)The level of sICAM-1 and sVCAM-1 were significantly decreased in the Irbesartan ischemia-reperfusion group compared with the ischemia-reperfusion group(p＜0.05).The level of sICAM-1 and sVCAM-1 were significantly increased in both the Irbesartan ischemia-reperfusion group and ischemia-reperfusion group compared with sham group(p＜0.01).
(5)Correlation analysis:The change between ICAM-1、VCAM-1 in brain and sICAM-1、sVCAM-1 in peripheral blood is positive correlation(r=p＜0.05=.The change of the infarct sizes is positive correlation with sICAM-1、sVCAM-1(all p＜0.05).The levels of sICAM-1、sVCAM-1 could imply the degree of severity of ischemia-reperfusion injury.
Conclusion:Pretreatment with AT1 receptor antagonist might protect brain from ischemia-reperfusion injury in rats by inhibiting leukocyteendothelial cell adhesion and decreasing cerebral infarct sizes.
方法:健康雄性SD大鼠随机分为假手术组、缺血再灌注组和厄贝沙坦缺血再灌注组。线栓法建立大鼠大脑中动脉闭塞(MCAO)模型,厄贝沙坦缺血再灌注组动物于MCAO前3周给予灌胃新鲜配置成的厄贝沙坦混悬液(6mg/ml,30mg/kg),同时缺血再灌注组以及假手术组给予安慰剂(生理盐水,5ml/kg)灌胃3周。缺血再灌注24h和72h进行神经功能评分,后处死动物,TTC染色测梗死体积百分比。用免疫组化法半定量检测梗死半球缺血带的ICAM-1和VCAM-1的表达。用ELISA法测定血清中sICAM-1和sVCAM-1的表达。
结果:
(1)厄贝沙坦缺血再灌注组神经行为学评分为1.30±0.48(24h)和1.40±0.52(72h),与缺血再灌注组比较,厄贝沙坦能够显著的改善大鼠局灶性脑缺血再灌注后24h和72h的神经功能(均p＜0.01)。
(2)厄贝沙坦缺血再灌注组梗死体积百分比为31.7±8.47%(24h)和45.48±5.93%(72h),与缺血再灌注组相比,无论缺血再灌注24h还是72h,其梗死面积均明显小于缺血再灌注组(均p＜0.01)。
(3)厄贝沙坦缺血再灌注组再灌注后214h和72h后的脑内ICAM-1、VCAM-1蛋白的表达和缺血再灌注组相比,缺血再灌注24h和72h均显著降低(p＜0.05)。
(4)厄贝沙坦缺血再灌注组再灌注后:24h和72h后sICAM-1水平、sVCAM-1水平均明显低于缺血再灌注(p＜0.05)。缺血再灌注组和厄贝沙坦缺血再灌注组sICAM-1、sVCAM-1表达水平均明显高于假手术组的表达水平(p＜0.01)。
(5)Pearson相关性显示ICAM-1和sICAM-1有显著正相关性的(p＜0.05),VCAM-1、sVCAM-1也具有显著的正相关性(p＜0.05)。sICAM-1、sVCAM-1与梗死面积也具有正相关性(p＜0.05)。sICAM-1、sVCAM-1水平反映了缺血再灌注的损伤程度。
结论:厄贝沙坦可以降低中枢及外周粘附分子的表达,减少梗死体积,改善神经功能,对脑缺血再灌注起保护作用。
Objective:To investigate the anti-inflammatory effect of pretreatment with AT1 receptor antagonist,Irbesartan on brain and peripheral blood of the rats in focal brain ischemia-reperfusioln injury.
Methods:Male SD rats were randomly assigned to sham operated group、ischemia/reperfusion group and Irbesartan ischemia-reperfusion group. Pretreatment with Irbesartan(6mg/ml,30mg/kg)for 3 weeks in Irbesartan ischemia-reperfusion group and pretreatment with saline (5ml/kg)for 3 weeks in both ischemia-reperfusion group and sham operated group before operation,we applied MCAO model of Longa, after 24 hours and 72 hours reperfusion following 90 minutes of cerebral ischemia,cerebral infarct size was measured by TTC,adhesion molecules in brain and peripheral blood were detected by ELISA and immunohistochemical technique.
Result:
(1)The scores of the Irbesartan ischemia-reperfusion group were 1.30±0.48(24h)and 1.40±0.52(72h).There were significant differences on the neurological impairment scores between the Irbesartan ischemia-reperfusion group and the ischemia-reperfusion group at 24h and 72h(all p＜0.01).
(2)The infarct volume percentage of the Irbesartan ischemia-reperfusion group were 31.7±8.47%(24h)and 45.48±5.93%(72h).The infarct volume was significantly reduced in the Irbesartan ischemia-reperfusion group compared with the ischemia-reperfusion group(all p＜0.01).
(3)The level of ICAM-1 and VCAM-1 were significantly decreased in the Irbesartan ischemia-reperfusion group compared with the ischemia/reperfusion group(p＜0.05).
(4)The level of sICAM-1 and sVCAM-1 were significantly decreased in the Irbesartan ischemia-reperfusion group compared with the ischemia-reperfusion group(p＜0.05).The level of sICAM-1 and sVCAM-1 were significantly increased in both the Irbesartan ischemia-reperfusion group and ischemia-reperfusion group compared with sham group(p＜0.01).
(5)Correlation analysis:The change between ICAM-1、VCAM-1 in brain and sICAM-1、sVCAM-1 in peripheral blood is positive correlation(r=p＜0.05=.The change of the infarct sizes is positive correlation with sICAM-1、sVCAM-1(all p＜0.05).The levels of sICAM-1、sVCAM-1 could imply the degree of severity of ischemia-reperfusion injury.
Conclusion:Pretreatment with AT1 receptor antagonist might protect brain from ischemia-reperfusion injury in rats by inhibiting leukocyteendothelial cell adhesion and decreasing cerebral infarct sizes.
引文
[1] Danton GH, Dietrich WD. Inflammatory mechanisms after ischemia and stroke[J]. J Neuropathol Exp Neurol,2003,62:127-137.
[2] Ruiz-Ortega M, Lorenzo O, Ruperez M. Angiotensin II activates nuclear transcription factor kB through AT1 and AT2 receptors in cultured vascular smooth muscle cells. Molecular mechanisms [J]. Circ Res,2000,23:1266.
[3] Ruiz-Ortega M, Bustos C, Hemandez-Presa A, et al. Angiotensin II participates in mononuclear cell recruitment in experimental immune complex nephritis through nuclear factor kB activation and monocyte[J]. JImmunol,1998,161:430.
[4]Walther T, Olah L, Harms C, et al. Ischemic injury in experimental stroke depends on angiotensin II[J]. FASEB J, 2002,16:169-176.
[5]Maeda K, Hata R, Bader M, et al. Larger Anastomoses in angiotensinogen-knockout mice attenuate early metabolic disturbances after middle cerebral artery occlusion[J]. Regulatory Peptides, 2003,110: 241-247.
[6]Groth W, Blume A, Gohlke P, et al. Chronic pretreatmentwith candesartan improves recovery from focal cerebral ischaemia in rats[J]. J Hypertens,2003, 21:2175-2182.
[7]Qing L,Yi ZZ, Peter TW, et al. Neuroprotective effects of candesartan against cerebral ischemia in spontaneously hypertensive rats[J]. Neuroreport,2005,16:1963-1966.
[8]Dahlof B,Devereux RB,Kjeldsen SE,et al.Cardiovascular morbidity and mortality in the Losartan Intervention For Endpoint reduction in hypertension study(LIFE):a randomised trial against atenolol[J].Lancet,2002,359:995-1003.
[9]Nishimura Y,Ito T,Saavedra JM.Angiotensin Ⅱ AT1 blockade normalizes cerebrovascular autoregulation and reduces cerebral ischemia in spoteneously hypertensive rats[J].Stroke.2000,31:2478-2486.
[10]Konemoto Y,Nakase H,Akita N,et al.Effects of anti-intercellular adhesion molecule-1 antibody on reperfusion injury included by late reperfusion in the rat middle cerebral artery occlusion model[J].Neurosygery,2002,51:1034-42.
[11]Longa EZ,Weinstein PR,Carlson S,et al.Reversible middle cerebral artery occlusion without craniotomy in rats[J].Stroke,1989,20:84-91.
[12]吴浩,苏万东,吉训明,等.大鼠局灶性脑缺血模型建立的研究进展[J].中国脑血管病杂志,2005,2:237-240.
[13]杜碧涛,王伟.大鼠脑缺血模型制作过程中麻醉方法的选择和应用[J].同济医科大学学报,1998,27:202-205.
[14]梅元武,张洪.不同药物麻醉后大鼠全脑缺血脑温的变化[J].卒中与神经疾病,2001,8:282-285.
[15]Rummond JC.Brain protection during anesthesia[J].Anesthesiology, 1993,79:877.
[16]Jutila MA,Berg EL,Kishimoto TK,et al.Inflammation-induced endothelial cell adhesion to lymphocytes,neutrophils,and monocytes.Role of homing receptors and other adhesion molecules[J].Transplantation,1989,48:727-731.
[17]陈风琴.脑缺血再灌注损伤炎症反应与黏附分子及抗黏附治疗[J].新生儿科杂志,2004,19:86-88.
[18]Hess DC,Zhao W,Carroll J,et al.Increased expression of ICAM-1during reoxygenation in brain endothelial cells[J].Stroke,1994,25:1463-1467.
[19]Zhang LH,Wei EQ.Time course of brain damage and exp ression of related molecules in ratswith transient global cerebral ischemia[J].J Zhejiang UnivM ed Sci,2002,31:77-80.
[20]Bitsch A,Klene W,Murtada L,et al.A longitudinal prospective study of soluble adhesion molecules in acute stroke[J].Stroke,1998,29:2129-2135.
[21]Vemuganti R,Dempsey RJ,Bowen KK.Inhibition of intercellular adhesion molecule-1 protein expression by antisense oligonucleotides is neuroprotective after transient middle cerebral artery occlusion in rat[J].Stroke,2004,35:179-184.
[22]石静萍,张颖冬,葛剑青,等.急性脑梗死患者血浆肾素、血管管紧张素Ⅱ的变化及临床意义[J].临床神经病学杂志,2002,15: 204-206.
[23]Bekay R, Alvarez M, Monteseirin J, et al. Oxidative stress is a critical mediator of the angiotensin II signal in human neutrophils: involvement of mitogen-activated protein kinase, calcineurin, and the transcription factor NF kappaB[J]. Blood,2003,102:662-671.
[1]田代实,刘俊丽.核转录因子KB在大鼠全脑缺血耐受中的表达及意义[J].脑与神经疾病杂志,2003,11:321.
[2]Mattson MP,Culmsee C,Yu Z,et al.Roles of nuclear factor kappaB in neuronal survival and plasticity[J].J Neurochem,2000,74:443-456.
[3]Yenari MA,Han HS.Influence of hypothermia on post-ischemic inflammation:role of nuclear factor kappa B(NFkappaB)[J].Neurochem Int,2006,49:164-169.
[4]Legos JJ,Whilmore RG,Erhardl JA,et al.Quantitative changes in interleukin proteins following focal stroke in the rat[J].Neurosci Lett,2000,282:189-192.
[5]Boutin H,LeFeuvre RA,Horai R,et al.Role of IL-lalpha and IL-1 beta in ischemic brain damage[J].J Neurosci,2001,21:5528-5534.
[6]Ohtaki H,Takaki A,Yin L,et al.Suppression of oxidative stress after transient focal ischemia in interleukin-1 knock out mice[J].Acta Neurochir Suppl,2003,86:191-194.
[7]Clark M,Rinker G,Lessov S,et al.Lack of interleukin-6 expression is not protective against focal central nervous system ischemia[J].Stroke,2000,31:1715-1720.
[8]Satriotomo I,Bowen KK,Vemuganti R.JAK2 and STAT3 activation contributes to neuronal damage following transient focal cerebral ischemia[J].J Neurochem,2006,98:1353-1368.
[9]Barone FC,Arvin B,White RF,et al.Tumor necrosis factor-alpha.A mediator of focal ischemic brain injury[J].Stroke,1997,28:1233-1244.
[10]Heldmann U,Thored P,Claasen JH,et al.TNF-alpha antibody infusion impairs survival of stroke-generated neuroblasts in adult rat brain[J].Exp Neurol,2005,196:204-208.
[11]Suzuki H,Abe K,Tojo SJ,et al.Reduction of ischemic brain injury by anti-P-selectin monoclonal antibody after permanent middle cerebral artery occlusion in rat[J].Neurol Res,1999,21:269-276.
[12]Htun P,Fateh-Moghadam S,Tomandl B,et al.Course of platelet activation and platelet-leukocyte interaction in cerebrovascular ischemia[J].Stroke,2006,37:2283-2287.
[13]Huang J,Choudhri TF,Winfree CJ,et al.Postischemic cerebrovascular E-selectin expression mediates tissue injury in murine stroke[J]. Stroke,2000,31:3047-3053.
[14]Kozuka K, Kohriyama T, Nomura E, et al. Endothelial markers and adhesion molecules in acute ischemic stroke—sequential change and differences in stroke subtype[J]. Atherosclerosis,2002,161:161-168.
[15]Connolly ES Jr, Winfree CJ, Springer TA, et al. Cerebral protection in homozygous null ICAM-1 mice after middle cerebral artery occlusion. Role of neutrophil adhesion in the pathogenesis of stroke[J]. J Clin Invest,1996,97:209-216.
[16]Stanimirovic DB, Wong J, Shapiro A, et al. Increase in surface expression of ICAM-1, VCAM-1 and E-selectin in human cerebromicrovascular endothelial cells subjected to ischemia-like insults[J]. Acta Neurochir Suppl,1997,70:12-16.
[17]Vemuganti R, Dempsey RJ, Bowen KK. Inhibition of intercellular adhesion molecule-1 protein expression by antisense oligonucleotides is neuroprotective after transient middle cerebral artery occlusion in rat[J]. Stroke,2004,35:179-184.
[18] Justicia C, Martin A, Rojas S, et al. Anti-VCAM-1 antibodies did not protect against ischemic damage either in rats or in mice[J]. J Cereb Blood Flow Metab,2006,26:421-432.
[19] Bitsch A, Klene W, Murtada L, et al. A longitudinal prospective study of soluble adhesion molecules in acute stroke[J]. Stroke, 1998,29:2129-2135.
[20]Nagayama M, Niwa K, Nagayama T, et al. The cyclooxygenase-2 inhibitor NS-398 ameliorates ischemic brain injury in wild-type mice but not in mice with deletion of the inducible nitric oxide synthase gene[J]. J Cereb Blood Flow Metab,1999,19:1213-1219.
[21]Kawano T, Anrather J, Zhou P, et al. Prostaglandin E2 EP1 receptors: downstream effectors of COX-2 neurotoxicity[J]. Nat Med,2006,12:225 -229.
[22] Lou M, Blume A, Zhao Y, et al. Sustained blockade of brain AT1 receptors before and after focal cerebral ischemia alleviates neurologic deficits and reduces neuronal injury, apoptosis, and inflammatory responses in the rat[J]. J Cereb Blood Flow Metab,2004,24:536-547.
[23] Zhou J, Ando H, Macova M, et al. Angiotensin II AT1 receptor blockade abolishes brain microvascular inflammation and heat shock protein responses in hypertensive rats[J]. J Cereb Blood Flow Metab, 2005,25:878-886.
[24] Ito T, Yamakawa H, Bregonzio C, et al. Protection against ischemia and improvement of cerebral blood flow in genetically hypertensive rats by chronic pretreatment with an angiotensin II AT1 antagonist[J]. Stroke,2002,33:2297-2303.
[25] Zhang L, Zhang ZG, Ding GL, et al. Multitargeted effects of statin-enhanced thrombolytic therapy for stroke with recombinant human tissue-type plasminogen activator in the rat[J].Circulation,2005,112:3486-3494.
[26]Wen Y,Yang S,Liu R,et al.Estrogen attenuates nuclear factor-kappa B activation induced by transient cerebral ischemia[J].Brain Res,2004,1008:147-154.
[27]Sunday L,Tran MM,Krause DN,et al.Estrogen and progestagens differentially modulate vascular proinflammatory factors[J].Am J Physiol Endocrinol Metab,2006,291:E261-E267.
[28]Liao SL,Kao TK,Chen WY,et al.Tetramethylpyrazine reduces ischemic brain injury in rats[J].Neurosci Lett,2004,372:40-45.
[2] Ruiz-Ortega M, Lorenzo O, Ruperez M. Angiotensin II activates nuclear transcription factor kB through AT1 and AT2 receptors in cultured vascular smooth muscle cells. Molecular mechanisms [J]. Circ Res,2000,23:1266.
[3] Ruiz-Ortega M, Bustos C, Hemandez-Presa A, et al. Angiotensin II participates in mononuclear cell recruitment in experimental immune complex nephritis through nuclear factor kB activation and monocyte[J]. JImmunol,1998,161:430.
[4]Walther T, Olah L, Harms C, et al. Ischemic injury in experimental stroke depends on angiotensin II[J]. FASEB J, 2002,16:169-176.
[5]Maeda K, Hata R, Bader M, et al. Larger Anastomoses in angiotensinogen-knockout mice attenuate early metabolic disturbances after middle cerebral artery occlusion[J]. Regulatory Peptides, 2003,110: 241-247.
[6]Groth W, Blume A, Gohlke P, et al. Chronic pretreatmentwith candesartan improves recovery from focal cerebral ischaemia in rats[J]. J Hypertens,2003, 21:2175-2182.
[7]Qing L,Yi ZZ, Peter TW, et al. Neuroprotective effects of candesartan against cerebral ischemia in spontaneously hypertensive rats[J]. Neuroreport,2005,16:1963-1966.
[8]Dahlof B,Devereux RB,Kjeldsen SE,et al.Cardiovascular morbidity and mortality in the Losartan Intervention For Endpoint reduction in hypertension study(LIFE):a randomised trial against atenolol[J].Lancet,2002,359:995-1003.
[9]Nishimura Y,Ito T,Saavedra JM.Angiotensin Ⅱ AT1 blockade normalizes cerebrovascular autoregulation and reduces cerebral ischemia in spoteneously hypertensive rats[J].Stroke.2000,31:2478-2486.
[10]Konemoto Y,Nakase H,Akita N,et al.Effects of anti-intercellular adhesion molecule-1 antibody on reperfusion injury included by late reperfusion in the rat middle cerebral artery occlusion model[J].Neurosygery,2002,51:1034-42.
[11]Longa EZ,Weinstein PR,Carlson S,et al.Reversible middle cerebral artery occlusion without craniotomy in rats[J].Stroke,1989,20:84-91.
[12]吴浩,苏万东,吉训明,等.大鼠局灶性脑缺血模型建立的研究进展[J].中国脑血管病杂志,2005,2:237-240.
[13]杜碧涛,王伟.大鼠脑缺血模型制作过程中麻醉方法的选择和应用[J].同济医科大学学报,1998,27:202-205.
[14]梅元武,张洪.不同药物麻醉后大鼠全脑缺血脑温的变化[J].卒中与神经疾病,2001,8:282-285.
[15]Rummond JC.Brain protection during anesthesia[J].Anesthesiology, 1993,79:877.
[16]Jutila MA,Berg EL,Kishimoto TK,et al.Inflammation-induced endothelial cell adhesion to lymphocytes,neutrophils,and monocytes.Role of homing receptors and other adhesion molecules[J].Transplantation,1989,48:727-731.
[17]陈风琴.脑缺血再灌注损伤炎症反应与黏附分子及抗黏附治疗[J].新生儿科杂志,2004,19:86-88.
[18]Hess DC,Zhao W,Carroll J,et al.Increased expression of ICAM-1during reoxygenation in brain endothelial cells[J].Stroke,1994,25:1463-1467.
[19]Zhang LH,Wei EQ.Time course of brain damage and exp ression of related molecules in ratswith transient global cerebral ischemia[J].J Zhejiang UnivM ed Sci,2002,31:77-80.
[20]Bitsch A,Klene W,Murtada L,et al.A longitudinal prospective study of soluble adhesion molecules in acute stroke[J].Stroke,1998,29:2129-2135.
[21]Vemuganti R,Dempsey RJ,Bowen KK.Inhibition of intercellular adhesion molecule-1 protein expression by antisense oligonucleotides is neuroprotective after transient middle cerebral artery occlusion in rat[J].Stroke,2004,35:179-184.
[22]石静萍,张颖冬,葛剑青,等.急性脑梗死患者血浆肾素、血管管紧张素Ⅱ的变化及临床意义[J].临床神经病学杂志,2002,15: 204-206.
[23]Bekay R, Alvarez M, Monteseirin J, et al. Oxidative stress is a critical mediator of the angiotensin II signal in human neutrophils: involvement of mitogen-activated protein kinase, calcineurin, and the transcription factor NF kappaB[J]. Blood,2003,102:662-671.
[1]田代实,刘俊丽.核转录因子KB在大鼠全脑缺血耐受中的表达及意义[J].脑与神经疾病杂志,2003,11:321.
[2]Mattson MP,Culmsee C,Yu Z,et al.Roles of nuclear factor kappaB in neuronal survival and plasticity[J].J Neurochem,2000,74:443-456.
[3]Yenari MA,Han HS.Influence of hypothermia on post-ischemic inflammation:role of nuclear factor kappa B(NFkappaB)[J].Neurochem Int,2006,49:164-169.
[4]Legos JJ,Whilmore RG,Erhardl JA,et al.Quantitative changes in interleukin proteins following focal stroke in the rat[J].Neurosci Lett,2000,282:189-192.
[5]Boutin H,LeFeuvre RA,Horai R,et al.Role of IL-lalpha and IL-1 beta in ischemic brain damage[J].J Neurosci,2001,21:5528-5534.
[6]Ohtaki H,Takaki A,Yin L,et al.Suppression of oxidative stress after transient focal ischemia in interleukin-1 knock out mice[J].Acta Neurochir Suppl,2003,86:191-194.
[7]Clark M,Rinker G,Lessov S,et al.Lack of interleukin-6 expression is not protective against focal central nervous system ischemia[J].Stroke,2000,31:1715-1720.
[8]Satriotomo I,Bowen KK,Vemuganti R.JAK2 and STAT3 activation contributes to neuronal damage following transient focal cerebral ischemia[J].J Neurochem,2006,98:1353-1368.
[9]Barone FC,Arvin B,White RF,et al.Tumor necrosis factor-alpha.A mediator of focal ischemic brain injury[J].Stroke,1997,28:1233-1244.
[10]Heldmann U,Thored P,Claasen JH,et al.TNF-alpha antibody infusion impairs survival of stroke-generated neuroblasts in adult rat brain[J].Exp Neurol,2005,196:204-208.
[11]Suzuki H,Abe K,Tojo SJ,et al.Reduction of ischemic brain injury by anti-P-selectin monoclonal antibody after permanent middle cerebral artery occlusion in rat[J].Neurol Res,1999,21:269-276.
[12]Htun P,Fateh-Moghadam S,Tomandl B,et al.Course of platelet activation and platelet-leukocyte interaction in cerebrovascular ischemia[J].Stroke,2006,37:2283-2287.
[13]Huang J,Choudhri TF,Winfree CJ,et al.Postischemic cerebrovascular E-selectin expression mediates tissue injury in murine stroke[J]. Stroke,2000,31:3047-3053.
[14]Kozuka K, Kohriyama T, Nomura E, et al. Endothelial markers and adhesion molecules in acute ischemic stroke—sequential change and differences in stroke subtype[J]. Atherosclerosis,2002,161:161-168.
[15]Connolly ES Jr, Winfree CJ, Springer TA, et al. Cerebral protection in homozygous null ICAM-1 mice after middle cerebral artery occlusion. Role of neutrophil adhesion in the pathogenesis of stroke[J]. J Clin Invest,1996,97:209-216.
[16]Stanimirovic DB, Wong J, Shapiro A, et al. Increase in surface expression of ICAM-1, VCAM-1 and E-selectin in human cerebromicrovascular endothelial cells subjected to ischemia-like insults[J]. Acta Neurochir Suppl,1997,70:12-16.
[17]Vemuganti R, Dempsey RJ, Bowen KK. Inhibition of intercellular adhesion molecule-1 protein expression by antisense oligonucleotides is neuroprotective after transient middle cerebral artery occlusion in rat[J]. Stroke,2004,35:179-184.
[18] Justicia C, Martin A, Rojas S, et al. Anti-VCAM-1 antibodies did not protect against ischemic damage either in rats or in mice[J]. J Cereb Blood Flow Metab,2006,26:421-432.
[19] Bitsch A, Klene W, Murtada L, et al. A longitudinal prospective study of soluble adhesion molecules in acute stroke[J]. Stroke, 1998,29:2129-2135.
[20]Nagayama M, Niwa K, Nagayama T, et al. The cyclooxygenase-2 inhibitor NS-398 ameliorates ischemic brain injury in wild-type mice but not in mice with deletion of the inducible nitric oxide synthase gene[J]. J Cereb Blood Flow Metab,1999,19:1213-1219.
[21]Kawano T, Anrather J, Zhou P, et al. Prostaglandin E2 EP1 receptors: downstream effectors of COX-2 neurotoxicity[J]. Nat Med,2006,12:225 -229.
[22] Lou M, Blume A, Zhao Y, et al. Sustained blockade of brain AT1 receptors before and after focal cerebral ischemia alleviates neurologic deficits and reduces neuronal injury, apoptosis, and inflammatory responses in the rat[J]. J Cereb Blood Flow Metab,2004,24:536-547.
[23] Zhou J, Ando H, Macova M, et al. Angiotensin II AT1 receptor blockade abolishes brain microvascular inflammation and heat shock protein responses in hypertensive rats[J]. J Cereb Blood Flow Metab, 2005,25:878-886.
[24] Ito T, Yamakawa H, Bregonzio C, et al. Protection against ischemia and improvement of cerebral blood flow in genetically hypertensive rats by chronic pretreatment with an angiotensin II AT1 antagonist[J]. Stroke,2002,33:2297-2303.
[25] Zhang L, Zhang ZG, Ding GL, et al. Multitargeted effects of statin-enhanced thrombolytic therapy for stroke with recombinant human tissue-type plasminogen activator in the rat[J].Circulation,2005,112:3486-3494.
[26]Wen Y,Yang S,Liu R,et al.Estrogen attenuates nuclear factor-kappa B activation induced by transient cerebral ischemia[J].Brain Res,2004,1008:147-154.
[27]Sunday L,Tran MM,Krause DN,et al.Estrogen and progestagens differentially modulate vascular proinflammatory factors[J].Am J Physiol Endocrinol Metab,2006,291:E261-E267.
[28]Liao SL,Kao TK,Chen WY,et al.Tetramethylpyrazine reduces ischemic brain injury in rats[J].Neurosci Lett,2004,372:40-45.