摘要
目的:应用蛛网膜下腔出血(SAH)后早期脑损伤(EBI)模型,探讨他莫昔芬(Tamoxifen TMX)对大鼠蛛网膜下腔出血后早期脑损伤是否具有神经保护作用。
方法:48只健康成年雄性SD大鼠随机分为对照组(n=12),SAH组(n=12),安慰剂组(n=12)和他莫昔芬治疗组(n=12)。应用视交叉前池一次注血法制成SAH后EBI模型,在蛛网膜下腔出血后2h、24h及36h分别腹腔注射他莫昔芬,48小时后处死大鼠,取颞底皮层脑组织做标本,测定脑水肿变化及血脑屏障变化,探讨他莫昔芬对大鼠SAH后EBI是否具有神经保护作用。
结果:与对照组相比,SAH组大鼠脑组织含水量明显增加,48h时水肿百分数达到82.51%,血脑屏障破坏明显,48h时测定皮层脑组织伊文氏蓝(EB)含量达到21.5ng/mg;与SAH组相比,他莫昔芬治疗后大鼠脑水肿指数降低,48h时水肿百分数80.55%,血脑屏障功能改善,48h时测定皮层脑组织EB含量13.2ng/mg;安慰剂组与SAH组相比改善不明显。
结论:1.通过构建大鼠SAH模型,能够观察到大鼠SAH后48h脑组织含水量增加明显,血脑屏障破坏明显,说明SAH后存在EBI。2.应用他莫昔芬治疗后,能有效降低SAH后脑水肿、改善血脑屏障,提示他莫昔芬对大鼠SAH后EBI具有神经保护作用。
目的:研究SAH后大脑皮层TLR4(Toll样受体4)/NF-κ B(核因子κB)信号通路及其下游炎症因子及细胞活素的表达变化及他莫昔芬对TLR4/NF-κ B信号通路的干预作用,探讨他莫昔芬对SAH后EBI神经保护作用机制。
方法:60只健康成年雄性SD大鼠随机分为:对照组(n=15), SAH组(n=15),SAH+安慰剂组(n=15)和SAH+他莫昔芬治疗组(n=15)。采用立体定向注射技术,构建视交叉前池一次注血SAH模型,对照组开骨窗但不注入动脉血,他莫昔芬治疗组给予他莫昔芬腹腔注射治疗,每次注射剂量5mg/kg,在SAH后2h、24h、36h分别腹腔注射。安慰剂组注射等容量溶剂,溶剂为1%乙醇。48小时后处死大鼠,取颞底皮层脑组织做标本,采用Western blot法测定TLR4、NF-κB及ICAM-1表达情况;免疫组化法检测TLR4、NF-κB及ICAM-1表达,EMSA测定NF-κB的DNA活性。通过ELISA方法分析大鼠脑皮层中细胞活素因子IL-1β, TNF-α和IL-6表达情况比较。
结果:Western blot结果显示对照组TLR4、NF-κB及ICAM-1蛋白水平较弱;与对照组相比,SAH组TLR4、NF-κB及ICAM-1蛋白水平明显增高(P <0.01);SAH组与安慰剂组对比无明显差异(P>0.05);他莫昔芬治疗组中TLR4、NF-κB及ICAM-1蛋白水平明显低于SAH组与安慰剂组(P <0.01)。免疫组化(TLR4、NF-κB及ICAM-1蛋白免疫反应性主要在神经元细胞,细胞核棕色黄染代表阳性)结果显示对照组TLR4、NF-κB及ICAM-1阳性率较低;与对照组相比,SAH组TLR4、NF-κB及ICAM-1阳性率明显增高(P <0.01);SAH组与安慰剂组对比无明显差异(P>0.05);他莫昔芬治疗组中TLR4、NF-κB及ICAM-1阳性率低于SAH组及安慰剂组(P <0.01)。EMSA结果显示对照组NF-κB的结合活性较弱;与对照组相比,SAH组NF-κB的结合活性明显增高(P <0.01);SAH组与安慰剂组对比无明显差异(P>0.05);他莫昔芬治疗组中NF-κB的结合活性明显低于SAH组与安慰剂组(P<0.01)。ELISA结果显示对照组中IL-1β,TNF-α和IL-6表达水平较低;与对照组相比,SAH组IL-1β, TNF-α和IL-6表达水平明显增高(P <0.01);SAH组与安慰剂组对比无明显差异(P>0.05);他莫昔芬治疗组中IL-1β, TNF-α和IL-6表达水平明显低于SAH组与安慰剂组(P <0.01)。
结论:SAH后早期能激活TLR4/NF-κB信号通路,激活其下游的细胞活素/趋化因子诱导炎症反应,可能是引起SAH后EBI的重要机制,他莫昔芬可能通过抑制此传导通路,减轻免疫炎症,从而对SAH后EBI起到神经保护作用。
Objective: To investigate neuroprotection of Tamoxifen on early brain injury in malerats after subarachnoid hemorrahage, such as brain edema, and blood-brain barrier (BBB)impairment.
Methods: forty-eight health male Sprague-dawley(SD) rats were assigned randomlyinto following groups: Control group(n=12), SAH group(n=12), SAH+vehicle group(n=12), SAH+Tamoxifen group(n=12).All SAH animals were subjected to injectionof0.3ml fresh arterial, non-heparinized blood into suprachiasmatic cistern in20seconds.Male rats were given5mg/kg injections of tamoxifen at post-SAH hours2h,24h and36h.Brain samples adjacent to the clotted blood were extracted at48h after SAH. Controlanimals underwent exactly the same procedure as described above with the exception thatno blood was injected intracisternally. Cerebral edema and blood-brain barrier permeabilitywere detected at48h after experimental SAH.
Results: Significant increase (P <0.01) in water content was detected in the brainsamples at48h after SAH when compared with rats in control group. The mean value ofbrain water content in the cortex was decreased by tamoxifen administration (P <0.01) ascompared with SAH+vehicle group. The pattern of EB extravasation in SAH or SAH+vehicle group demonstrated a significant increase (P <0.01) in BBB permeability of EBrelative to rats of control group. Administration of tamoxifen significantly inhibited EBextravasation(P <0.01) after SAH.
Conclusions:1. As compared with control group, clinical behavior functionimpairment caused by SAH was evident in SAH subjects. SAH group significantlyattenuate blood-brain barrier (BBB), increase brain edema compared to control group.2.Post-SAH tamoxifen treatment significantly ameliorated the EBI, such as the clinicalbehavior scale, brain edema, and blood-brain barrier (BBB) impairment. It suggests thatTamoxifen could attenuate EBI in this rat SAH model.
Objective: The aim of the current study was to investigate whether tamoxifenadministration modulate TLR4/NF-κB signaling pathway in the brain at the early braininjury (EBI) of SAH.
Methods: Sixty male Sprague Dawley rats weighing from300to350g wererandomly divided into control group(n=15), SAH group(n=15), SAH+vehicle group(n=15) and SAH+tamoxifen group(n=15).All SAH animals were subjected toinjection of0.3ml fresh arterial, non-heparinized blood into suprachiasmatic cistern in20seconds. Male rats were given5mg/kg injections of tamoxifen at post-SAH hours2h24hand36h. Rats of SAH+vehicle group received equal volumes of vehicle (1%ethanol) atcorresponding time points. Brain samples(adjacent to the clotted blood) were extracted at48h after SAH. Control animals underwent exactly the same procedure as described abovewith the exception that no blood was injected intracisternally.We measured the expressionsof TLR4, NF-κB, intercellular adhesion molecule-1(ICAM-1) by Western Blot;andTLR4、NF-κB and ICAM-1expressions by Immunohistochemistry.NF-κB DNA bindingactivity were quantified by EMSA.
Results: Western Blot Analysis for detecting TLR4, NF-κB and ICAM-1expressionsafter SAH. These proteins were expressed at a low level in the rat brains of control group. The levels of TLR4, NF-κB and ICAM-1were significantly increased in the cortex inSAH group and SAH+vehicle group as compared with that of control group (P <0.01). Theprotein expressions had no significant difference between SAH group and SAH+vehiclegroup (P>0.05). After tamoxifen injections, the decreased expression of TLR4, NF-κBand ICAM-1was markedly further induced in animals of SAH+tamoxifen group (P<0.01).Immunohistochemical study showed that positive TLR4, NF-κB and ICAM-1were mainlylocated at the neurons, with little expression at glial cells. The immunoreactivity of TLR4,NF-κB and ICAM-1was weak in the cortex samples in control group with only a fewTLR4, NF-κB and ICAM-1positive cells in the brain. More TLR4, NF-κB and ICAM-1positively immunostained neurons appeared in SAH group and SAH+vehicle group. InSAH+tamoxifen group, the number of TLR4, NF-κB and ICAM-1positive cells was lessthan SAH group and SAH+vehicle group. TLR4,NF-κB and ICAM-1immunoreactivities of parenchymal cells in the cortex were progressively induced bytamoxifen therapy at48h after blood injection(P <0.01). EMSA autoradiography of NF-κBDNA binding activity in the brain was shown that Low NF-κB binding activity (weakEMSA autoradiography) was found in the control group. Compared with the control group,NF-κB binding activity significantly increased (P <0.01) in SAH group and SAH+vehiclegroup. There was no statistically significant difference between SAH group and SAH+vehicle group (P>0.05). In SAH+tamoxifen group, NF-κB binding activity wassignificantly down-regulated (P <0.01)after tamoxifen injections.
Conclusions: SAH could induce an activation of TLR4/NF-κB signaling pathway thatmight play a central role in the inflammatory response that leads to secondary insults afterSAH. The therapeutic benefit of post-SAH tamoxifen administration might be due to itssalutary effect on modulating TLR4/NF-κB signaling pathway.
引文
[1] Sehba FA, Bederson JB. Mechanisms of acute brain injury after subarachnoidhemorrhage.Neurol Res,2006,28:381-398.
[2] Ostrowski RP, Colohan AR, Zhang JH. Molecular mechanisms of early brain injuryafter subarachnoid hemorrhage. Neurol Res,2006,28:399-414.
[3] Ostrowski RP, Colohan AR, Zhang JH. Mechanisms of hyperbaric oxygen-inducedneuroprotection in a rat model of subarachnoid hemorrhage. J Cereb Blood Flow Metab,2005,25:554-571.
[4] Prunell GF, Svendgaard NA, Alkass K, et al. Delayed cell death related to acutecerebral blood flow changes following subarachnoid hemorrhage in the rat brain. JNeurosurg,2005,102:1046-1054.
[5] Park S, Yamaguchi M, Zhou C, et al. Neurovascular protection reduces early braininjury after subarachnoid hemorrhage. Stroke,2004,35(10):2412-2417.
[6] Kusaka G, Ishikawa M, Nanda A, et al. Signaling pathways for early brain injury aftersubarachnoid hemorrhage. J Cereb Blood Flow Metab,2004,24(8):916-925.
[7] Suzuki H, Ayer R, Sugawara T, et al. Protective effects of recombinant osteopontin onearly brain injury after subarachnoid hemorrhage in rats. Crit Care Med,2010,38(2):612-618.
[8] Barton GM, Medzhitov R. Toll-like receptor signaling pathways. Science,2003,300(5625):1524-1525.
[9] Akira S, Takeda K. Toll-like receptor signaling. Nat Rev Immunol,2004,4(7):499-511.
[10] Ma CX, Yin WN, Cai BW, et al. Activation of TLR4/NF-kappaB signaling pathway inearly brain injury after subarachnoid hemorrhage. Neurol Res,2010.[Epub ahead ofprint]
[11] King MD, Laird MD, Ramesh SS, et al. Elucidating novel mechanisms of brain injuryfollowing subarachnoid hemorrhage: an emerging role for neuroproteomics.Neurosurg Focus,2010,28(1):E10.
[12] Chiang, C. S.; McBride, W. H. Radiation enhances tumor necrosis factor alphaproduction by murine brain cells. Brain Res1991,566,(1-2):265-9.
[13] Chiang, C. S.; Hong, J. H.; Stalder, A., et al. Delayed molecular responses to brainirradiation. Int J Radiat Biol1997,72,(1):45-53.
[14] Monje, M. L.; Toda, H.; Palmer, T. D. Inflammatory blockade restores adulthippocampal neurogenesis. Science2003,302,(5651):1760-5.
[15] Suuronen, T.; Nuutinen, T.; Huuskonen, J., et al. Anti-inflammatory effect of selectiveestrogen receptor modulators (SERMs) in microglial cells. Inflamm Res2005,54,(5):194-203.
[16] Tapia-Gonzalez, S.; Carrero, P.; Pernia, O., et al. Selective oestrogen receptor (ER)modulators reduce microglia reactivity in vivo after peripheral inflammation:potential role of microglial ERs. J Endocrinol2008,198,(1):219-30.
[17] Tian, D. S.; Liu, J. L.; Xie, M. J., et al. Tamoxifen attenuates inflammatory-mediateddamage and improves functional outcome after spinal cord injury in rats. JNeurochem2009,109,(6):1658-67.
[18] Esposito, E.; Iacono, A.; Raso, G. M., et al. Raloxifene, a selective estrogen receptormodulator, reduces carrageenan-induced acute inflammation in normal andovariectomized rats. Endocrinology2005,146,(8):3301-8.
[19] Misiewicz, B.; Griebler, C.; Gomez, M., et al. The estrogen antagonist tamoxifeninhibits carrageenan induced inflammation in LEW/N female rats. Life Sci1996,58,(16): PL281-6.
[20] Cushman, M.; Costantino, J. P.; Tracy, R. P., et al. Tamoxifen and cardiac risk factorsin healthy women: Suggestion of an anti-inflammatory effect. Arterioscler ThrombVasc Biol2001,21,(2):255-61
[21] Rola, R.; Raber, J.; Rizk, A., et al. Radiation-induced impairment of hippocampalneurogenesis is associated with cognitive deficits in young mice. Exp Neurol2004,188,(2):316-30.
[22] Monje, M. L.; Mizumatsu, S.; Fike, J. R., et al. Irradiation induces neuralprecursor-cell dysfunction. Nat Med2002,8,(9):955-62.
[23] Rutledge, E. M.; Aschner, M.; Kimelberg, H. K. Pharmacological characterization ofswelling-induced D-[3H] aspartate release from primary astrocyte cultures. Am JPhysiol1998,274,(6Pt1): C1511-20.
[24] Osuka, K.; Feustel, P. J.; Mongin, A. A., et al. Tamoxifen inhibits nitrotyrosineformation after reversible middle cerebral artery occlusion in the rat. J Neurochem2001,76,(6):1842-50.
[25] Wiseman, H.; Cannon, M.; Arnstein, H. R., et al. Tamoxifen inhibits lipid peroxidationin cardiac microsomes. Comparison with liver microsomes and potential relevance tothe cardiovascular benefits associated with cancer prevention and treatment bytamoxifen. Biochem Pharmacol1993,45,(9):1851-5.
[26] Feng, Y.; Fratkins,J.D.; LeBlanc, M. H. Treatment with tamoxifen reduceshypoxic-ischemic brain injury in neonatal rats. Eur J Pharmacol2004,484,(1):65-74.
[27] Suuronen, T.; Nuutinen, T.; Huuskonen, J., et al. Anti-inflammatory effect of selectiveestrogen receptor modulators (SERMs) in microglial cells. Inflamm Res2005,54,(5):194-203.
[1] Schievink WI.Intracranial aneurysms.N Engl J Med.1997;336:28-40.
[2] Hop JW, Rinkel GJ, Algra A, van GJ. Case-fatality rates and functional outcome aftersubarachnoid hemorrhage: A systematic review. Stroke28:660-664,1997
[3] Schievink WI. Intracranial aneurysms. N Engl J Med.1997;336:28-40,
[4] Broderick JP, Brott TG, Duldner JE, Tomsick T, Leach A Initial and recurrent bleedingare the major causes of death following subarachnoid hemorrhage. Stroke25:1342-1347,1994
[5] Cahill J, Calvert JW, Zhang JH. Mechanisms of early brain injury after subarachnoidhemorrhage. J Cereb Blood Flow Metab26:1341-1353,2006
[6] Kusaka G, Ishikawa M, Nanda A, Granger DN, Zhang JH. Signaling pathways for earlybrain injury after subarachnoid hemorrhage. J Cereb Blood Flow Metab24:916-925,2004
[7] Ostrowski RP, Colohan AR, Zhang JH. Molecular mechanisms of early brain injuryafter subarachnoid hemorrhage. Neurol Res28:399-414,2006
[8] Cook DA. Mechanisms of cerebral vasospasm in subarachnoid hemorrhage. PharmacolTher66:259-284,1995
[9] Kim I, Leinweber BD, Morgalla M, Butler WE, Seto M, Sasaki Y, Peterson JW,Morgan KG. Thin and thick filament regulation of contractility in experimentalcerebral vasospasm. Neurosurgery46:440-446,2000
[10] Macdonald RL, Weir B, Zhang J, Marton LS, Sajdak M, Johns LM. Adenosinetriphosphate and hemoglobin in vasospastic monkeys. Neurosurg Focus3: e3,1997
[11] Jacob Hansen—Sehwaflz, Peter Vajkoczy, Robert Loch, Macdonald, Ryszard M.Pluta, John H. Zhang. Cerebral vasospasm: looking beyond vasoconstriction.Pharmacological Sciences,2007,28:252-256.
[12] Gules I, Satoh M, Clower BR, et al. Comparison of three rat models of cerebralvasospasm. Am J Physiol Heart CircPhysiol,2002;283(6):2551-2559.
[13] Meguro T, Clower BR, Carpenter R, et a1. Improved rat model for cerebral vasospasmstudies. Neurol Res,2001;23(7):761-766.
[14] Suzuki H, Kanamaru K, Tsunoda H, et al. Heme oxygenase-1gene induction as anintrinsic regulation against delayed cerebral vasospasm in rats. J Clin Invest,1999;104(1):59-66.
[15] Harada S, Kamiya K, Masago A, et a1. Subarachnoid hemorrhage induces c-fos, c-junand hsp70mRNA expression in rat brain. Neuroreport,1997;8(15):3399-3404.
[16] Megyesi JF, Vollrath B, Cook DA, et a1. In vivo animal models of cerebral vasospasm:a review. Neurosurgery,2000;46(2):448-461.
[17] Bederson JB, Gemmo IM, Guarino L.Cortical blood flow and cerebral peffusionpressure in a new noncraniotomy model of subarachnoid hemorrhage in the rat. Stroke,1995;26(6):1086-1092.
[18] Veelken JA, Laing RJ, Jakubowski J. The Sheffield model of subarachnoidhemorrhage in rats. Stroke,1995;26(7):1279-1284.
[19] Carpenter RC, Miao L, Miyagi Y, et a1. Altered expression of P2receptor mRNAs inthe basilar artery in a rat double hemorrhage model. Stroke,2001;32(2):516-522.
[20] Ono S, Date I, Onoda K, et a1. Time course of the diameter of the major cerebralarteries after subarachnoid hemorrhage using corrosion cast technique. Neurol Res,2003;25(4):383-389.
[21] Ram Z, Sahar A, Hadani M. Vasospasm due to massive subarachnoid hemorrhage a ratmodel. Acta Neuroehir (Wien),1991;110(3-4):181-184.
[22] Piepgras A, Thome C, Schmiedek P. Characterization of anterior circulation ratsubarachnoid hemorrhage model. Stroke,1995;26(12):2347-2352.
[23] Kassell NF, Tomer JC, Haley EC Jr, et a1. The international cooperative study on thetiming of aneurysm surgery. Part1: overall management results. J Neurosug,1990;73(1):18-36.
[24] Megyesi JF. Volllrath B. Cook DA. Et al. In vivo animal models of Cerebralvasospasm:a review. Neurosurgery.2000;46(2):448-60; discussion460-1,
[25] Neff S. In vivoanimal models of cerebral vasospasm: a review. Neurosurgery.2000;47(3):794-5,
[26] Megyesi JF. Findlay JM. In vivo animal models of Cerebral vasospasm: a review. ActaNeurochirurgica-Supplement.200l;77:99-102,
[27] Dutch N,Branston NM,Symon L,Jakubowski J. Intracranial pressure changesfollowing primate subarachnoid hemorrhage. Neurol Res,1989;4:201-204.
[28] Lee JY,Sagher O,Keep R,Hua Y,Xi G. Comparison of experimental rat models ofearly brain injury after subarachnoid hemorrhage. Neurosurgery.2009;65:331-343.
[29] Ostrowski RP, Colohan AR, Zhang JH. Mechanisms of hyperbaric oxygen-inducedneuroprotection in a rat model of subarachnoid hemorrhage. J Cereb Blood FlowMetab,2005,25:554-571.
[30] Prunell GF, Svendgaard NA, Alkass K, et al. Delayed cell death related to acutecerebral blood flow changes following subarachnoid hemorrhage in the rat brain. JNeurosurg,2005,102:1046-1054.
[31] Echlin F. Experimental vasospasm, acute and chronic, due to blood in thesubarachnoid space. J Neurosurg,1971,35:646-656.
[32] Uhl E, Le hmberg J, Steiger HJ, et a1.Intraoperative detection of earlymicrovasospasm in patients with subarachnoid hemorhage by using o~hogonalpolarization spectral imaging. Neurosurgery,2003,52:1307-13l5.
[33] Unterberg AW, Stover J, Kress B, Kiening KL.2004. Edema and brain trauma.Neuroscience129:1021-1029.
[34] Kawamata T, Katayama Y, Aoyama N, Mori T.2000. Heterogeneous mechanisms ofearly edema formation in cerebral contusion: diffusion MRI and ADC mapping study.Acta Neurochir Suppl (Wien)76:9-12.
[35] Marmarou A, Signoretti S, Fatouros PP, Portella G, Aygok GA, Bullock MR.2006.Predominance of cellular edema in traumatic brain swelling in patients with severehead injuries. J Neurosurg.104:720-730.
[36] Stroop R, Thomale UW, P user S, Bernarding J, Vollmann W, Wolf KJ.1998.Magnetic resonance imaging studies with cluster algorithm for characterization ofbrain edema after controlled cortical impact injury (CCII). Acta Neurochir Suppl(Wien)71:303-305.
[37] Claassen J, Carhuapoma JR, Kreiter KT, Du EY, Connolly ES, Mayer SA. Globalcerebral edema after subarachnoid hemorhage: equency, predictors, and impact onoutcome. Stroke,2002,33:1225-1232
[38] Hara A, Yoshimi N,Mori H. Evidence for apoptosis in human intracranialaneurysms. Neurol Res,1998,20(2):127-130.
[39] Kondo S,Hashimoto N,Kikuchi H,et al.Apoptosis of medial smooth muscle cellsin the development of saccular cerebral aneurysms in rats. Stroke,1998,29:181-189.
[40] Hutter BO,Kreitschmann-Andermahr I,Gilsbach JM,e1.al. Healthrelated qualityof life after aneurysmal subarachnoid hemorrhage:impacts of bleeding severity,computerized tomography findings,surgery,vasospasm,and neurological grade.Neurosurg,2001,94,241-251.
[41] Zhou C,Yamaguchi M,Kusaka G,et al.Caspase inhibitors prevent endothelialapoptosis and cerebral vasospasm in dog model of experimental subarachnoidhemorrhage. Cereb Blood Flow Metab,2004,24,419-431.
[42] Park S,Yamaguchi M,Zhou C,et al. Neurovascular protection reduces early braininjury after subarachnoid hemorrhage. Stroke,2004,35(10),2412-2417.
[43] Matz PG, Fujimura M, Lewen A, et al. Increased cytochrome-cmediated DNAfragmentation and cell death in manganesesuperoxide dismutase-deficient mice afterexposure to subarachnoid hemolysate. Stroke,2001,32,506-515.
[44] Nau R,Haase S,Bunkowski S,et a1. Neuronal apoptosis in the dentate gyrus inhumans with subarachnoid hemorrhage and cerebral hypoxia. Brain Pathol,2002,12,329-336.
[45] Cahill J,Calvert JW,Marcantonio S,et a1. p53may play an orchestrating role inapoptotic cell death after experimental subarachnoid hemorrhage. Neurosurgery,2007,60,531-545.
[46] Sabri, M. Kawashima, A. Ai, J. Macdonald, R.L. Neuronal and astroeytie apoptosisafter subarachnoid hemorrhage: a possible cause for poor prognosis. Brain Res,2008,1238:163-171.
[47] Akpinar G, Acikgoz B, Surucu S, Celik HH, Cagavi F. Uhrastructural changes in thecircumventricular organs after experimental subarachnoid hemorrhage. Neurol Res2005,27:580-585.
[48] Zhong Wang, Gang Zuo, Xiao-Yong Shi et al. Progesterone AdministrationModulates Cortical TLR4/NF-κB Signaling Pathway after SubarachnoidHemorrhage in Male Rats.Mediators of Inflammation.2011;2011:848309.
[49] Zhong Wang, Cao Ma, Cheng-Jie Meng. et al. Melatonin activates the Nrf2-AREpathway when it protects against early brain injury in a subarachnoid hemorrhagemodel.Journal of Pineal Research.2012Jan11. doi:10.1111/j.1600-079X.2012.00978.x.[Epub ahead of print]
[50] Zhong Wang, Xiao-Yong Shi, Yin Jia. et al. Role of autophagy in early brain injuryafter experimental subarachnoid hemorrhage. Journal of Molecular Neuroscience.2012Jan;46(1):192-202..
[51] Ghezzi P, Brines M. Erythropoietin as an antiapoptotic, tissue-protectivecytokine.Cell Death Differ,2004,11Suppl1:s37—44
[52] Zhong Wang, Cheng-Jie Meng. et al. Potential contribution of hypoxia-induciblefactor-1α, aquaporin-4, and matrix metalloproteinase-9to blood-brain barrierdisruption and brain edema after exper-imental subarachnoid hemorrhage. Journal ofMolecular Neuroscience.2012:012:97696
[53] Kopp MD, Schomcrus C, Dehghani F, et a1.Pituitary adenylate cyclase—activatingpolypeptide and melatonin in the suprachiasmatic nucleus:effects on the calciumsignal transduction cascade.J Neuro sci.1999.19(1):206—219.
[54] Escames G, Leon J, Macias M, et a1. Melatonin counteractslipopolysaccharide—induced expression and activity of mit02chondrial nitric oxidesynthase in rats.[J]. FASEB J,2003,17(8):932·934.
[55] Hardeland R, Pandi2Perumal S R, Cardinali DP.Molecules in focus:Melatonin [J].Int J Biochem Cell Biol,2006,38:313-316
[56] Rutledge, E. M.; Aschner, M.; Kimelberg, H. K. Pharmacological characterization ofswelling-induced D-[3H] aspartate release from primary astrocyte cultures. Am JPhysiol1998,274,(6Pt1): C1511-20.
[57] Wiseman, H.; Cannon, M.; Arnstein, H. R., et al. Tamoxifen inhibits lipid peroxidationin cardiac microsomes. Comparison with liver microsomes and potential relevance tothe cardiovascular benefits associated with cancer prevention and treatment bytamoxifen. Biochem Pharmacol1993,45,(9):1851-5.
[58] Osuka, K.; Feustel, P. J.; Mongin, A. A., et al. Tamoxifen inhibits nitrotyrosineformation after reversible middle cerebral artery occlusion in the rat. J Neurochem2001,76,(6):1842-50.
[59] Suuronen, T.; Nuutinen, T.; Huuskonen, J., et al. Anti-inflammatory effect of selectiveestrogen receptor modulators (SERMs) in microglial cells. Inflamm Res2005,54,(5):194-203.
[60] Tapia-Gonzalez, S.; Carrero, P.; Pernia, O., et al. Selective oestrogen receptor (ER)modulators reduce microglia reactivity in vivo after peripheral inflammation:potential role of microglial ERs. J Endocrinol2008,198,(1):219-30.
[61] Tian, D. S.; Liu, J. L.; Xie, M. J., et al. Tamoxifen attenuates inflammatory-mediateddamage and improves functional outcome after spinal cord injury in rats. JNeurochem2009,109,(6):1658-67.
[62] Roberts, I., Schierhout, G., Alderson, P. Absence of evidence for the effectiveness offive interventions routinely used in the intensive care management of severe headinjury: a systematic review. J. Neurol. Neurosurg. Psychiatry.1998;65:729–733.
[1] Ostrowski RP, Colohan AR, Zhang JH. Molecular mechanisms of early brain injuryafter subarachnoid hemorrhage. Neurol Res.2006,28:399.
[2] Medzhitov R, Presto2Hurlburt P, Janeway CA. A human homologue of the drosophilaToll protein signals activation of adaptive immunity[J]. Nature,1997,388(3):3942397.
[3] Poltorak A, He X, Smirnova I, et al. Defective LPS signaling in C3H/HeJ and C57BL/10ScCr mice: mutations in TLR4gene [J]. Science,1998,282(4):208522088.
[4] Pastor CM, Pugin J, Kwak B, et al. Role of Toll-like receptor4on pancreatic andpulmonary injury in a mice model of acute pancreatitis associated withendotoxemia[J]. Crit CareMed,2004,32(8):175921763.
[5] Shi H, KokoevaMV, Inouye K, et al. TLR4links innate immunity and fattyacid-induced insulin resistance [J]. J Clin Invest,2006,116(11):301523025.
[6] Janeway CA,Medzhitov R. Innate immune recognition [J]. Annu Rev Immunol,2002,20(5):1972216.
[7] BacharO,AdnerM,Uddman R, et al. Toll-like receptor stimulation induces airwayhyperresponsiveness to bradykinin, an effectmediated by JNK and NF2kappa Bsignaling pathways[J]. Eur J Immunol,2004,34(4):119621207.
[8] Yan ZQ. Regulation of TLR4expression is a tale about tail arteriosclerosis[J].Thromb Vasc Biol,2006,26(4):258222584.
[9] Gioannini TL,Weiss JP. Regulation of interactions of Gramnegative bacterialendotoxins with mammalian cells[J]. Immunol Res,2007,39(1/3):2492260.
[10] Erridge C,Moncayo2Nieto OL,Morgan R, et al. Acinetobacter baumanniilipopolysaccharides are potent stimulators of human monocyte activation via Toll-likereceptor4signaling[J]. J MedMicrobiol,2007,56(Pt2):1652171.
[11] Calvano JE, Agnese DM, Um JY, et al. Modulation of the lipopolysaccharide receptorcomplex (CD14, TLR4, MD22) and toll-like receptor2in systemic inflammatoryresponse syndrome positive patients with and without infection: relationship totolerance [J].Shock,2006,20(3):4172419.
[12] Haeberle HA, Takizawa R, Casola A, et al. Resp iratory syncytia virus-inducedactivation of nuclear factor kappa B in the lung involvesalveolar macrophages andtoll-like receptor4dependent pathways[J]. Infect Dis,2002,186(9):119921206.
[13] Schnapp ingerD, Schoolnik GK, Ehrt S. Exp ression p rofiling of host pathogeninteractions: how Mycobacterium tuberculosis and the macrophage adapt to oneanother [J]. Microbes Infect,2006,8(4):111721118.
[14] Takeda K, Akira S. Microbial recognition by Toll-like receptors [J]. J Dermatol Sci,2004,34(8):73282.
[15] Kumpf O, Hamann L, Schlag PM, et al. Pre and postoperative cytokine release after invitro whole blood lipopolysaccharide stimulation and frequent Toll-like receptor4polymorphisms [J]. Shock,2006,25(2):1232128.
[16] Lendemans S, Kreuzfelder E, RaniM, et al. Toll-like receptor2and4expression aftersevere injury is not involved in the dysregulation of the innate immune system[J]. JTrauma,2007,63(4):7402746.
[17] Sen R,Baltimore D.Multiple nuclear factor interact with the immunoglobulin enhancersequences. Cell,1986,46(5):705.
[18]柳青,李风雷,黄本友.核因子-кB在局部脑缺血再灌注损伤大鼠脑组织中的表达.Stroke and Nervous diseases,2002,9(2):104-106.
[19]刘冰熔.核转录因子NF-КB---肿瘤基因治疗的新焦点.国外医学免疫学分册.2001,24:129-132.
[20] Lee JI,Burckart GJ.Nuclear factor kappa B:important transcription factor andtherapeutic target[J].Clin Pharmacol,1998,38(11):981.
[21]高俊凤,丁新生.核因子-κB与缺血性脑血管病研究.医学综述,2004,10(7):418-419.
[22]刘玲,等.NF-κB的活化与神经细胞凋亡.国外医学·生理、病理科学与临床分册.2003,23(6):621-623.
[23] Flohe L,Brigelius-Flohe R,Saliou C,et al.Packer L redox regulation of NF-κBactivation.[J].Free Radic Biol Med,1997,22(6):1115-1126.
[24] MayMJ, Ghosh S. Signal transduction through NF-κB[J].Immuunol Today,1998,19(2):80-88.)
[25]陈立杰,梁松岚,梁庆成.核转录因子-κB在局部脑缺血及再灌注损伤后大鼠脑细胞中的表达及N-乙酰半胱氨酸的干预作用.中华神经科杂志,2005,38(3):179-182)
[26] Numi A,Lindsberg PJ,Koistinaho M,et al.Nuclear factor-kappa B contributestoinfarction after permanent focal ischemia.Stroke,2004,35:987-991.
[27]蒋红玉,等.芪棱汤对大鼠局灶性脑缺血再灌注后核因子κB表达的影响.中国中医急症,2005,14(12):1201-1203.
[28]邢成名,主编.缺血性脑血管病[M]:人民卫生出版社,2003,124-127.
[29] Domanska-Janik K,Bronisz-KowalczykA,ZajacH,et al.Interrelations betweennuclear-factor kappa B activation, glial response and neuronal apoptosis ingerbilhippocampus after ischemia[J]. Acta Neurobiol Exp(Warsz),2001,61(1):45-51.
[30] Carroll JE,Howard EF,Hess DC,et al.Nuclear factor-kappa B activation duringcerebral reperfusion effect of attenuation with N-acetylcysteine treatment[J].Brain ResMol Brain Res,1998,56(1-2):186-191.
[31] Stephenson D,Yin T,Smalstig EB, et al.Transcription factor nuclearfactor kappa B isactivated in neurons after focal cerebral ischemia [J].Cereb BloodFlowMetab,2000,20(3):592-603.
[32]万东,罗勇.大鼠局灶脑缺血再灌注后脑组织中核因子κB的核转位现象及其意义.[J]重庆医学,2003,32(11):1496.
[33] Clemens JA, StephensonDT, SmalstigEB, et al. Global ischemia activates nuclearfactor-κB in forebrain neurons of rats. Stroke,1997,28:1073-1080.
[34] SeegersH,Grillon E,TrioullierY, et al.Nuclear factor-kappa B activation in permanentintraluminal focal cerebral ischemia in the rat. NeurosciLett,2000,288:241-245.
[35]田晔,万琪,王洪典.核因子κB在脑缺血及再灌注损伤炎症机制中的作用.国外医学脑血管疾病分册,2002,10:143-144.
[36]徐江,黄晓琳.高压氧对脑缺血再灌注大鼠核因子-κB及细胞间粘附分子-1表达的影响[J].中华物理医学与康复杂志,2005,27(5):259-262.
[37] Lindsberg PJ, Carpen O, Paetau A, et al.Endothelial ICAM-1expressionassociatedwith inflammatory cell response in human ischemic stroke.Circulation,1996,94:939-945.
[38] Aronowski J, Strong R, Kang HS,et al.Selective up-regulation of IkappaB-alpha inischemic penumbra following focal cerebral ischemia[J].Neuroreport,2000,11(7):1529-1533.
[39] Liu T, Clark R, Yong P R, et al.Tumor necrosis factor in ischemic neurons. Stroke,1994,25:1481.
[40] De-Graba TJ. The role of inflammation after acute stroke: utility of pursuinganti-adhesion molecule therapy.Neurology,1998,51:S62.
[41]王晓梅,等.降纤酶对大鼠局灶脑缺血/再灌后Caspase-3mRNA表达和细胞凋亡的影响[J].中国临床神经科学,2003,11(1):8-11.
[42] Kim GM, Xu J, Xu J,et al. Tumor necrosisfactor receptor deletion reduces nuclearfactor-kappaB activation,cellular inhibitor of apoptosis protein2expression, andfunctional recovery after traumatic spinal cord injury[J]. JNeurosci,2001,21(17):6617-6625.
[43] Tamatani M,Mitsuda N,Matsuzaki H,et al.A pathway of neuronal apoptosis inducedby hypoxia/reoxygenation: roles of nuclear factor-kappaB and Bcl-2[J]. JNeurochem,2000,75(2):683-693.
[44] Tamatani M, Che YH, Matsuzaki H,et al. Tumor necrosis factor induces Bcl-2andBcl-x expression through NfkappaB activation in primary hippocampal neurons[J].JBiol Chem,1999,274(13):8531-8538.
[45] Ravati A,Ahlemeyer B,Becker A,et al.Preconditioning-induced neuroprotection ismediated by reactive oxygen species and activation of the transcription factor nuclearfactor-kappaB[J]. J Neurochem,2001,78(4):909-919.
[46] Clemens JA, Stephenson DT, Yin T,et al. Drug-induced neuroprotection from globalischemia is associated with prevention of persistent but not transient activation ofnuclear factor-kappaB in rats[J].Stroke,1998,29(3):677-682.
[47] Shou Y, Li N, Li L,et al.NF-kappaB-mediated up-regulation of Bcl-X(S) and Baxcontributes to cytochrome c release in cyanide-induced apoptosis[J]. J Neurochem,2002,81(4):842-852.
[48] Velier JJ,Elisson JA,Kikly KK,et al.Caspase8a and Caspase3a reexpressed bydifferent populations of cortical neurons undergoing deleyed cell death after focalstroke in the rat[J].J Neurosei.1999,19(14):5932-5941.
[49]王越晖,等.大鼠脑缺血再灌注损伤后NF-κB蛋白、Caspase-3mRNA表达及细胞凋亡的研究[J].Apoplexy and Nervous Diseases,2004,21(3):208-210.
[50] Clemens JA.Cerebral ischemia:gene activation,neuronal injury,and the protective roleof antioxidants[J].Free Radic Biol Med,2000,28(10):1526-1531.
[51] Schneider A,Martin-Villalba A.NF-kappa B is activated and promoes cell death infocal cerebral ischemia[J].Nat Med,1999,5(5):554-559.
[52] Danton GH, Dietrich WD. Inflammatory mechanisms after ischemia and stroke.[J].JNeuropathol Exp Neurol.2003.62(2):127-36.
[53] Frijns CJ, Kappelle LJ. Inflammatory celladhesion molecules in ischemiccerebrovasular disease.[J]. Stroke.2002.33:2115-22.
[54] Yang J, Shen YX, Ma CG et al. The inflammatory and immune mechanisms followingcerebral ischemia.]J[. Chin Pharmacol Bull.2001.17(1):9-13.
[55] Wang GJ. Deng HY, Maier CM et al. Mild hypothermia reduces ICAM-1expression,neutrophil infiltration and microglia/monocyte accumulation following experimentalstroke.[J]. Neuroscience.2002.114:1081-90.
[56] Zaremba J. Losy J. Adhesion molecules of immunoglobulin gene superfamily instroke.[J]. FOLIA Morphol.2002.61(1):1-6.
[57] Zhang LH, Wei EQ. Time eourse of brain damage and expression of related moleculesin rats with transient global cerebral ischemia [J]. J Zhejiang Unir Med Sci,2002,31:77-80.
[58] Selakovic V, Colie M, Jovanovie M et al. Cerebrospinal fluid and plasmaconcentration of soluble intercellular adhesion molecule1, vascular cell adhesionmolecule1and endothelial leukocyte adhesion molecule in patients with acuteischemic brain disease [J]. Vojnosanit Pregl,2003,60(2):139-46.
[59] Montaner J, Rovira A, Molina CA et al. Plasmatic level of neuroinflammatory markerspredict the extent of diffusion-weighted image lesions in hyperacute stroke[J]. J CerebBlood Flow Metab,2003,23(12):1403-7.
[60] Ritter LS, Orozco JA, Coull BM et al. Leukocyte accumulation and hemodynamicchange in the cerenral microcirculation during early reperfusion after stroke[J]. Stroke,2000,31(5):1153-61.
[61] Yin L, Ohtaki H, Nakamachi T et al. Delayed expressed TNFR1co-localize withICAM-1in astrocyte in mice brain after transient focal ischemia[J]. Neurosci Lett,2004,370(1):30-5.
[62]徐皓亮,冯亦璞.细胞因子、趋化细胞因子和脑缺血后炎症损伤[J].中国药理学通报,1999,15(3):209-11.
[63] Vemuganti R, Dempsey RJ, Bowen KK. Inhibition of Intercellular adhesionmolecule-1protein expression by antisense oligonucleotides is neuroroprotective aftertransient middle cerebral artery occlusion in rat[J]. Stoke,2004,5(1):179-84.
[64] Yamagami S,Tamura M,Hayshi M,et al.Differential production of MCP-1andcytokine-induced neurophil chemoatt ractant in the ischemic brain after transicentfocal ischemia in rats. J Leukoc Biol,1999,65:744~749
[65] Chen L,Vicatu E,Sercombe R.Polymorphonuclear leukocyte activation inducescerebral hypoperfusion in rats in the absence of previous ischemia-reperfusiondamage. Neurosci Lett,2002,331(3):203~207
[66]杨银治,夏时海.磷脂酶A2在炎症反应中的作用[J].世界华人消化杂志,2006.14(8):795~799
[67]张国红,王春霖,吕平,王永利.大鼠局灶性脑缺血再灌注后不同时间E-选择素、P-选择素和细胞间粘附分子-1的表达[J].中国药理学通报,2005,21(10):1218~1223
[68] von Asmuth EJ,van der Linden CJ,Leeuwenberg JF,Buurman WA.Involvement of theCD11b/CD18integrin,but not of the endothelial cell adhesion molecules ELAM-1andICAM-1in tumor necrosis factor-alpha-induced neutrophil toxicity[J]. JImmounol,1991,147(11):3869-3875
[69]张雪萍,李亚丽,石碧明等.PMN释放H2O2与CD11b及ICAM-1关系的研究[J].国际医药卫生导报,2007,13(16):57~59
[70] Minamiya Y,Motoyama S,Kitamura M,SaitoS,Terada K,Ogawa J.The requirement ofintercellular adhesion molecule-1for neutrophil respiratory burst in the pulmonarycirculation of rats infused with endotoxin[J].Am J Respir Crit CareMed,1998,158(2):635-642
[71] Joo F. Endothelial cells of the brain and other organ systems: some similarities anddifferences. Prog Neurobiol,1996,48:255~273
[72]郝延磊,蒲传强.细胞粘附分子与缺血性脑血管病.中华神经科杂志,1996,29:368-370
[73]郝延磊,蒲传强,朱克等.血脑屏障内皮细胞与细胞间粘附分子-1在鼠脑缺血性脑水肿发生机制中的作用[J].中华神经科杂志,2000,33(2):86~89
[74] Peng xin,Dong zhi.Progress on inflammatory reaction mechanism of ischemiareperfusion injury[J]. Chin J Clin Pharmacol Ther,2006,11(4):365~368
[75] Zhang JT,Wu WP,Zhang FY. The Interleukin1B Converting Enzyme Gene Expressionafter Cerebral Ischemia Reperfusion[J]. J Mil Med,2002;27:56~58
[76] Bin X,Liu XW,Liu XW.Interleukir-1Changing in Cerebral Cortex and Hippocampiafter all Brain Ischemia Reperfusion[J].Clin Recovery,2002,6:50~51
[77]张玲,余绍祖,吴国祥.大鼠脑缺血再灌注后TNF-α、IL-β及细胞间粘附分子-1mRNA的表达[J].卒中与神经疾病,2001,8(2)77~79
[78] Wang CX,Shuaib A.Involvement of inflammatory cytokines incentral nervous systeminjury[J].Prog Neurobiol,2002;67:161
[79] Kostula N,Li HL,Xiao BG,Huang YM, Kostulsa MD,HansMD,et al.Dendritic cell arepresent in ischemic brain after permanent middle cerebral artery occlusion in the rats[J].Stroke,2002;33:ll29~1135
[80] Abillerira S,Montaner J,Molina CA,Monasterio J,Costillo J,Alvarez-Sabin J. Matrixmetalloproteinase-9pretreatment level predict sin-tracranial hemorrhagiccomplications after thrombolysis in human stroke[J].Circulation,2003;107:598~603
[81]李伟等.大鼠局灶性脑缺血再灌注模型纹状体内IL-1β和TNF-α动态变化及药物干预[J].中风与神经疾病杂志1998;15(5):262
[82] Klinge PM, Beck H, Brinker T, et al. Induction of heat shock protein70in the ratbrain following intracisternal infusion of autologous blood:evaluation of acuteneuronal damage. J Neurosurg1999;91:843.
[83] Karikó K, Weissman D, Welsh FA. Inhibition of toll-like receptor and cytokinesignaling--a unifying theme in ischemic tolerance. J Cereb Blood Flow Metab.2004,24:12
[84] Park S, Yamaguchi M, Zhou C, et al. Neurovascular protection reduces early braininjury after subarachnoid hemorrhage. Stroke,2004,35(10):2412-2417.
[85] Kusaka G, Ishikawa M, Nanda A, et al. Signaling pathways for early brain injury aftersubarachnoid hemorrhage. J Cereb Blood Flow Metab,2004,24(8):916-925.
[86] Suzuki H, Ayer R, Sugawara T, et al. Protective effects of recombinant osteopontin onearly brain injury after subarachnoid hemorrhage in rats. Crit Care Med,2010,38(2):612-618.
[87] Barton GM, Medzhitov R. Toll-like receptor signaling pathways. Science,2003,300(5625):1524-1525.
[88] Akira S, Takeda K. Toll-like receptor signaling. Nat Rev Immunol,2004,4(7):499-511.
[89] Chen G, Shi J, Jin W, et al. Progesterone administration modulates TLRs/NF-kappaBsignaling pathway in rat brain after cortical contusion. Ann Clin Lab Sci,2008,38(1):65-74.
[90] Chiang, C. S.; McBride, W. H. Radiation enhances tumor necrosis factor alphaproduction by murine brain cells. Brain Res1991,566,(1-2):265-9.
[91] Chiang, C. S.; Hong, J. H.; Stalder, A., et al. Delayed molecular responses to brainirradiation. Int J Radiat Biol1997,72,(1):45-53.
[92] Monje, M. L.; Toda, H.; Palmer, T. D. Inflammatory blockade restores adulthippocampal neurogenesis. Science2003,302,(5651):1760-5.
[93] Suuronen, T.; Nuutinen, T.; Huuskonen, J., et al. Anti-inflammatory effect of selectiveestrogen receptor modulators (SERMs) in microglial cells. Inflamm Res2005,54,(5):194-203.
[94] Tapia-Gonzalez, S.; Carrero, P.; Pernia, O., et al. Selective oestrogen receptor (ER)modulators reduce microglia reactivity in vivo after peripheral inflammation:potential role of microglial ERs. J Endocrinol2008,198,(1):219-30.
[95] Tian, D. S.; Liu, J. L.; Xie, M. J., et al. Tamoxifen attenuates inflammatory-mediateddamage and improves functional outcome after spinal cord injury in rats. JNeurochem2009,109,(6):1658-67.
[96] Ma CX, Yin WN, Cai BW, et al. Activation of TLR4/NF-kappaB signaling pathway inearly brain injury after subarachnoid hemorrhage. Neurol Res.2009Aug21.[Epubahead of print]
[1] American Heart Association. Heart disease and stroke statistics-2005update. Dallas:American Heart Association,2005.
[2] Maberg MR, Batjer HH, Dacey R, et a1. Guidelines for the management of aneurismalsubarachnoid hemorrhage. a statement for healthcare professionals from a specialwriting group of the Stroke Council, American Heart Association. Stroke.1994,25(11):2351-2328.
[3] Sudlow CL, Warlow CP. Comparable studies of the incidence of stroke and itspathological types: results from an international co11aboration. Stroke1997,28(3):491-499.
[4] Van Gijn J, Rinkel GJ. Subarachnoid hemorrhage:diagnosis,causes and management.Brain2001,124(2):249—278.
[5] Linn FH, Rinkel GJ, A1qra A,et a1.Incidence of subarachnoid hemorrhage:role ofregion, year, and rate of computed tomography:a meta—analysis. strokel996,27(4):625—629.
[6] Huang J, van Gelder JM. The probability of sudden death from rupture of intracranialaneurysms:a meta-analysis.Neurosurgery.2002,5l(5):1101-1105.
[7] Hop JW, Rinkel GJ, Algra A, van GJ Case-fatality rates and functional outcome aftersubarachnoid hemorrhage: A systematic review. Stroke28:660-664,1997
[8] Schievink WI Intracranial aneurysms. N Engl J Med336:28-40,1997
[9] Broderick JP, Brott TG, Duldner JE, Tomsick T, Leach A Initial and recurrent bleedingare the major causes of death following subarachnoid hemorrhage. Stroke25:1342-1347,1994
[10] Cahill J, Calvert JW, Zhang JH Mechanisms of early brain injury after subarachnoidhemorrhage. J Cereb Blood Flow Metab26:1341-1353,2006
[11] Kusaka G, Ishikawa M, Nanda A, Granger DN, Zhang JH Signaling pathways forearly brain injury after subarachnoid hemorrhage. J Cereb Blood Flow Metab24:916-925,2004
[12] Ostrowski RP, Colohan AR, Zhang JH Molecular mechanisms of early brain injuryafter subarachnoid hemorrhage. Neurol Res28:399-414,2006
[13] Cook DA Mechanisms of cerebral vasospasm in subarachnoid haemorrhage.Pharmacol Ther66:259-284,1995
[14] Kim I, Leinweber BD, Morgalla M, Butler WE, Seto M, Sasaki Y, Peterson JW,Morgan KG Thin and thick filament regulation of contractility in experimentalcerebral vasospasm. Neurosurgery46:440-446,2000
[15] Macdonald RL, Weir B, Zhang J, Marton LS, Sajdak M, Johns LM Adenosinetriphosphate and hemoglobin in vasospastic monkeys. Neurosurg Focus3: e3,1997
[16] Cahill J, Calvert JW, Zhang JH Mechanisms of early brain injury after subarachnoidhemorrhage. J Cereb Blood Flow Metab26:1341-1353,2006
[17] Sehba FA, Bederson JB. Mechanisms of acute brain injury after subarachnoidhemorrhage. Neurol Res,2006,28:381.
[18] Ostrowski RP, Colohan AR, Zhang JH. Mechanisms of hyperbaric oxygen-inducedneuroprotection in a rat model of subarachnoid hemorrhage. J Cereb Blood FlowMetab,2005,25:554-571.
[19] Prunell GF, Svendgaard NA, Alkass K, et al. Delayed cell death related to acutecerebral blood flow changes following subarachnoid hemorrhage in the rat brain. JNeurosurg,2005,102:1046-1054.
[20] Echlin F.Experimental vasospasm,acute and chronic,due to blood in the subarachnoidspace.J Neurosurg,1971,35:646-656.
[21] Uhl E,Le hmberg J,Steiger HJ,et a1.Intraoperative detection ofearly microvasospasmin patients with subarachnoid hemorhage by using o~hogonal polarization spectralimaging.Neurosurgery,2003,52:1307-13l5.
[22] Hara A, Yoshimi N,Mori H. Evidence for apoptosis in human intracranialaneurysms[J].Neurol Res,1998,20(2):127-130.
[23] Kondo S,Hashimoto N,Kikuchi H,et al.Apoptosis of medial smooth muscle cellsin the development of saccular cerebral aneurysms in rats[J].Stroke,1998,29:181-189.
[24] Hutter BO,Kreitschmann-Andermahr I,Gilsbach JM,e1.al. Healthrelated qualityof life after aneurysmal subarachnoid hemorrhage:impacts of bleeding severity,computerized tomography findings, surgery, vasospasm, and neurologicalgrade[J].Neurosurg,2001,94,241-251.
[25] Zhou C,Yamaguchi M,Kusaka G,et al.Caspase inhibitors prevent endothelialapoptosis and cerebral vasospasm in dog model of experimental subarachnoidhemorrhage[J].Cereb Blood Flow Metab,2004,24,419-431.
[26] Park S,Yamaguchi M,Zhou C,et al. Neurovascular protection reduces early braininjury after subarachnoid hemorrhage[J].Stroke,2004,35(10),2412~2417.
[27] Matz PG,Fujimura M,Lewen A,et al.Increased cytochrome-cmediated DNAfragmentation and cell death in manganesesuperoxide dismutase-deficient mice afterexposure to subarachnoid hemolysate[J].Stroke,2001,32,506-515.
[28] Nau R,Haase S,Bunkowski S,et a1. Neuronal apoptosis in the dentate gyrus inhumans with subarachnoid hemorrhage and cerebral hypoxia[J].Brain Pathol,2002,12,329-336.
[29] Cahill J,Calvert JW,Marcantonio S,et a1. p53may play an orehestrating role inapoptotic cell death after experimental subarachnoid hemorrhage[J].Neurosurgery,2007,60,531-545.
[30] Sabri, M. Kawashima, A. Ai, J. Macdonald, R.L. Neuronal and astroeytie apoptosisafter subarachnoid hemorhage: a possible cause for poor prognosis.Brain Res,2008,1238:163-171.
[31] Akpinar G,Acikgoz B,Surucu S,Celik HH,Cagavi F.Uhrastructural changes in thecircumventricular organs after experimental subarachnoid hemorrhage.Neurol Res2005,27:580-585.
[32] Unterberg AW, Stover J, Kress B, Kiening KL.2004. Edema and brain trauma.Neuroscience129:1021-1029.
[33] Kawamata T, Katayama Y, Aoyama N, Mori T.2000. Heterogeneous mechanisms ofearly edema formation in cerebral contusion: diffusion MRI and ADC mappingstudy.Acta Neurochir Suppl (Wien)76:9-12.
[34] Marmarou A, Signoretti S, Fatouros PP, Portella G, Aygok GA, Bullock MR.2006.Predominance of cellular edema in traumatic brain swelling in patients with severehead injuries. J Neurosurg104:720-730.
[35] Stroop R, Thomale UW, P user S, Bernarding J, Vollmann W, Wolf KJ.1998.Magnetic resonance imaging studies with cluster algorithm for characterization ofbrain edema after controlled cortical impact injury (CCII). Acta Neurochir Suppl(Wien)71:303-305.
[36] Claassen J,Carhuapoma JR,Kreiter KT,Du EY,Connolly ES,Mayer SA.Global cerebraledema after subarachnoid hemorhage:~equency,predictors,and impact onoutcome.Stroke,2002,33:1225-1232
[37] Petzold GC,Einhaupl KM,Dirnagl U,et a1.Ischemia triggered by spreading neuronalactivation is induced by endothelin--1and hemoglobin in the subarachnoidspace.Ann Neurol,2003,54:591-598.
[38] Cambj-Sapunar L,Yu M,Harder DR,et a1.Contribution of5--hydroxytryptamine1Breceptors and20hydroxyeiscosatetraenoic acid to fall in cerebral blood flow aftersubarachnoid hemorhage.Stroke,2003,34:1269.1275.
[39] Hengartner MO.The biochemistry of apoptosis[J].Nature,2000,407:770-777.
[40] Leist M,Jaattela M. Four deaths and a funeral:from caspases to alternativemechanisms[J].Nat Rev Mol Cell Biol,2001,2:589-598.
[41] Jaattela M Tschopp J. Caspase-indePendent cell death in T lymphocytes[J].NatImmunol,2003,4:416-423.
[42] Ma CX,Yin WN,Cai BW,et a1. Toll-like receptor4/nuclear factor--kappa Bsignaling detected in brain after early subarachnoid hemorrhage[J]. Chin MedJ(Ens1),2009,122(13):1575-1581.
[43]任会荣,钱令嘉.线粒体通透性转换孔、细胞色素与细胞凋亡[J].生命的化学,2002,22(4):316-318.
[44] Cregan SP,Fortin A,MacLaurin JG,Callaghan SM,Cecconi F.Yu SW et a1.Apoptosis-inducing factor is involved in the regulation of caspase-·independent neuronal celldeath. J Cell Biol,2002.158:507-517.
[45] Ma CX, Yin WN, Cai BW, et al. Activation of TLR4/NF-kappaB signaling pathway inearly brain injury after subarachnoid hemorrhage. Neurol Res.2009Aug21.[Epubahead of print]
[46] Klinge PM, Beck H, Brinker T, et al. Induction of heat shock protein70in the ratbrain following intracisternal infusion of autologous blood:evaluation of acuteneuronal damage. J Neurosurg1999;91:843.
[47] Karikó K, Weissman D, Welsh FA. Inhibition of toll-like receptor and cytokinesignaling--a unifying theme in ischemic tolerance. J Cereb Blood Flow Metab.2004,24:1288.
[48] Zhong Wang, Gang Zuo, Xiao-Yong Shi et al. Progesterone AdministrationModulates Cortical TLR4/NF-κB Signaling Pathway after Subarachnoid Hemorrhagein Male Rats.Mediators of Inflammation.2011;2011:848309.
[49] Zhong Wang,Cao Ma, Cheng-Jie Meng.et al. Melatonin activates the Nrf2-AREpathway when it protects against early brain injury in a subarachnoid hemorrhagemodel.Journal of Pineal Research.2012Jan11. doi:10.1111/j.1600-079X.2012.00978.x.[Epub ahead of print]
[50] Zhong Wang, Xiao-Yong Shi, Yin Jia. et al. Role of autophagy in early brain injuryafter experimental subarachnoid hemorrhage. Journal of Molecular Neuroscience.2012Jan;46(1):192-202.
[51] Fujimura M,Cache Y.Early appearance of activated matrixmetalloproteinase--9andblood-brain barrier disruption in mice after focal cerebral ischemia andreper-fusion[J].Brain Res,1999,842:92-1130.
[52] Hansen-Schwartz J,Vajkoczy P,Macdonald RL,et a1.Cerebral vasospasm:lookingbeyond vaso-constriction[J].Trends Pharmacol Sci,2007,28:252-256.
[53] Cahill J,Calvert,Solaroglu I,et a1. Vasospasm and p53-induced apoptosis in anexperimental model of subarachnoid hemorrhage[J].Stroke,2006,37:1868-1874.
[54] Cunningham LA,Wetzel M,Rosenberg GA. Multiple roles for MMPs and TIMPsin cerebral ischemia[J].Glia,2005,50(4):329-339.
[55] Vikman P,Beg S,Khurana TS,et a1. Gene expression and molecular changes incerebral arteries following subarachnoid hemorrhage in the rat[J].J Neurosurg,2006,105(3):438-444.
[56] Sehba FA,Mostafa G,Knopman J,et a1. Acute alterations inmicrovascular basallamina after subarachnoid hemorrhage[J].Journal of Neurosurgery,2004,101(4):633-640.
[57] Castillo J,Leira R,Blanco M, et a1.Metalloproteinases and neurovascularinjury[J].Neurologia,2004,19(6):312-320.
[58] Higashida T, Kreipke CW, Rafols JA, Peng C, Schafer S, Schafer P, Ding JY, DornbosD3rd, Li X, Guthikonda M, Rossi NF, Ding Y.2011. The role of hypoxia-induciblefactor-1α, aquaporin-4, and matrix metalloproteinase-9in blood-brain barrierdisruption and brain edema after traumatic brain injury. J Neurosurg114:92-101.
[59] Badaut J, Brunet JF, Grollimund L, Hamou MF, Magistretti PJ, Villemure JG, RegliL.2003. Aquaporin1and aquaporin4expression in human brain after subarachnoidhemorrhage and in peritumoral tissue. Acta Neurochir Suppl86:495-498.
[60] Tait MJ, Saadoun S, Bell BA, Verkman AS, Papadopoulos MC.2010. Increased brainedema in aqp4-null mice in an experimental model of subarachnoid hemorrhage.Neuroscience167:60-67.
[61] Hishikawa T, Ono S, Ogawa T, Tokunaga K, Sugiu K, Date I.2008. Effects ofdeferoxamine-activated hypoxia-inducible factor-1on the brainstem aftersubarachnoid hemorrhage in rats. Neurosurgery62:232-240.
[62] Feiler S, Plesnila N, Thal SC, Zausinger S, Scheller K.2011. Contribution of MatrixMetalloproteinase-9to Cerebral Edema and Functional Outcome followingExperimental Subarachnoid Hemorrhage. Cerebrovasc Dis32:289-295.
[63] Guo ZD, Zhang XD, Wu HT, Lin B, Sun XC,Zhang JH.2011.Matrix metalloproteinase9inhibition reduces early brain injury in cortex after subarachnoid hemorrhage.ActaNeurochir Suppl110(Pt1):81-84.
[64] Clark JF, Sharp FR. Bilirubin oxidation products (BOXes) and their role in cerebralvasospasm after subarachnoid hemorrhage. J Cereb Blood Flow Metab2006;26(10):1223–1233
[65] Pyne2Geithman GJ,MorganCJ,Wagner K, et al.BillrublnProduetionand Oxidation inCSF of Patients with cerebral vasospasm after subarachnoid hemorrhage.J CerebBlood Flow Metab,2005,25(8):1070-1077
[66] Clark JF,Sharo FR. Bilirubin oxidation produets(BOXes) and their role in Cerebralvasospasm after subarachnoid hemorrhage.J Cereb Blood F IOW Metab,2006,26(10):1223-1233.
[67] Obara K, Nishizawa S, Koide,M et al.Inieraetive role of protein kinase C-delta withrho-kinase in the development of cerebral vasospasm in a canine two-hemorrhagemodel. J VascRes,2005,42(l):67-76
[68] Dietrich HH, Dacey RG Jr. Molecular keys to the problems of cerebral vasospasm.Neurosurgery2000;46(3):517–30.
[69] Santhanam, A.V.R. et al. Role of endothelialNOsynthase phosphorylation incerebrovascular protective effect of recombinant erythropoietin during subarachnoidhemorrhage-induced cerebral vasospasm. Stroke2005,36:2731–2737
[70] Kasuya H, Weir B, White D, et al. Mechanism of oxyhemoglobin-induced release ofendothelin-1from cultured vascular endothelial cells and smooth-muscle cells. JNeurosurg1993;79:892–898.
[71] Fassbender K, Hodapp B, Rossol S, et al. Endothelin-1in subarachnoid hemorrhage:An acute-phase reactant produced by cerebrospinal fluid leukocytes. Stroke2000;31:2971–2975.
[72] Macdonald RL, Pluta RM, Zhang JH. Cerebral vasospasm after subarachnoidhemorrhage: The emerging revolution. Nat Clin Pract Neurol2007;3(5):256–263.
[73] AL Kwan, CL Lin, CS Wu,et al. Delayed Administration of the K+Channel ActivatorCromakalim Attenuates Cerebral Vasospasm after Experimental SubarachnoidHemorrhage. ACTA Neurochirurgica2000,142:193-197
[74] Ishiguro M, Wellman TL, Honda A, et al. Emergence of a R-type Ca2+channel (CaV2.3) contributes to cerebral artery constriction after subarachnoid hemorrhage. CircRes2005;96(4):419–426.
[75] Schoch B, Regel JP, Wichert M, et al. Analysis of intrathecal inierleukin-6asa potential predictive factor for vasospasm in subarachnoid hemorrhage. Neurosurgery,2007,60(5):828一836
[76] Nakayama T, Ilbh K, Ruetzler C, et al. Intranasal adminis-tration of E一selectin toinduce immunological tolerization can suppress subarachnoid hemorrhage-inducedvasospasm implicating immune and inflammatory mechanisms in its genesis.BrainRes,2007,1132(1):177-184
[77] Zhou C, Yamaguchi M, Colohan AR, et al. Role of P53and apoptosis in cerebralvasospasm after experimental subarachnoid hemorrhage. J Cereb Blood FlowMetab2005,25(5):572一582
[78] Hiroshi Yatsushige, MD; Mitsuo Yamaguchi, MD; Changman Zhou, MD,et al. Role ofc-Jun N-Terminal Kinase in Cerebral Vasospasm After Experimental SubarachnoidHemorrhage. Stroke.2005;36:1538-1543.
[79] Roberts, I., Schierhout, G., Alderson, P. Absence of evidence for the effectiveness offive interventions routinely used in the intensive care management of severe headinjury: a systematic review. J. Neurol. Neurosurg. Psychiatry.1998;65:729–733.
[80] Zhong Wang, Gang Zuo, Xiao-Yong Shi et al. Progesterone AdministrationModulates Cortical TLR4/NF-κB Signaling Pathway after SubarachnoidHemorrhage in Male Rats.Mediators of Inflammation.2011;2011:848309.
[81] Zhong Wang,Cao Ma, Cheng-Jie Meng.et al. Melatonin activates the Nrf2-AREpathway when it protects against early brain injury in a subarachnoid hemorrhagemodel.Journal of Pineal Research.2012Jan11. doi:10.1111/j.1600-079X.2012.00978.x.[Epub ahead of print]
[82] Zhong Wang, Xiao-Yong Shi, Yin Jia. et al. Role of autophagy in early brain injuryafter experimental subarachnoid hemorrhage. Journal of Molecular Neuroscience.2012Jan;46(1):192-202..
[83] Ghezzi P, Brines M. Erythropoietin as an antiapoptotic, tissue-protectivecytokine.Cell Death Differ,2004,11Suppl1:s37—44
[84] Zhong Wang, Cheng-Jie Meng. et al. Potential contribution of hypoxia-induciblefactor-1α, aquaporin-4, and matrix metalloproteinase-9to blood-brain barrierdisruption and brain edema after exper-imental subarachnoid hemorrhage. Journal ofMolecular Neuroscience.2012:012:97696
[85] Kopp MD, Schomcrus C, Dehghani F, et a1.Pituitary adenylate cyclase—activatingpolypeptide and melatonin in the suprachiasmatic nucleus:effects on the calciumsignal transduction cascade.J Neuro sci.1999.19(1):206—219.
[86] Escames G, Leon J, Macias M, et a1. Melatonin counteractslipopolysaccharide—induced expression and activity of mit02chondrial nitric oxidesynthase in rats.[J]. FASEB J,2003,17(8):932·934.
[87] Hardeland R, Pandi2Perumal S R, Cardinali DP.Molecules in focus:Melatonin [J].Int J Biochem Cell Biol,2006,38:313-316/
[88] Rutledge, E. M.; Aschner, M.; Kimelberg, H. K. Pharmacological characterization ofswelling-induced D-[3H] aspartate release from primary astrocyte cultures. Am JPhysiol1998,274,(6Pt1): C1511-20.
[89] Wiseman, H.; Cannon, M.; Arnstein, H. R., et al. Tamoxifen inhibits lipid peroxidationin cardiac microsomes. Comparison with liver microsomes and potential relevance tothe cardiovascular benefits associated with cancer prevention and treatment bytamoxifen. Biochem Pharmacol1993,45,(9):1851-5.
[90] Osuka, K.; Feustel, P. J.; Mongin, A. A., et al. Tamoxifen inhibits nitrotyrosineformation after reversible middle cerebral artery occlusion in the rat. J Neurochem2001,76,(6):1842-50.
[91] Suuronen, T.; Nuutinen, T.; Huuskonen, J., et al. Anti-inflammatory effect of selectiveestrogen receptor modulators (SERMs) in microglial cells. Inflamm Res2005,54,(5):194-203.
[92] Tapia-Gonzalez, S.; Carrero, P.; Pernia, O., et al. Selective oestrogen receptor (ER)modulators reduce microglia reactivity in vivo after peripheral inflammation:potential role of microglial ERs. J Endocrinol2008,198,(1):219-30.
[93] Tian, D. S.; Liu, J. L.; Xie, M. J., et al. Tamoxifen attenuates inflammatory-mediateddamage and improves functional outcome after spinal cord injury in rats. JNeurochem2009,109,(6):1658-67.