缺血缺氧预适应对抗脑缺血缺氧损伤的机制研究进展
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摘要
缺血缺氧预适应现象最初见于心脏,一经发现即引起了学术界的广泛关注,随后研究者分别从不同层面证实了大脑同样具有预适应现象,并进行了大量的研究,成为抗脑缺血缺氧研究的热点。脑缺血缺氧预适应(cerebral ischemia/hypoxia preconditioning,CIP)可以通过多种信号传导途径,减少细胞凋亡,提高机体抗氧化能力,减少氧化损伤,升高低氧诱导因子和热休克蛋白HSP70的生成等,各种机制相互联接,相对独立。
The phenomenona of ischemia/hypoxia preconditioning were first discovered in heart.Numerous studies,carried out at different levels,have confirmed that there are also preconditioning phenomenona in brain,and the phenomenona of ischemia/hypoxia preconditioning in brain have become a hot topic in the field of ischemia and hypoxia.Cerebral ischemia/hypoxia preconditioning(CIP) can decrease cell apoptosis,increase the anti-oxidant ability and decrease oxidant injury,increase the generation of hypoxic inducible factor-1 and heat shock protein 70 through multiple signal transduction pathways.There are interactions among the mechanisms about CIP which are relatively independent.
The phenomenona of ischemia/hypoxia preconditioning were first discovered in heart.Numerous studies,carried out at different levels,have confirmed that there are also preconditioning phenomenona in brain,and the phenomenona of ischemia/hypoxia preconditioning in brain have become a hot topic in the field of ischemia and hypoxia.Cerebral ischemia/hypoxia preconditioning(CIP) can decrease cell apoptosis,increase the anti-oxidant ability and decrease oxidant injury,increase the generation of hypoxic inducible factor-1 and heat shock protein 70 through multiple signal transduction pathways.There are interactions among the mechanisms about CIP which are relatively independent.
引文
1 Liu Yajun,Sercombe Richard,Xie Dongping,et al.Inhibitionof caspase-9 activation and apoptosis is involved in ischemicpreconditioning-induced neuroprotection in rat brain[J].Neurol Res,2007,29(8):855-861.
2 Henrik Hagberg,Carina Mallard,Catherine I.Rousset,et al.Apoptotic mechanisms in the immature brain:involvement ofmitochondria[J].J Child Neurol,2009,24(9):1141-1146.
3 Li Danqing,Bao Yongming,Li Yang,et al.Catalpol modu-lates the expressions of Bcl-2 and Bax and attenuates apop-tosis in gerbils after ischemic injury[J].Brain Res,2006,1115(1):179-185.
4 Rybnikova E,Sitnik N,Gluschenko T,et al.The precondi-tioning modified neuronal expression of apoptosis-relatedproteins of Bcl-2 superfamily following severe hypobarichypoxia in rats[J].Brain Res,2006,1089(1):195-202.
5 Wang Guangsong,Zhou Deshan,Wang Changzheng,et al.Hypoxic preconditioning suppresses groupⅢsecreted phos-pholipase A2-induced apoptosis via JAK2-STAT3 activation incortical neurons[J].J Neurochem,2010,114(4):1039-1048.
6 Racay P,Tatarkova Z,Drgova A,et al.Effect of ischemicpreconditioning on mitochondrial dysfunction and mitochon-drial p53 translocation after transient global cerebral isch-emia in rats[J].Neurochem Res,2007,32(11):1823-1832.
7 Watters O,O′Connor JJ.A role for tumor necrosis factor-αinischemia and ischemic preconditioning[J].J Neuroinflam-mation,2011,8(2):87.
8 Zhang Quanguang,Wang Ruimin,Han Dong,et al.Pecondi-tioning neuroprotection in global cerebral ischemia involvesNMDA receptor-mediated ERK-JNK3 crosstalk[J].Neuro-sci Res,2009,63(3):205-212
9 Wang Ruiming,Zhang Quanguang,Li Jie,et al.The ERK5-MEF2C transcription factor pathway contributes to anti-apoptotic effect of cerebral ischemia preconditioning in thehippocampal CA1 region of rats[J].Brain Res,2009,1255(19):32-41.
10 Du Yang,Li Chong,Hu Wei-wei,et al.Neuroprotection of pre-conditioning against ischemic brain injury in rat hippocampusthrough inhibition of the assembly of GluR6-PSD95-mixedlineage kinase 3 signaling module via nuclear and non-nucle-ar pathways[J].Neuroscience,2009,161(2):370-380.
11李永旺,金海龙,王保国,等.Toll样受体4信号通路在缺氧预处理诱导的大鼠脑缺血耐受中的作用[J].中华医学杂志,2007,87(35):2458-2462.
12 Alkan Tulin,G ren Buleut,Vatansever Ebru,et al.Effects ofhypoxic preconditioning in antioxidant enzyme activities inhypoxic-ischemic brain damage in immature rats[J].TurkNeurosurg,2008,18(2):165-171.
13 Yuan Hengjie,Zhu Xuehui,Luo Qiong,et al.Noninvasivedelayed limb ischemic preconditioning in rats increases an-tioxidant activities in cerebral tissue during severe ischemia-reperfusion injury[J].J Surg Res,2012,174(1):176-183.
14 Racay Peter,Chomova Maria,Tatarkova Zuzana,et al.Isch-emia-induced mitochondrial apoptosis is significantly attenu-ated by ischemic preconditioning[J].Cell Mol Neurobiol,2009,29(6-7):901-908.
15 Sonia C.Correia,Cristina Carvalho,Susana Cardoso,et al.Mitochondrial preconditioning:a potential neuroprotectivestrategy[J].Front Aging Neurosci,2010,2:138.
16 Ulrich Dirnagl,Andreas Meisel.Endogenous neuroprotec-tion:mitochondria as gateways to cerebral preconditioning[J].Neuropharmacology,2008,55(3):334–344.
17 Hansson MJ,Morota S,Teilum M,et al.Increased potassiumconductance of brain mitochondria induces resistance to per-meability transition by enhancing matrix volume[J].J BiolChem,2010,285(1):741-750.
18 Jou Meijie.Pathophysiological and pharmacological implica-tions of mitochondria-targeted reactive oxygen species gen-eration in astrocytes[J].Adv Drug Deliv Rev,2008,60(13-14):1512–1526.
19 Dirnagl Ulrich,Becker Kyra,Meisel Andreas.Precondition-ing and tolerance against cerebral ischaemia:from experi-mental strategies to clinical use[J].Lancet Neurol,2009,8(4):398-412.
20 Simerabet Malika,Robin Emmanuel,Aristi Ines,et al.Pre-conditioning by an in situ administration of hydrogen perox-ide:involvement of reactive oxygen species and mitochondri-al ATP-dependent potassium channel in a cerebral ischemia-reperfusion model[J].Brain Res,2008,1240:177-184.
21 Rehni Ashish.K,Shri Richa,Singh Manjeet.Remote ischae-mic preconditioning and prevention of cerebral injury[J].Indian J Exp Biol,2007,45(3):247-252.
22 Miyawaki Takahiro,Mashiko Toshihiro,Ofengeim Dim-mitry,et al.Ischemic preconditioning blocks BAD translo-cation,Bcl-xL cleavage,and large channel activity in mito-chondria of postischemic hippocampal neurons[J].ProcNatl Acad Sci USA,2008,105(12):4892-4897.
23 Lin HY,Wu CL,Huang CC.The Akt-endothelial nitric oxidesynthase pathway in lipopolysaccharide preconditioning-induced hypoxic-ischemic tolerance in the neonatal rat brain[J].Stroke,2010,41(7):1543-1551.
24 Zhan Lixuan,Wang Tao,Li Wen,et al.Activation of Akt/FoxO signaling pathway contributes to induction of neu-roprotection against transient global cerebral ischemia byhypoxic pre-conditioning in adult rats[J].J Neurochem,2010,114(3):897-908.
25 Wang Ruimin,Zhang Quanguang,Li Jie,et al.The ERK5-MEF2C transcription factor pathway contributes to anti-apoptotic effect of cerebral ischemia preconditioning in thehippocampal CA1 region of rats[J].Brain Res,2009,1255:32-41.
26 Sawe Nik,Steinberg Gary,Zhao Hong.Dual roles of theMAPK/ERK1/2 cell signaling pathway after stroke[J].JNeurosci Res,2008,6(8):1659-1669.
27 Yang Chengwei,Ren Yongxin,Liu Feng,et al.Ischemic pre-conditioning suppresses apoptosis of rabbit spinal neurocytesby inhibiting ASK1-14-3-3 dissociation[J].Neurosci Lett,2008,441(3):267-271.
28 Li Liyuan,Chikezie O.Madu,Andrew Lu,et al.HIF-1αpro-motes a hypoxia-independent cell migration[J].Open BiolJ,2010,3(1):8-14.
29 Hare GM,Tsui AK,McLaren AT,et al.Anemia and cerebraloutcomes:many questions,fewer answers[J].Anesth An-alg,2008,107(4):1356-1370.
30 Peng Zhaoyun,Ren Ping,Kang Zhimin,et al.Up-regulatedHIF-1alpha is involved in the hypoxic tolerance induced byhyperbaric oxygen preconditioning[J].Brain Res,2008,1212:71-78.
31 Christian Grimm,A Wenzel,N Acar,et al.Hypoxic precon-ditioning and erythropoietin protect retinal neurons from de-generation[J].Adv Exp Med Biol,2006,588:119-131.
32 Ara Jahan,Fekete Saskia,Frank Melissa,et al.Hypoxic-preconditioning induces neuroprotection against hypoxia-ischemia in newborn piglet brain[J].Neurobiol Dis,2011,43(2):473-485.
33 Gao CJ,Niu L,Ren PC,et al.Hypoxic preconditioning at-tenuates global cerebral ischemic injury following asphyxialcardiac arrest through regulation of delta opioid receptor sys-tem[J].Neuroscience,2012,202:352-362.
34 Müller BA,Naranjan S Dhalla.Mechanisms of the beneficialactions of ischemic preconditioning on subcellular remodel-ing in ischemic-reperfused heart[J].Curr Cardiol Rev,2010,6(4):255-164.
35蒋淑君,张楠,李俊发.cPKCγ-HSP60信号通路参与小鼠脑低氧预适应[J].中国病理生理杂志,2011,27(6):1066-1070.
36卢娜,李晓娟,李成长,等.低氧预适应对大鼠缺血-再灌注性脑损伤中HSP-70、Survivin蛋白和学习记忆能力的影响[J].南方医科大学学报,2007,27(12):1856-1860.
37 Sun XC,Xian XH,Li WB,et al.Activation of p38 MAPKparticipates in brain ischemic tolerance induced by limbischemic preconditioning by up-regulating HSP70[J].ExpNeurol,2010,224(2):347-355.
38袁恒杰,罗琼,朱学慧,等.无创性延迟肢体预适应对大鼠脑缺血再灌注皮层的保护作用[J].中国临床药理与治疗学,2009,14(2):144-149.
2 Henrik Hagberg,Carina Mallard,Catherine I.Rousset,et al.Apoptotic mechanisms in the immature brain:involvement ofmitochondria[J].J Child Neurol,2009,24(9):1141-1146.
3 Li Danqing,Bao Yongming,Li Yang,et al.Catalpol modu-lates the expressions of Bcl-2 and Bax and attenuates apop-tosis in gerbils after ischemic injury[J].Brain Res,2006,1115(1):179-185.
4 Rybnikova E,Sitnik N,Gluschenko T,et al.The precondi-tioning modified neuronal expression of apoptosis-relatedproteins of Bcl-2 superfamily following severe hypobarichypoxia in rats[J].Brain Res,2006,1089(1):195-202.
5 Wang Guangsong,Zhou Deshan,Wang Changzheng,et al.Hypoxic preconditioning suppresses groupⅢsecreted phos-pholipase A2-induced apoptosis via JAK2-STAT3 activation incortical neurons[J].J Neurochem,2010,114(4):1039-1048.
6 Racay P,Tatarkova Z,Drgova A,et al.Effect of ischemicpreconditioning on mitochondrial dysfunction and mitochon-drial p53 translocation after transient global cerebral isch-emia in rats[J].Neurochem Res,2007,32(11):1823-1832.
7 Watters O,O′Connor JJ.A role for tumor necrosis factor-αinischemia and ischemic preconditioning[J].J Neuroinflam-mation,2011,8(2):87.
8 Zhang Quanguang,Wang Ruimin,Han Dong,et al.Pecondi-tioning neuroprotection in global cerebral ischemia involvesNMDA receptor-mediated ERK-JNK3 crosstalk[J].Neuro-sci Res,2009,63(3):205-212
9 Wang Ruiming,Zhang Quanguang,Li Jie,et al.The ERK5-MEF2C transcription factor pathway contributes to anti-apoptotic effect of cerebral ischemia preconditioning in thehippocampal CA1 region of rats[J].Brain Res,2009,1255(19):32-41.
10 Du Yang,Li Chong,Hu Wei-wei,et al.Neuroprotection of pre-conditioning against ischemic brain injury in rat hippocampusthrough inhibition of the assembly of GluR6-PSD95-mixedlineage kinase 3 signaling module via nuclear and non-nucle-ar pathways[J].Neuroscience,2009,161(2):370-380.
11李永旺,金海龙,王保国,等.Toll样受体4信号通路在缺氧预处理诱导的大鼠脑缺血耐受中的作用[J].中华医学杂志,2007,87(35):2458-2462.
12 Alkan Tulin,G ren Buleut,Vatansever Ebru,et al.Effects ofhypoxic preconditioning in antioxidant enzyme activities inhypoxic-ischemic brain damage in immature rats[J].TurkNeurosurg,2008,18(2):165-171.
13 Yuan Hengjie,Zhu Xuehui,Luo Qiong,et al.Noninvasivedelayed limb ischemic preconditioning in rats increases an-tioxidant activities in cerebral tissue during severe ischemia-reperfusion injury[J].J Surg Res,2012,174(1):176-183.
14 Racay Peter,Chomova Maria,Tatarkova Zuzana,et al.Isch-emia-induced mitochondrial apoptosis is significantly attenu-ated by ischemic preconditioning[J].Cell Mol Neurobiol,2009,29(6-7):901-908.
15 Sonia C.Correia,Cristina Carvalho,Susana Cardoso,et al.Mitochondrial preconditioning:a potential neuroprotectivestrategy[J].Front Aging Neurosci,2010,2:138.
16 Ulrich Dirnagl,Andreas Meisel.Endogenous neuroprotec-tion:mitochondria as gateways to cerebral preconditioning[J].Neuropharmacology,2008,55(3):334–344.
17 Hansson MJ,Morota S,Teilum M,et al.Increased potassiumconductance of brain mitochondria induces resistance to per-meability transition by enhancing matrix volume[J].J BiolChem,2010,285(1):741-750.
18 Jou Meijie.Pathophysiological and pharmacological implica-tions of mitochondria-targeted reactive oxygen species gen-eration in astrocytes[J].Adv Drug Deliv Rev,2008,60(13-14):1512–1526.
19 Dirnagl Ulrich,Becker Kyra,Meisel Andreas.Precondition-ing and tolerance against cerebral ischaemia:from experi-mental strategies to clinical use[J].Lancet Neurol,2009,8(4):398-412.
20 Simerabet Malika,Robin Emmanuel,Aristi Ines,et al.Pre-conditioning by an in situ administration of hydrogen perox-ide:involvement of reactive oxygen species and mitochondri-al ATP-dependent potassium channel in a cerebral ischemia-reperfusion model[J].Brain Res,2008,1240:177-184.
21 Rehni Ashish.K,Shri Richa,Singh Manjeet.Remote ischae-mic preconditioning and prevention of cerebral injury[J].Indian J Exp Biol,2007,45(3):247-252.
22 Miyawaki Takahiro,Mashiko Toshihiro,Ofengeim Dim-mitry,et al.Ischemic preconditioning blocks BAD translo-cation,Bcl-xL cleavage,and large channel activity in mito-chondria of postischemic hippocampal neurons[J].ProcNatl Acad Sci USA,2008,105(12):4892-4897.
23 Lin HY,Wu CL,Huang CC.The Akt-endothelial nitric oxidesynthase pathway in lipopolysaccharide preconditioning-induced hypoxic-ischemic tolerance in the neonatal rat brain[J].Stroke,2010,41(7):1543-1551.
24 Zhan Lixuan,Wang Tao,Li Wen,et al.Activation of Akt/FoxO signaling pathway contributes to induction of neu-roprotection against transient global cerebral ischemia byhypoxic pre-conditioning in adult rats[J].J Neurochem,2010,114(3):897-908.
25 Wang Ruimin,Zhang Quanguang,Li Jie,et al.The ERK5-MEF2C transcription factor pathway contributes to anti-apoptotic effect of cerebral ischemia preconditioning in thehippocampal CA1 region of rats[J].Brain Res,2009,1255:32-41.
26 Sawe Nik,Steinberg Gary,Zhao Hong.Dual roles of theMAPK/ERK1/2 cell signaling pathway after stroke[J].JNeurosci Res,2008,6(8):1659-1669.
27 Yang Chengwei,Ren Yongxin,Liu Feng,et al.Ischemic pre-conditioning suppresses apoptosis of rabbit spinal neurocytesby inhibiting ASK1-14-3-3 dissociation[J].Neurosci Lett,2008,441(3):267-271.
28 Li Liyuan,Chikezie O.Madu,Andrew Lu,et al.HIF-1αpro-motes a hypoxia-independent cell migration[J].Open BiolJ,2010,3(1):8-14.
29 Hare GM,Tsui AK,McLaren AT,et al.Anemia and cerebraloutcomes:many questions,fewer answers[J].Anesth An-alg,2008,107(4):1356-1370.
30 Peng Zhaoyun,Ren Ping,Kang Zhimin,et al.Up-regulatedHIF-1alpha is involved in the hypoxic tolerance induced byhyperbaric oxygen preconditioning[J].Brain Res,2008,1212:71-78.
31 Christian Grimm,A Wenzel,N Acar,et al.Hypoxic precon-ditioning and erythropoietin protect retinal neurons from de-generation[J].Adv Exp Med Biol,2006,588:119-131.
32 Ara Jahan,Fekete Saskia,Frank Melissa,et al.Hypoxic-preconditioning induces neuroprotection against hypoxia-ischemia in newborn piglet brain[J].Neurobiol Dis,2011,43(2):473-485.
33 Gao CJ,Niu L,Ren PC,et al.Hypoxic preconditioning at-tenuates global cerebral ischemic injury following asphyxialcardiac arrest through regulation of delta opioid receptor sys-tem[J].Neuroscience,2012,202:352-362.
34 Müller BA,Naranjan S Dhalla.Mechanisms of the beneficialactions of ischemic preconditioning on subcellular remodel-ing in ischemic-reperfused heart[J].Curr Cardiol Rev,2010,6(4):255-164.
35蒋淑君,张楠,李俊发.cPKCγ-HSP60信号通路参与小鼠脑低氧预适应[J].中国病理生理杂志,2011,27(6):1066-1070.
36卢娜,李晓娟,李成长,等.低氧预适应对大鼠缺血-再灌注性脑损伤中HSP-70、Survivin蛋白和学习记忆能力的影响[J].南方医科大学学报,2007,27(12):1856-1860.
37 Sun XC,Xian XH,Li WB,et al.Activation of p38 MAPKparticipates in brain ischemic tolerance induced by limbischemic preconditioning by up-regulating HSP70[J].ExpNeurol,2010,224(2):347-355.
38袁恒杰,罗琼,朱学慧,等.无创性延迟肢体预适应对大鼠脑缺血再灌注皮层的保护作用[J].中国临床药理与治疗学,2009,14(2):144-149.