黄蜀葵花总黄酮预处理的脑缺血保护作用及作用机理
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摘要
缺血预处理(Ischemic preconditioning,IP)是指预先短暂性缺血或轻度缺氧后激发或动员机体内在的防护能力,使机体对随后严重的缺血、缺氧产生防御和保护现象。而药物预处理(pharmacological preconditioning,PP)是通过药物模拟缺血预处理激发机体内源性物质,如腺苷、NMDA受体阻断剂等而发挥保护作用。PP的研究开辟了脑保护研究的一个新领域。黄蜀葵花总黄酮(total flavones ofAbelmoschl Manihot,TFA)是锦葵属植物黄蜀葵的花中提取的有效部位。本室曾发现TFA药理性预处理(pharmacological preconditioning of TFA,PPA)对大鼠心肌缺血再灌注损伤有保护作用,但未见PPA对脑缺血再灌注损伤影响的研究报道,因此,本研究就PPA对脑缺血再灌注损伤的影响及其机制进行了初步研究。主要研究结果如下:
1.PPA早期相对大鼠脑缺血再灌注损伤的影响
PPA(20,40,80,160 mg·kg~(-1))30min对大鼠MCAO 90min致缺血后脑梗死体积百分比增高有明显的抑制作用,可不同程度的降低血清中乳酸脱氢酶(lactatedehydrogenase,LDH)的活性、丙二醛(methylenedioxyamphetamine,MDA)、前列腺素E_2(Prostaglandin E_2,PGE_2)的含量,同时升高一氧化氮合酶(nitric oxide synthasc,NOS)的活力及血清中一氧化氮(nitric oxide,NO)的含量。
2.PPA中间时相预处理对大鼠脑缺血再灌注损伤的影响
PPA(80,160 mg·kg~(-1))7h对大鼠MCAO 90min致脑梗死体积百分比增高无明显的影响。
3.PPA延迟相预处理对大鼠脑缺血再灌注损伤的影响
PPA(20,40,80,160 mg·kg~(-1))36h对大鼠MCAO 90min致缺血后脑梗死体积百分比增高有明显的抑制作用,不同程度的降低血清中LDH的活性,MDA的含量,同时升高血清中一氧化氮的含量,其中160 mg·kg~(-1)PPA能显著提高脑组织中iNOSmRNA的表达。
4.PPA对小鼠脑缺血再灌注损伤的影响
小鼠PPA(25,50,100,200 mg·kg~(-1))30min时对MCAO 90min致脑梗死体积百分比增高有明显的抑制作用,不同程度的降低血清中LDH、小鼠神经特异性烯醇化酶(nervous specific enolase,NSE)的活性及MDA的含量,同时升高血清中NO的含量。
5.内皮依赖性超级化因子(Endothelium-derived hyperpolarizing factor,EDHF)在海马神经元缺氧复氧损伤的作用
海马神经元培养至第8天,加入乙酰胆碱(Acetylcholine,Ach)和一段3mm脑基底环动脉后后行缺氧4h复氧24h.结果表明Ach(1μmol·L-1)+血管明显地抑制缺氧复氧后海马神经元活力的降低,同时能显著降低培养上清液中的LDH活性,但Ach及血管段单独均没有作用。加入前列腺环素(PGI_2)合成酶抑制剂吲哚美辛(indomethacin,Indo)及NO合酶抑制剂左旋硝基精氨酸甲酯(Nω-nitro-L-arginine-methyl-ester,L-NAME)预处理对Ach合用血管的作用无明显的影响,提示Ach介导的血管内皮EDHF释放对神经细胞缺氧再给氧损伤有保护作用。
6.TFA对海马神经元缺氧复氧损伤的影响及可能的EDHF机制
与单独应用TFA比较,联合使用TFA(3,10,30,100mg·L-1)和血管对缺氧复氧后海马神经元的活力有明显的升高作用,同时降低培养上清液中LDH的活性和海马神经元细胞内的游离Ca~(2+)的增高。加入Indo及L-NAME预处理对TFA的保护作用无明显的影响,提示TFA对缺氧复氧致神经细胞损伤有一定的保护作用,其机制可能与EDHF有关。
结论:TFA药理性预处理对脑缺血再灌注损伤有明显的保护作用,其机制可能与减轻细胞膜脂质过氧化、增加NO的生成、降低细胞内钙离子超载及释放EDHF等有关。
The term "brain tolerance" describes as a phenomenon of transient resistance to a lethal insult evoked by preconditioning with a mild insult of short duration. Preconditioning stimulus,while inadequate to damage neurons,somehow increases their ability,and sometimes the ability of the whole organism as well,to survive subsequent lethal challenge.IP has been described to be a biphasic event:the acute phase is limited to 1-3 h after a brief ischemic stimulus,and the delayed phase emerges 24 h later and may last up to 72h.A series of recent studies have described another relevant phenomenon termed "chemical preconditioning".Abelmoschl Manihot is one of the plants that rich in flavones,such as quercetin,hyperin and rutin,Recent studies have shown that total flavones of Abelmoschl Manihot(TFA) have protective effects against cerebral ischemic injury in rabbit and rat.Also,pharmacological preconditioning of TFA(PPA) has been shown to possess a protective effect against myocardial ischemia-reperfusion injury in rabbit.However,there is no information reported about the effect of PPA on cerebral ischemic injury.By using rat,mice model of cerebral ischemia and the hypoxia-reoxygen model of foetal hippocamal neurons,we set out to investigate the effect of PPA on cerebral and its mechanism.
1.Effects of PPA in the acute phase on the model of cerebral ischemic injury in rat
Ischemia and reperfusion(I/R) injury was induced by a middle cerebral artery occlusion(MCAO) for 90 minutes occlusion and 60 minutes of reperfusion in rat.PPA rats received 2 cycles of 5 minutes intravenous injection of TFA 20,40,80,160 mg·kg~(-1) 30 min before I/R.20,40,80,160 mg·kg~(-1) PPA significantly reduced the infarction volume,markedly inhibited the elevated levels of serum LDH,MDA,PGE2 and decrement of serum NO and NOS.
2.Effect of PPA of the middle phase on the model of cerebral ischemic injury in rat
The rat I/R injury was induced by MCAO for 90 minutes occlusion and 60 minutes of reperfusion.TFA(20,40,80,160 mg·kg~(-1) )pretreatment 7 h has no significant effect on the infarction volume.
3.Effect of PPA in the delayed phase on the model of cerebral ischemic injury in rat
The rat I/R injury was induced by MCAO for 90 minutes occlusion and 60 minutes of reperfusion.TFA or Nim pretreatment 36 h significantly decreased the infarction volume.PPA(20,40,80,160 mg·kg~(-1)) or Nim significantly inhibited the elevated levels of serum LDH and MDA,indicating a delayed protective effect of TFA preconditioning on cerebral ischemic reperfusion injury.In addition,the serum NO level and the cerebral iNOS mRNA were up-regulated.
4.Effect of PPA in the acute phase on the model of cerebral ischemic injury in mice
The mouse I/R injury was induced by MCAO for 90 minutes occlusion and 60 minutes of reperfusion.PPA animals received 2 cycles of 5 minutes intravenous injection of TFA 25,50,100,200 mg·kg~(-1) 30 min before I/R.TFA or Nim pretreatment significantly decreased the infarction volume.Increases of serum LDH,NSE activity and MDA level were observed after I/R,but these changes were inhibited in mice pretreated with either TFA(25,50,100,200 mg·kg~(-1)) or Nim,In addition,the serum NO level were up-regulated.
5.Effect of EDHF on hippocampal neurons subjected to oxygen deprivation/reperfusion in primary culture
Treatment with 1μmol·L~(-1) Ach and a segment of cerebral artery significant increase the neuron viability(P＜0.01,compared with model),and reduce the activity of LDH in culture medium.Plus with the Indo and the L-NAME didn't influence the effect of Ach plus cerebral artery.
6.Effect of TFA on hippocampal neurons subjected to oxygen deprivation/reperfusion in primary culture.
Pretreatment with TFA(100 mg·kg(-1)) and cerebral artery significantly increase the neuron viability(P＜0.01,compared with model),reduce the activity of LDH in culture medium.TFA(3,10,30,100 mg·kg~(-1)) plus with cerebral artery lowered the calcium concentration in neuron(compared with model).
Conclusion:PPA has marked protective effect on cerebral ischemia and reperfusion injury,the mechanisms of PPA might be related to attenuating oxygen free radicals, increasing of NO production,inhibiting the calcium concentration in neuron.
1.PPA早期相对大鼠脑缺血再灌注损伤的影响
PPA(20,40,80,160 mg·kg~(-1))30min对大鼠MCAO 90min致缺血后脑梗死体积百分比增高有明显的抑制作用,可不同程度的降低血清中乳酸脱氢酶(lactatedehydrogenase,LDH)的活性、丙二醛(methylenedioxyamphetamine,MDA)、前列腺素E_2(Prostaglandin E_2,PGE_2)的含量,同时升高一氧化氮合酶(nitric oxide synthasc,NOS)的活力及血清中一氧化氮(nitric oxide,NO)的含量。
2.PPA中间时相预处理对大鼠脑缺血再灌注损伤的影响
PPA(80,160 mg·kg~(-1))7h对大鼠MCAO 90min致脑梗死体积百分比增高无明显的影响。
3.PPA延迟相预处理对大鼠脑缺血再灌注损伤的影响
PPA(20,40,80,160 mg·kg~(-1))36h对大鼠MCAO 90min致缺血后脑梗死体积百分比增高有明显的抑制作用,不同程度的降低血清中LDH的活性,MDA的含量,同时升高血清中一氧化氮的含量,其中160 mg·kg~(-1)PPA能显著提高脑组织中iNOSmRNA的表达。
4.PPA对小鼠脑缺血再灌注损伤的影响
小鼠PPA(25,50,100,200 mg·kg~(-1))30min时对MCAO 90min致脑梗死体积百分比增高有明显的抑制作用,不同程度的降低血清中LDH、小鼠神经特异性烯醇化酶(nervous specific enolase,NSE)的活性及MDA的含量,同时升高血清中NO的含量。
5.内皮依赖性超级化因子(Endothelium-derived hyperpolarizing factor,EDHF)在海马神经元缺氧复氧损伤的作用
海马神经元培养至第8天,加入乙酰胆碱(Acetylcholine,Ach)和一段3mm脑基底环动脉后后行缺氧4h复氧24h.结果表明Ach(1μmol·L-1)+血管明显地抑制缺氧复氧后海马神经元活力的降低,同时能显著降低培养上清液中的LDH活性,但Ach及血管段单独均没有作用。加入前列腺环素(PGI_2)合成酶抑制剂吲哚美辛(indomethacin,Indo)及NO合酶抑制剂左旋硝基精氨酸甲酯(Nω-nitro-L-arginine-methyl-ester,L-NAME)预处理对Ach合用血管的作用无明显的影响,提示Ach介导的血管内皮EDHF释放对神经细胞缺氧再给氧损伤有保护作用。
6.TFA对海马神经元缺氧复氧损伤的影响及可能的EDHF机制
与单独应用TFA比较,联合使用TFA(3,10,30,100mg·L-1)和血管对缺氧复氧后海马神经元的活力有明显的升高作用,同时降低培养上清液中LDH的活性和海马神经元细胞内的游离Ca~(2+)的增高。加入Indo及L-NAME预处理对TFA的保护作用无明显的影响,提示TFA对缺氧复氧致神经细胞损伤有一定的保护作用,其机制可能与EDHF有关。
结论:TFA药理性预处理对脑缺血再灌注损伤有明显的保护作用,其机制可能与减轻细胞膜脂质过氧化、增加NO的生成、降低细胞内钙离子超载及释放EDHF等有关。
The term "brain tolerance" describes as a phenomenon of transient resistance to a lethal insult evoked by preconditioning with a mild insult of short duration. Preconditioning stimulus,while inadequate to damage neurons,somehow increases their ability,and sometimes the ability of the whole organism as well,to survive subsequent lethal challenge.IP has been described to be a biphasic event:the acute phase is limited to 1-3 h after a brief ischemic stimulus,and the delayed phase emerges 24 h later and may last up to 72h.A series of recent studies have described another relevant phenomenon termed "chemical preconditioning".Abelmoschl Manihot is one of the plants that rich in flavones,such as quercetin,hyperin and rutin,Recent studies have shown that total flavones of Abelmoschl Manihot(TFA) have protective effects against cerebral ischemic injury in rabbit and rat.Also,pharmacological preconditioning of TFA(PPA) has been shown to possess a protective effect against myocardial ischemia-reperfusion injury in rabbit.However,there is no information reported about the effect of PPA on cerebral ischemic injury.By using rat,mice model of cerebral ischemia and the hypoxia-reoxygen model of foetal hippocamal neurons,we set out to investigate the effect of PPA on cerebral and its mechanism.
1.Effects of PPA in the acute phase on the model of cerebral ischemic injury in rat
Ischemia and reperfusion(I/R) injury was induced by a middle cerebral artery occlusion(MCAO) for 90 minutes occlusion and 60 minutes of reperfusion in rat.PPA rats received 2 cycles of 5 minutes intravenous injection of TFA 20,40,80,160 mg·kg~(-1) 30 min before I/R.20,40,80,160 mg·kg~(-1) PPA significantly reduced the infarction volume,markedly inhibited the elevated levels of serum LDH,MDA,PGE2 and decrement of serum NO and NOS.
2.Effect of PPA of the middle phase on the model of cerebral ischemic injury in rat
The rat I/R injury was induced by MCAO for 90 minutes occlusion and 60 minutes of reperfusion.TFA(20,40,80,160 mg·kg~(-1) )pretreatment 7 h has no significant effect on the infarction volume.
3.Effect of PPA in the delayed phase on the model of cerebral ischemic injury in rat
The rat I/R injury was induced by MCAO for 90 minutes occlusion and 60 minutes of reperfusion.TFA or Nim pretreatment 36 h significantly decreased the infarction volume.PPA(20,40,80,160 mg·kg~(-1)) or Nim significantly inhibited the elevated levels of serum LDH and MDA,indicating a delayed protective effect of TFA preconditioning on cerebral ischemic reperfusion injury.In addition,the serum NO level and the cerebral iNOS mRNA were up-regulated.
4.Effect of PPA in the acute phase on the model of cerebral ischemic injury in mice
The mouse I/R injury was induced by MCAO for 90 minutes occlusion and 60 minutes of reperfusion.PPA animals received 2 cycles of 5 minutes intravenous injection of TFA 25,50,100,200 mg·kg~(-1) 30 min before I/R.TFA or Nim pretreatment significantly decreased the infarction volume.Increases of serum LDH,NSE activity and MDA level were observed after I/R,but these changes were inhibited in mice pretreated with either TFA(25,50,100,200 mg·kg~(-1)) or Nim,In addition,the serum NO level were up-regulated.
5.Effect of EDHF on hippocampal neurons subjected to oxygen deprivation/reperfusion in primary culture
Treatment with 1μmol·L~(-1) Ach and a segment of cerebral artery significant increase the neuron viability(P＜0.01,compared with model),and reduce the activity of LDH in culture medium.Plus with the Indo and the L-NAME didn't influence the effect of Ach plus cerebral artery.
6.Effect of TFA on hippocampal neurons subjected to oxygen deprivation/reperfusion in primary culture.
Pretreatment with TFA(100 mg·kg(-1)) and cerebral artery significantly increase the neuron viability(P＜0.01,compared with model),reduce the activity of LDH in culture medium.TFA(3,10,30,100 mg·kg~(-1)) plus with cerebral artery lowered the calcium concentration in neuron(compared with model).
Conclusion:PPA has marked protective effect on cerebral ischemia and reperfusion injury,the mechanisms of PPA might be related to attenuating oxygen free radicals, increasing of NO production,inhibiting the calcium concentration in neuron.
引文
1.Akins PT,Liu PK,Hsu CY.Immediate early gene expression in response to cerebral ischemia[J].Friend or foe Stroke,1996,27(2):1682-1687.
2.Weih M,Ruscher K.Ischemia tolerance model for research,hope for clinical practice[J].Nervenarzt,2001,72(4):255-260.
3.Bowen KK,Naylor M,Vemuganti R.Prevention of inflammation is a mechanism of preconditioning-induced neuroprotection against focal cerebral schemia[J].Neurochem Int,2006,49(2):127-135.
4.张仲慧,郭子江,尹琳,等.金辉.西乐葆预处理对大鼠脑缺血再灌注损伤ICAM-1表达及白细胞浸润的影响[J].中国民康医学,2004,16(12):721-726.
5.梁庆成,吕海燕,吴云.TNF-α预处理对鼠脑缺血及再灌注过程中ICAM-1诱导作用的研究[J].中国神经精神疾病杂志,2004,30(1):13-16.
6.郝玉曼,罗祖明.秋水仙碱联合环磷酰胺增强大鼠脑缺血耐受的作用及其对热休克蛋白70表达的影响[J].中国神经精神疾病杂志,2004,30(2):147-155.
7.Centeno JM,Orti M,Salom JB,et al.Nitric oxide is involve in anoxic preconditioning neuroprotction in rat hippocampal slices[J].Brain Res,1999;836(1-2):62-69.
8.Gonzalez-Zulueta M,Feldman AB,Klessa LJ,et al.Requirement for nitric oxide activation of p21(ras)/extra cellular regulated kinase in neuronal ischemic preconditioning[J].Proc Acad Sci USA,2000;97(1):436-441.
9.Gidday JM,Shah AR,Maceren RG,et al.Nitric oxide mediates cerebral ischemic tolerance in a neonatal rat model of hypoxic preconditioning[J].J Cereb Blood Flow Metab,1999;19(3):331-340.
10.Enari M,Sakahira H,Yokoyama H,et al.A capase-activated DNase that degrades DNA during apoptosis and its inhibitor ICAD[J].Nature,1998,391(2):43-50.
11.王倩,闵连秋.阿司匹林预处理对大鼠局造性脑缺血的神经保护作用[J].国外医学脑血管疾病分册,2004,12(12):901-903.
12.雒东江,平蕾.环磷腺苷葡胺预处理对大鼠局灶性脑缺血海马iNOS含量的影响.中国现代医学杂志[J].2005,15(15):2281-2284.
13.Davole MA,Fourtounis J,Tam J,et al.Immunohistochemical and biochemical assessment of caspase-3 activation and DNA fragmentation following transient focal ischemia in the rat[J].Neuro Science,2002,11(3):125-36.
14.朱红灿,孙圣刚,李红戈.小剂量3-硝基丙酸预处理对脑缺血沙士鼠海马CAl 区及纹状体神经元的影响[J].郑州大学学报(医学版),2003,38(3):356-360.
15.Wiegand F,Liao W,Busch C,et al.Respiratory chain inhibition induces tolerance to focal cerebral ischemia[J].J Cereb Blood Flow Metab,1999,19(11):1229-1237.
16.Horiguchi T,Kis B,Rajapakse N,et al.Opening of mitochondrial ATP-sensitive potassium channels is a trigger of 3-nitropropionic acid-induced tolerance to transient focal cerebral ischemia in rats[J].Stroke,2003,34(4):1015-1020.
17.胡明,刘昌勤,冯作化.尼莫地平预处理和梗塞后治疗对大鼠脑缺血损伤研究保护作用的比较研究[J].脑与神经疾病杂志.2005,13(3):182-185.
18.Haspolat S,Anlar B,Kose C,et al.Inteukin-lbeta,interleukin-1 receptir antagonist levers in patients with subacute sclerosing panencephalitis and effects of different treatment protocols[J].J Child Neurol,2001.16(6):417-420
19.向强,文亮,解军,等.内毒素预处理对大鼠全脑缺血后海马内生性IL-1R α的影响[J].第三军医大学学报,2005,27(4):320-322.
20.刘永海,高殿帅.沙鼠脑缺血再灌注后海马中c-fos蛋白表达及纳络酮影响[J].中国神经免疫学和神经病学杂志,1999,6(1):12-14.
21.Takemoto,O.Tomimoto,H.and Yanagihara,T..Induction of c-fos and c-jun gene products and heat shock protein after brief and prolonged cerebral ischemia in gerbils[J].Stroke 26(2):1639-1648
22.Kiessling M,Stumn G,Xie Y,et al.Differential transcription and translation of immediate early genes in the gerbil hippocampus after transient global ischemia[J].J Cereb Blood Flow Metab,1993,13(6):914-924
23.Young-Bae KWON,Ⅱ-Suk YANG and Kyung-Sun Kang.Effects of dizocilpine pretreatment on parvalbumin immunoreactivity and los expression after cerebral ischemia in the hippocampus of the Mongolian gerbil[J].J.Vet.Med.Sci,62(2):141-146,2000
24.Fetter,Lopez,E.,Pozas,E.,Ballabriga,et al.Multiple neurotrophic sigals converge in surviving CAl neurons of the gerbil hippocampus following transient forebrain ischemia[J].J.Comp.Neurol,1998,394(4):416-30.
25.Brambrink AM,Koerner IP,Diehl K,et al.The antibioticerythromycin induces tolerance against transient global cerebral ischemia in rats(pharmacologic preconditioning)[J].2006,104(6):1208-1215.
26.金石,牛国忠,许国正.尼莫地平和硫氮卓酮对大鼠脑缺血再灌流期自由基损伤的保护作用研究[J].临床脑电学杂志,1994,3(3):167-169.
27.温宝书,张敏,吕金胜.尼莫地平对老龄大鼠大脑皮层和海马细胞内游离钙浓度的影响[J].中国老年学杂志,1998,4(18):238-239.
28.Rubaj A,Gustaw K,Zgodzinski W,et al.The role of opioid receptors in hypoxic preconditioning against serzures in brain[J].Pharmacol Biochem Behav,2000,67(1):65-70.
29.Lim Y J.Zuo Z.Morphine preconditions Purkinje cells against cell death under in vitro simulated ischemia-reperfusion conditions[J].Anesthesiology,2004,100(3):562-568.
30.Junhui Zhang,Hong Qian,et al.Rapid Hypoxia Preconditiong Protects Cortical Neurons From Gultamate Toxicity Through delta-Opioid Recetor[J].Journal Of The American Heat Association.2006,37(3):1094-1099.
1.Murry CE,Jennings RB,Reimer KA.Preconditioning with ischemia:a delay of lethal cell injury in ischemic myocardium[J].Circulation 1986,74(5):1124-1136.
2.Kitagawa K,Matsumoto M,Oda T,et al.Free radical generation during brief of cerebral ischemia trigger delayed neuronal death[J].Stroke,1990,35(3):551-558.
3.Rejdak R,Rejdak K,Sieklucka-Dziuba M,et al.Brain tolerance and preconditioning[J].Pol J Pharmacol,2001,53(1):73-79.
4.Rubaj A,Gustaw K,Zgodzinski W,et al.The role of opioid receptors in hypoxic preconditioning against serzures in brain[J].Pharmacol Biochem Behav,2000,67(1):65-70.
5.高杉,范丽,董六一,等.黄蜀葵花总黄酮对MCAO大鼠脑细胞凋亡的影响[J].中国药理学通报,2003,19(6):704-707.
6.范丽,袁丽萍,陈志武,等.黄蜀葵花总黄酮药理性预适应对家兔心肌缺血再灌注损伤的保护作用[J].中国药学杂志,2005,40(11):836-839.
7.Longa EZ,Weinstein PR,Carlson S,et al.Reversible middle cerebral artery occlusion without craniectomyin rats[J].Stroke,1989(1),20:80-91.
8.赵菁,徐超,王忠诚.多巴胺D2、D3受体在大鼠暂时性局灶性脑缺血中的作用[J].中华神经外科杂志,2002,18(3):160-164.
9.Kiryushko D,Kofoed T,Skladchikova G,et al.A synthetic peptide ligand of neural cell adhesion molecule(NCAM),C3d,promotes neurito-genesis and synaptogensis and modulates presynaptic function inprimary cultures of rat hippocampal neurons[J].J Biolchem,2003,278(14):12325-12334.
10.Akins PT,Liu PK,Hsu CY.Immediate early gene expression in response to cerebral ischemia[J].Friend or foe Stroke,1996,27(2):1682-1687.
11.Weih M,Ruscher K,et al.Ischemia tolerance model for research,hope for clinical practice[J].Nervenarzt,2001,72(4):255-260.
12.Yi Yang,Ashfaq Shuaib,Qiu Li.Quantification of infarct size on focal cerebral ischemia model of rats using a simple and economical method[J].Journal of Neuroscience Methods,1998,84(2):9-16.
13.Nadashima M,Niwa M,Twai T,et al.Involvement of free radicals in cerebral vascular reperfusion injury evaluated in a transient focal cerebral sichemia model of rat[J].Free Radical Biol Med,1999,25(6):722-729.
14.Moncayo J,de Freitas GR,Bogousslavsky J,et al.Do transient ischemic attacks have a neuroprotective effect[J].Nerology,2000,54(11):2089-2094.
15.胡明,刘昌勤,冯作化.尼莫地平预处理和梗塞后治疗对大鼠脑缺血损伤保护作用的比较研究[J].脑与神经疾病杂志,2005,13(3):182-185.
16.甘国胜,段玮,姜立等.异丙酚预处理对全脑缺血再灌注大鼠脑组织S100β和神经元特异性烯醇化酶的影响[J].中国康复医学,2006,10(38):79-81.
17.Tomioka H,Hattori Y,Fukao M,et al.Relaxation in different-sized rat blood vessels mediated by endothelium-derived hyperpolarizing factor:importance of processes mediating precontractions[J].J Vasc Res,1999,36(4):311-320.
18.Koh J Y,Choi D W.Quantitative detemination of glumate mediated cortical neuronal injury in cell culture by lactate dehydrogenase efflux assay[J].J Nuerosci Method,1987,20(1):83-87.
19.Nadashima M,Niwa M,Twai T,et al.Involvement of free radicals in cerebral vascular reperfusion injury evaluated in a transient focal cerebral sichemia model of rat[J].Free Radical Biol Med,1999,125(6):722-729.
20.Lochner A,Marais E,Du Toit E,et al.Nitric oxide triggers classic ischemic preconditioning[J].Ann N Y Acad Sci.2002;962:402-414.
21.Caban A,Oczkowicz G,Abdel-Samad O,et al.Influence of ischemic preconditioning and nitric oxide on microcirculation and the degree of rat liver injury in the model of ischemia and reperfusion[J].Transplant Proc,2006Jan-Feb;38(1):196-8
22.Andelova E,Bartekova M,Pancza D,et al.The role of NO in ischemia/reperfusion injury in isolated rat heart[J].Gen Physiol Biophys.2005 Dec;24(4):411-26.
23. Cohen MV, Yang XM, Downey JM. Nitric oxide is a preconditioning mimetic and cardioprotectant and is the basis of many available infarct-sparing strategies [J]. Cardiovasc Res. 2006 May 1 ;70(2):231-9.
24. Dawn B, Beli R. Role of nitric oxide in myocardial preconditioning[J]. Ann N Y Acad, 2002,962:18-41.
25.Moncayo J, de Freitas GR, Bogousslavsky J,et al. Do transient ischemic attacks have a neuroprotective effect[J]. Nerology, 2000, 54(11):2089-2094.
26. Pabla R, Buda AJ, Flynn DM. Intracoronary nitric oxide improves postischemic coronary blood flow and myocardial contractile function [J]. Am J Physiol, 1995 , 269(3): 1113-1121.
27. Langford EJ, Wainwright RJ, Martin JF. Platelet activation in acute myocardial infarction and unstable angina is inhibited by nitric oxide donors [J]. Arterioscler Thromb Vasc Biol, 1996 ,16(1):51-55.
28. Han J, Kim N, Joo H, et al. ATP-sensitive K(+)channel activationby nitric oxide and protein kinase G in rabbit ventricularmyocytes[J]. Am J Physiol Heart Circ Physiol, 2002, 283(4):1545-1554.
29. Warren JB, Pons F, Brady AJ. Nitric Oxide biology: implication for cardiovascular therapertics[J]. Cardiovasc Res,1994;28(1):25-30
30. Jiang X, Shi E, Nakajima Y, et al. Inducible nitric oxide synthase mediates delayed cardioprotection induced by morphine in vivo: evidence from pharmacologic inhibition and gene-knockout mice[J]. Anesthesiology, 2004, 101 (1):82-88.
31.Shi EY, Jiang XJ, Bai H, et al. Morphine-induced late cardioprotection: potential role of inducible nitric oxide synthase [J]. Zhonghua Yi Xue Za Zhi. 2004 , 84(11):891-895.
32. Jiang X, Shi E, Nakajima Y, et al. COX-2 mediates morphine-induced delayed cardioprotection via an iNOS-dependent mechanism. [J] Life Sci. 2006 , 78(22):2543-2549
33.Joyeux-Faure M, Ramond A, Beguin PC, et al. Early pharmacological preconditioning by erythropoietin mediated by inducible NOS and mitochondrial ATP-dependent potassium channels in the rat heart [J]. Fundam Clin Pharmacol, 2006 , 20(1):51-56.
34. Xie J, Guo Q, Zhu H, et al. Protein kinase C iota protect neural cell against apoptosis induced by amyloid beta-peptide[J]. Brain Res, 2000,82:107-113.
35. Sobrado M, Lopez MG, Carceller F, et al. Combined nimodipine and citicoline reduce infarct size, attenuate apoptosis and increase bcl-2 expression after focal cerebral ischemia. [J] Neuroscience, 2003,118(2):107-113.
36. Fjimura M, Morita-Fujimura Y, Noshita N, et al. The cytosolic antioxidant copper/zinc-superoxide dismutase prevents the early release of mitochondrial cytochrme C in ischemic brain after transient focal cerebral ischemia in mice [J]. J Neurosci, 2000, 20(8):2817-2824.
37. Takel N, Endo Y. Ca~(2+) ionophre-induced apoptosis on cultured embryonic rat cortical neurons[J]. Brain Res, 1994,652(1)65:70.
2.Weih M,Ruscher K.Ischemia tolerance model for research,hope for clinical practice[J].Nervenarzt,2001,72(4):255-260.
3.Bowen KK,Naylor M,Vemuganti R.Prevention of inflammation is a mechanism of preconditioning-induced neuroprotection against focal cerebral schemia[J].Neurochem Int,2006,49(2):127-135.
4.张仲慧,郭子江,尹琳,等.金辉.西乐葆预处理对大鼠脑缺血再灌注损伤ICAM-1表达及白细胞浸润的影响[J].中国民康医学,2004,16(12):721-726.
5.梁庆成,吕海燕,吴云.TNF-α预处理对鼠脑缺血及再灌注过程中ICAM-1诱导作用的研究[J].中国神经精神疾病杂志,2004,30(1):13-16.
6.郝玉曼,罗祖明.秋水仙碱联合环磷酰胺增强大鼠脑缺血耐受的作用及其对热休克蛋白70表达的影响[J].中国神经精神疾病杂志,2004,30(2):147-155.
7.Centeno JM,Orti M,Salom JB,et al.Nitric oxide is involve in anoxic preconditioning neuroprotction in rat hippocampal slices[J].Brain Res,1999;836(1-2):62-69.
8.Gonzalez-Zulueta M,Feldman AB,Klessa LJ,et al.Requirement for nitric oxide activation of p21(ras)/extra cellular regulated kinase in neuronal ischemic preconditioning[J].Proc Acad Sci USA,2000;97(1):436-441.
9.Gidday JM,Shah AR,Maceren RG,et al.Nitric oxide mediates cerebral ischemic tolerance in a neonatal rat model of hypoxic preconditioning[J].J Cereb Blood Flow Metab,1999;19(3):331-340.
10.Enari M,Sakahira H,Yokoyama H,et al.A capase-activated DNase that degrades DNA during apoptosis and its inhibitor ICAD[J].Nature,1998,391(2):43-50.
11.王倩,闵连秋.阿司匹林预处理对大鼠局造性脑缺血的神经保护作用[J].国外医学脑血管疾病分册,2004,12(12):901-903.
12.雒东江,平蕾.环磷腺苷葡胺预处理对大鼠局灶性脑缺血海马iNOS含量的影响.中国现代医学杂志[J].2005,15(15):2281-2284.
13.Davole MA,Fourtounis J,Tam J,et al.Immunohistochemical and biochemical assessment of caspase-3 activation and DNA fragmentation following transient focal ischemia in the rat[J].Neuro Science,2002,11(3):125-36.
14.朱红灿,孙圣刚,李红戈.小剂量3-硝基丙酸预处理对脑缺血沙士鼠海马CAl 区及纹状体神经元的影响[J].郑州大学学报(医学版),2003,38(3):356-360.
15.Wiegand F,Liao W,Busch C,et al.Respiratory chain inhibition induces tolerance to focal cerebral ischemia[J].J Cereb Blood Flow Metab,1999,19(11):1229-1237.
16.Horiguchi T,Kis B,Rajapakse N,et al.Opening of mitochondrial ATP-sensitive potassium channels is a trigger of 3-nitropropionic acid-induced tolerance to transient focal cerebral ischemia in rats[J].Stroke,2003,34(4):1015-1020.
17.胡明,刘昌勤,冯作化.尼莫地平预处理和梗塞后治疗对大鼠脑缺血损伤研究保护作用的比较研究[J].脑与神经疾病杂志.2005,13(3):182-185.
18.Haspolat S,Anlar B,Kose C,et al.Inteukin-lbeta,interleukin-1 receptir antagonist levers in patients with subacute sclerosing panencephalitis and effects of different treatment protocols[J].J Child Neurol,2001.16(6):417-420
19.向强,文亮,解军,等.内毒素预处理对大鼠全脑缺血后海马内生性IL-1R α的影响[J].第三军医大学学报,2005,27(4):320-322.
20.刘永海,高殿帅.沙鼠脑缺血再灌注后海马中c-fos蛋白表达及纳络酮影响[J].中国神经免疫学和神经病学杂志,1999,6(1):12-14.
21.Takemoto,O.Tomimoto,H.and Yanagihara,T..Induction of c-fos and c-jun gene products and heat shock protein after brief and prolonged cerebral ischemia in gerbils[J].Stroke 26(2):1639-1648
22.Kiessling M,Stumn G,Xie Y,et al.Differential transcription and translation of immediate early genes in the gerbil hippocampus after transient global ischemia[J].J Cereb Blood Flow Metab,1993,13(6):914-924
23.Young-Bae KWON,Ⅱ-Suk YANG and Kyung-Sun Kang.Effects of dizocilpine pretreatment on parvalbumin immunoreactivity and los expression after cerebral ischemia in the hippocampus of the Mongolian gerbil[J].J.Vet.Med.Sci,62(2):141-146,2000
24.Fetter,Lopez,E.,Pozas,E.,Ballabriga,et al.Multiple neurotrophic sigals converge in surviving CAl neurons of the gerbil hippocampus following transient forebrain ischemia[J].J.Comp.Neurol,1998,394(4):416-30.
25.Brambrink AM,Koerner IP,Diehl K,et al.The antibioticerythromycin induces tolerance against transient global cerebral ischemia in rats(pharmacologic preconditioning)[J].2006,104(6):1208-1215.
26.金石,牛国忠,许国正.尼莫地平和硫氮卓酮对大鼠脑缺血再灌流期自由基损伤的保护作用研究[J].临床脑电学杂志,1994,3(3):167-169.
27.温宝书,张敏,吕金胜.尼莫地平对老龄大鼠大脑皮层和海马细胞内游离钙浓度的影响[J].中国老年学杂志,1998,4(18):238-239.
28.Rubaj A,Gustaw K,Zgodzinski W,et al.The role of opioid receptors in hypoxic preconditioning against serzures in brain[J].Pharmacol Biochem Behav,2000,67(1):65-70.
29.Lim Y J.Zuo Z.Morphine preconditions Purkinje cells against cell death under in vitro simulated ischemia-reperfusion conditions[J].Anesthesiology,2004,100(3):562-568.
30.Junhui Zhang,Hong Qian,et al.Rapid Hypoxia Preconditiong Protects Cortical Neurons From Gultamate Toxicity Through delta-Opioid Recetor[J].Journal Of The American Heat Association.2006,37(3):1094-1099.
1.Murry CE,Jennings RB,Reimer KA.Preconditioning with ischemia:a delay of lethal cell injury in ischemic myocardium[J].Circulation 1986,74(5):1124-1136.
2.Kitagawa K,Matsumoto M,Oda T,et al.Free radical generation during brief of cerebral ischemia trigger delayed neuronal death[J].Stroke,1990,35(3):551-558.
3.Rejdak R,Rejdak K,Sieklucka-Dziuba M,et al.Brain tolerance and preconditioning[J].Pol J Pharmacol,2001,53(1):73-79.
4.Rubaj A,Gustaw K,Zgodzinski W,et al.The role of opioid receptors in hypoxic preconditioning against serzures in brain[J].Pharmacol Biochem Behav,2000,67(1):65-70.
5.高杉,范丽,董六一,等.黄蜀葵花总黄酮对MCAO大鼠脑细胞凋亡的影响[J].中国药理学通报,2003,19(6):704-707.
6.范丽,袁丽萍,陈志武,等.黄蜀葵花总黄酮药理性预适应对家兔心肌缺血再灌注损伤的保护作用[J].中国药学杂志,2005,40(11):836-839.
7.Longa EZ,Weinstein PR,Carlson S,et al.Reversible middle cerebral artery occlusion without craniectomyin rats[J].Stroke,1989(1),20:80-91.
8.赵菁,徐超,王忠诚.多巴胺D2、D3受体在大鼠暂时性局灶性脑缺血中的作用[J].中华神经外科杂志,2002,18(3):160-164.
9.Kiryushko D,Kofoed T,Skladchikova G,et al.A synthetic peptide ligand of neural cell adhesion molecule(NCAM),C3d,promotes neurito-genesis and synaptogensis and modulates presynaptic function inprimary cultures of rat hippocampal neurons[J].J Biolchem,2003,278(14):12325-12334.
10.Akins PT,Liu PK,Hsu CY.Immediate early gene expression in response to cerebral ischemia[J].Friend or foe Stroke,1996,27(2):1682-1687.
11.Weih M,Ruscher K,et al.Ischemia tolerance model for research,hope for clinical practice[J].Nervenarzt,2001,72(4):255-260.
12.Yi Yang,Ashfaq Shuaib,Qiu Li.Quantification of infarct size on focal cerebral ischemia model of rats using a simple and economical method[J].Journal of Neuroscience Methods,1998,84(2):9-16.
13.Nadashima M,Niwa M,Twai T,et al.Involvement of free radicals in cerebral vascular reperfusion injury evaluated in a transient focal cerebral sichemia model of rat[J].Free Radical Biol Med,1999,25(6):722-729.
14.Moncayo J,de Freitas GR,Bogousslavsky J,et al.Do transient ischemic attacks have a neuroprotective effect[J].Nerology,2000,54(11):2089-2094.
15.胡明,刘昌勤,冯作化.尼莫地平预处理和梗塞后治疗对大鼠脑缺血损伤保护作用的比较研究[J].脑与神经疾病杂志,2005,13(3):182-185.
16.甘国胜,段玮,姜立等.异丙酚预处理对全脑缺血再灌注大鼠脑组织S100β和神经元特异性烯醇化酶的影响[J].中国康复医学,2006,10(38):79-81.
17.Tomioka H,Hattori Y,Fukao M,et al.Relaxation in different-sized rat blood vessels mediated by endothelium-derived hyperpolarizing factor:importance of processes mediating precontractions[J].J Vasc Res,1999,36(4):311-320.
18.Koh J Y,Choi D W.Quantitative detemination of glumate mediated cortical neuronal injury in cell culture by lactate dehydrogenase efflux assay[J].J Nuerosci Method,1987,20(1):83-87.
19.Nadashima M,Niwa M,Twai T,et al.Involvement of free radicals in cerebral vascular reperfusion injury evaluated in a transient focal cerebral sichemia model of rat[J].Free Radical Biol Med,1999,125(6):722-729.
20.Lochner A,Marais E,Du Toit E,et al.Nitric oxide triggers classic ischemic preconditioning[J].Ann N Y Acad Sci.2002;962:402-414.
21.Caban A,Oczkowicz G,Abdel-Samad O,et al.Influence of ischemic preconditioning and nitric oxide on microcirculation and the degree of rat liver injury in the model of ischemia and reperfusion[J].Transplant Proc,2006Jan-Feb;38(1):196-8
22.Andelova E,Bartekova M,Pancza D,et al.The role of NO in ischemia/reperfusion injury in isolated rat heart[J].Gen Physiol Biophys.2005 Dec;24(4):411-26.
23. Cohen MV, Yang XM, Downey JM. Nitric oxide is a preconditioning mimetic and cardioprotectant and is the basis of many available infarct-sparing strategies [J]. Cardiovasc Res. 2006 May 1 ;70(2):231-9.
24. Dawn B, Beli R. Role of nitric oxide in myocardial preconditioning[J]. Ann N Y Acad, 2002,962:18-41.
25.Moncayo J, de Freitas GR, Bogousslavsky J,et al. Do transient ischemic attacks have a neuroprotective effect[J]. Nerology, 2000, 54(11):2089-2094.
26. Pabla R, Buda AJ, Flynn DM. Intracoronary nitric oxide improves postischemic coronary blood flow and myocardial contractile function [J]. Am J Physiol, 1995 , 269(3): 1113-1121.
27. Langford EJ, Wainwright RJ, Martin JF. Platelet activation in acute myocardial infarction and unstable angina is inhibited by nitric oxide donors [J]. Arterioscler Thromb Vasc Biol, 1996 ,16(1):51-55.
28. Han J, Kim N, Joo H, et al. ATP-sensitive K(+)channel activationby nitric oxide and protein kinase G in rabbit ventricularmyocytes[J]. Am J Physiol Heart Circ Physiol, 2002, 283(4):1545-1554.
29. Warren JB, Pons F, Brady AJ. Nitric Oxide biology: implication for cardiovascular therapertics[J]. Cardiovasc Res,1994;28(1):25-30
30. Jiang X, Shi E, Nakajima Y, et al. Inducible nitric oxide synthase mediates delayed cardioprotection induced by morphine in vivo: evidence from pharmacologic inhibition and gene-knockout mice[J]. Anesthesiology, 2004, 101 (1):82-88.
31.Shi EY, Jiang XJ, Bai H, et al. Morphine-induced late cardioprotection: potential role of inducible nitric oxide synthase [J]. Zhonghua Yi Xue Za Zhi. 2004 , 84(11):891-895.
32. Jiang X, Shi E, Nakajima Y, et al. COX-2 mediates morphine-induced delayed cardioprotection via an iNOS-dependent mechanism. [J] Life Sci. 2006 , 78(22):2543-2549
33.Joyeux-Faure M, Ramond A, Beguin PC, et al. Early pharmacological preconditioning by erythropoietin mediated by inducible NOS and mitochondrial ATP-dependent potassium channels in the rat heart [J]. Fundam Clin Pharmacol, 2006 , 20(1):51-56.
34. Xie J, Guo Q, Zhu H, et al. Protein kinase C iota protect neural cell against apoptosis induced by amyloid beta-peptide[J]. Brain Res, 2000,82:107-113.
35. Sobrado M, Lopez MG, Carceller F, et al. Combined nimodipine and citicoline reduce infarct size, attenuate apoptosis and increase bcl-2 expression after focal cerebral ischemia. [J] Neuroscience, 2003,118(2):107-113.
36. Fjimura M, Morita-Fujimura Y, Noshita N, et al. The cytosolic antioxidant copper/zinc-superoxide dismutase prevents the early release of mitochondrial cytochrme C in ischemic brain after transient focal cerebral ischemia in mice [J]. J Neurosci, 2000, 20(8):2817-2824.
37. Takel N, Endo Y. Ca~(2+) ionophre-induced apoptosis on cultured embryonic rat cortical neurons[J]. Brain Res, 1994,652(1)65:70.