脑缺血预处理和脑缺血耐受机制的研究进展

摘要/Abstract

摘要： 脑缺血预处理（cerebral ischemic preconditioning，CIP）是指短暂的、亚致死性的缺血诱导脑组织产生内源性保护机制，可以提高脑组织对缺血的耐受性。这种脑缺血预处理诱导脑组织对后续致死性脑缺血产生迟发性的抵抗能力的现象称为脑缺血耐受（cerebral ischemic tolerance，CIT）。CIP及CIT潜在的神经保护机制涉及NO及NO相关信号通路、兴奋性或抑制性神经递质、炎症因子、腺苷、细胞能量代谢和线粒体、自噬溶酶体的激活、抑制细胞死亡与凋亡、激活DNA修复和自我修复/重塑机制、血管重塑和保护血脑屏障等。通过对CIP及CIT内源性神经保护的机制的深入研究有助于为临床防治缺血缺氧脑病提供新策略。

关键词: 脑缺血预处理, 脑缺血耐受, 一氧化氮, 兴奋性氨基酸, 炎症因子

Abstract: Cerebral ischemic preconditioning (CIP) demonstrates an endogenous protective mechanism against ischemic injury with a brief sublethal ischemia increases the tolerance of the brain tissue to subsequent ischemia. Cerebral ischemic tolerance refers to a phenomenon of central nervous system adaptation to any subsequent ischemia by CIP. Establishing such a tolerance involved multiple mechanisms: the NO and NO related signaling pathways, excitatory and inhibitory neurotransmitter, inflammation factors, adenosine, cell energy metabolism and mitochondrial, autophagy-lysosome activation, inhibition of cell death and activate DNA repair and self-repair/remodeling mechanism, vascular remodeling and protect the blood brain barrier, etc. A better understanding of the endogenous neuroprotective mechanisms by which CIP and IP protects against cerebral ischemic insults could help us develop new therapeutic and preventive strategies for ischemia anoxic encephalopathy.

Key words: cerebral ischemic preconditioning, cerebral ischemic tolerance, nitric oxide, excitatory amino acid, inflammatory cytokines

王小琴，邹玉安，郭春燕. 脑缺血预处理和脑缺血耐受机制的研究进展[J]. 神经药理学报, 2015, 5(2): 30-37.

WANG Xiao-qin, ZOU Yu-an, GUO Chun-yan. Research Progress of the Mechanism of Cerebral Ischemic Preconditionining and Cerebral Ischemic Tolerance[J]. Acta Neuropharmacologica, 2015, 5(2): 30-37.

参考文献

[1]Kitagawa K, Matsumoto M, Tagaya M, et al. Ischemic tolerance phenomenon found in the brain [J].Brain Res,1990, 528 (1):21-24.

[2]Noble R. The development of resistance by rats and guinea pigs to amount of trauma usually fatal[J]．Am J Physiol, 1943, 138(2): 346-356.

[3]Aaron Janoff. Alterations in lysosomes (intracellular enzymes) during shock; effects of preconditioning (tolerance) and protective drugs[J].Int Anesthesiol Clin, 1964, 2(2): 251-269.

[4]Reimer K A, Murry C E, Yamasawa I, et al. Four brief periods of myocardial ischemia cause no cumulative ATP loss or necrosis[J].AM J Physiol, 1986, 251(6): 1306-1315.

[5]Murrry C E, Jennings R B, Teachings R B, et al. Preconditioning with ischemia: a delay of lethal cell injury in ischemic myocardium [J].Circulation, 1986, 74 (5):1124 -1136.

[6]Karin Przyklenk, Bauer Barbara, Michel Ovize, et al. Regional ischemic preconditioning protects remote virgin myocardium from subsequence sustained coronary occlusion[J]. Circulation, 1993, 87(3):893-899.

[7] Ulrich Dirnagl, Roger P Simon, John M Hallenbeck. Ischemic tolerance and endogenous neuroprotection[J]. Trends Neurosci, 2003, 26(5): 248–254.

[8] CHEN Xing-miao, CHEN Han-sen, XU Ming-jing, et al. Targeting reactive nitrogen species: a promising therapeutic strategy for cerebral ischemia-reperfusion

injury [J].Acta Pharmacologica Sinica, 2013, 34: 67-77.

[9] Malinski T, F Bailey, Z G Zhang, et al. Nitric oxide measured by a porphyrinic microsensor in rat brain after transient middlecerebral artery occlusion[J].J Cereb Blood Flow Metab, 1993, 13(3):355-358.

[10]张超，季晖，赵倩，等.一氧化氮在脑缺血预处理中的作用及其机制[J].药学进展，2011，35(10): 433-438.

[11]Zhang Quan-guang, Wang Rui-min, Han Dong, et al. Preconditioning neuroprotection in global cerebral ischemia involves NMDA receptor-mediated ERK-JNK3 crosstalk[J].Neurosci Res, 2009, 63(3): 205-212.

[12]Zhang Yun-hong, Tae S Park, Jeffrey M Gidday. Hypoxic preconditioning protects human brain endothelium from ischemic apoptosis by Akt-dependent survivin activation[J].Am J Physiol Heart Circ Physiol, 2007, 292(6): H2573-H2581.

[13]Mohammad Iqbal Hossain Buhiyan, Seo Yun Jung, Hyoung Ja Kim, et al. Major role of the PI3K/Akt pathway in ischemic tolerance induced by sublethal oxygen-glucose deprivation in cortical neurons in vitro[J].Arch Pharm Res, 2011, 34(6):1023-1034.

[14]Hao Yu-man, Luo Zu-ming, Zhou Dong, et al. Dual role of NF-κB and its target gene iNOS in cerebral ischemic tolerance induced by focal ischemic preconditioning[J].Zhonghua Yi Xue Za Zhi, 2010, 90(39):2787-2791.

[15]Hao Y M, Luo Z M, et al. Dual role of NF-κB and its target gene iNOS in cerebral ischemic tolerance induced by focal ischemic preconditioning[J].Zhonghua Yi Xue Za Zhi,，2010, Oct 26;90(39):2787-2791.

[16]Bruno B Queliconi, Andrew P Wojtovich, Sergiy M Nadtochiy, et al. Redox regulation of the mitochondrial K+(ATP) channel in cardioprotection[J]. Biochim Biophys Acta, 2010, 1813(7):1309-1315.

[17]Prime T A, Blaikie F H, Evans C, et al. A mitochondriatargeted S-nitrosothiol modulates respiration, nitrosates thiols, and protects against ischemia-reperfusion injury[J].Proc Natl Acad Sci USA, 2009, 106 (26):10764-10769.

[18]Sun Hong-shuo, Feng Zhong-ping. Neuroprotective role of ATP-sensitive potassium channel s in cerebral ischemia[J].Acta Pharmacol Sin, 2013, 34(1):24-32.

[19] Hiba A Awooda. Down-regulation of Rho-kinases induce tolerance in Ischemic preconditioning model after transient cerebral ischemia/reperfusion in rats[J]. Health, 2013, 5(7E): 7-13.

[20]Anthony Lau, Michael Tymianski. Glutamate receptors, neurotoxicity and neurodegeneration [J].Pflugers Archv, 2010, 460(2): 525-542.

[21] Ana Cristina do Nascimento Pinheiro, Adriano Jesus da Silva, Marco Antonio M Prado, et al. Phoneutria spider toxins block ischemia-induced glutamate release,neuronal death and loss of neurotransmission in hippocampus[J].Hippocampus, 2009, 19(11):1123-1129.

[22]路娇扬, 唐雅玲. 海马缺血损伤机制的研究进展［J］.中国动脉硬化杂志, 2014, 22(5): 529-534.

[23]Pirusha Ketheeswaranathan, Neil A Turner, Emma J Spary, et al. Changes in glutamate transporter expression in mouse forebrain areas folloing focal ischemia[J].Brain Res, 2011, 1418: 93-103.

[24]Cao Min, Zhang Min, Zhang Lian-wei, et al. Up-regulation of neuronal and astrocytic GLT-1 mRNA in the hippocampal CA1 subfield during the induction of brain ischemic tolerance in rats[J]. Arch Ital Biol, 2013, 151(2):43-53.

[25]Gong Jian-xue, Gong Shu-juan, Zhang Min, et al. Cerebral ischemic preconditioning reduces glutamate excitotoxicity by up-regulating the uptake activity of GLT-1 in rats[J].Amino Acids, 2014, 46(6):1537-1545.

[26] Pradillo J M, Olivia Hurtado, Romera C, et al.TNFR1 mediates increased neuronal membrane EAAT3 expression after in vivo cerebral ischemic preconditioning[J]. Neuroscience, 2006, 138(4):1171-1178.

[27]Bong Geom Jang, Seok joon Won, Jin Hee Kim, et al. EAAC1 gene deletion alters zinc homeostasis and enhances cortical neuronal injury after transient cerebral ischemia in mice[J]. J Trace Elem Med Biol, 2012, 26(2-3):85-88.

[28] Li Liao-liao, Zuo Zhi-yi. Glutamate transporter type 3 knockout reduces brain tlerance to focal brain ischemia in mice[J].J Cereb Blood Flow Metab, 2011, 31(5):1283–1292.

[29]Francesc X Soriano, Sofia Papadia, Frank Hofmann, et al. Preconditioning doses of NMDA promote neuroprotection by enhancing neuronal excitability[J]. J Neurosci, 2006, 26(17):4509- 4518.

[30] Vizi E S, Kisfali M, Lorincz T. Role of nonsynaptic GluN2B-containing NMDA receptors in excitotoxicity: evidence that fluoxetine selectively inhibits these receptors and may have neuroprotective effects[J].Brain Res Bull, 2013, 93:32–38.

[31] Susan L, Stevens BS, Keri B, et al. Reprogramming the response to stroke by preconditioning [J]. Stroke, 2014, 45(8):2527–2531.

doi: 10.1038/nm.2399

[32]Richard Macrez, Carine Ali, Olivier Toutirais, et al. Stroke and the immune system: from pathophysiology to new therapeutic strategies[J].Lancet Neurol. 2011,10: 471–480

[33]Lidia Garcia-Bonilla, Corinne Benakis, Jamie Moore, et al. Immune mechanisms in cerebral ischemic tolerance[J].Front Neurosci, 2014: 44.

[34]Cao Can-xiang, Yang Qing-wu, Lv Feng-lin, et al. Reduced cerebral ischemia-reperfusion injury in Toll-like receptor 4 deficient mice[J].Biochem Biophys Res Commun, 2007, 353(2): 509–514.

[35]Pan L N, Zhu W, Li Y, et al. Astrocytic Toll-like receptor 3 is associated with ischemic preconditioning-induced protection against brain ischemia in rodents[J]. PLoS One, 2014, 9(6):e99526.

[36]Ramendra N Saha, Anamitra Ghosh, Carlos A Palencia, et al. TNF-alpha preconditioning protects neurons via neuron-specific up-regulation of CREB-binding protein[J].J Immunol, 2009, 183(3): 2068-2078.

[37]Orla Watters, John J O'Connor. A role for tumor necrosis factor-α in ischemia and ischemic preconditioning[J].J Neuroinflammation, 2011, 8:87.

[38]宋锡瑞, 李倩, 张予阳. 脑缺血耐受机制及雌激素通过此机制介导的神经保护作用[J].沈阳药科大学学报, 2014, 31(5): 416-422.

[39]吴浩, 甘解华, 郭秒, 等. 脑缺血患者血清中腺苷水平的变化[J].中国脑血管病杂志, 2008, 54: 184-185.

[40]Maslov L N. Trigger mechanism of neuroprotective effect of ischemic preconditioning[J] .Patol Fiziol Eksp Ter, 2011, 2: 47-54.

[41]Hu Sheng, Dong Hai-long, Zhang Hao-peng, et al. Noninvasive limb remote ischemic precon-ditioning contributes neuroprotective effects via activation ofadenosine A1 re- ceptor and redox status after transient focal cerebral ischemia in rats[J].Brain Res, 2012, 1459: 81-90.

[42]Busija, David W, Katakam, et al. Mitochondrial mechanisms in cerebral vascular control: shared signaling pathways with preconditioning[J]. J Vascular Research, 2014, 51(3):175-189.

[43] Giacomo Scornavacca, Raffaella Gesuete, Franca Orsini, et al. Proteomic analysis of mouse brain cortex identifies metabolic down-regulation as a general feature of ischemic pre-conditioning[J].J Neurochem, 2012, 122 (6):1219-1229.

[44]Sheng Rui, Zhang Li-sha, Han Rong, et al. Autophagy activation is associated with neuroprotection in a rat model of focal cerebral ischemic preconditioning [J].Autophagy, 2010, 6(4): 428-494.

[45]Jan Lehotsky, Jozef Burda, Viera Danielisova, et al. Ischemic tolerance: the mechanisms of neuroprotective strategy[J].Anatomical Record, 2009, 292(12): 2002-2012.

[46]张慧, 姜咏梅, 尹琳. PI3K/AKT/GSK-3β信号在脑缺血预处理中的作用及对海马细胞凋亡的影响[J].华中科技大学学报医学版, 2011, 40(4): 408-412.

[47]Liu Yong, Zhu Sui-qiang, Wang Yun-fu, et al. Neuroprotective effect of ischemic preconditioning in focal cerebral infarction:relationship with upregulation of vascular endothelial growth factor[J].Neural Regen Res, 2014, 9(11): 1117-1121.

[48]R Weber, H C Diener, C Weimar. Why do acute ischemic stroke patients with a preceding transient ischemic attack present with less severe strokes? – insights from the german stroke study[J].European Neurology, 2011, 66(5): 265-270.

[49]Dipankar Dutta, Emily Bowen. Four-year follow-up transient ischemic attacks, strokes, and mimics: a retrospective transient ischemic attack clinic cohort study [J].Stroke, 2015, 46(5): 1227-1232.

[50]Susanne W, Barbara G, Verica J, et al. Transient ischemic attacks before ischemic stroke: preconditioning the human brain: A multi-center magnetic resonance imaging study[J].J Vascular Surgery, 2004, 40(1): 202-203.

[51]Yomna Badawi, Ranu Pal, Hui Dong-wei, et al. Ischemic tolerance in an in vivo model of glutamate preconditioning[J].J Neurosci Res,2015,93(4):623-632.

[52]Celso Constantino, Carla Ines Tasca, Carina Rodrigues Boeck, et al. The role of NMDA receptors in the development of brain resistance through Pre-and postonditioning[J].Aging Dis, 2014, 5(6):430-441.

[53]Sebastian Koch, Michael Katsnelson, Dong Chuan-hui, et al. Remote ischemic limb preconditioning after subarachnoid hemorrhage: a phase ib study of safety and feasibility[J]. Stroke, 2011, 42(5):1387-1391.

[54]黄龙飞, 钱贻崧, 关腾, 等. 谷氨酸转运体靶点药物的抗脑缺血作用研究进展[J].中国新药杂志, 2012, 21(4): 390-395.