线粒体K_（ATP）通道介导七氟醚对局灶性脑缺血再灌注损害的保护作用
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摘要
目的1990年Kitagawa首先报道了脑缺血预适应(IPC)现象,随后的研究发现药物预处理、缺血后处理、药物后处理均可模拟IPC。七氟醚作为一种临床常用的吸入麻醉药,具有麻醉诱导及苏醒迅速、麻醉状态平稳、心律失常和心血管抑制发生率低等优点,且能增加脑血流,保留中枢自主调节,对颅内压影响小。在离体培养细胞、脑片及心肌保护中,均有研究表明七氟醚预处理及后处理具有器官保护作用。线粒体是介导脑缺血再灌注后神经细胞损伤的重要细胞器,线粒体ATP敏感性钾通道(mitoK_(ATP))是预处理细胞保护的作用靶点,已证实多种吸入麻醉药对脑的保护作用与mitoK_(ATP)的开放有关。本实验通过TTC染色测定大脑梗死面积、病理切片HE染色、免疫组化分析、神经功能损害评分检测1.0MAC七氟醚预处理及后处理对大鼠局灶性脑缺血再灌注损伤的作用,并通过应用mitoK_(ATP)通道特异性阻断剂5—羟葵酸(5—HD),研究七氟醚预处理及后处理中激活mitoK_(ATP)通道产生脑保护的机制。
方法雄性SD大鼠56只,随机分为假手术组、缺血再灌注组、七氟醚预处理组、七氟醚后处理组、5-HD组、5-HD干预七氟醚预处理组、5-HD干预七氟醚后处理组(n=8)。采用大脑中动脉线栓法阻断前脑血供2 h、再灌注24 h制备大鼠局灶性脑缺血再灌注(middlecerebral artery occlusion,MCAO)模型。七氟醚处理组于缺血前1h或恢复再灌注后立即经半密闭的吸入箱吸入七氟醚(呼吸末浓度维持2.4%),持续30min。5-HD干预组于缺血前或七氟醚预处理前经尾静脉注射mitoK_(ATP)通道阻断剂5-HD。再灌注24h后用Zea Longa评分法进行神经功能缺陷评分,TTC染色法测大鼠脑梗死体积,免疫组化法测定大脑皮质bcl-2和bax蛋白表达。
结果七氟醚预处理组和后处理组与对照组相比,脑梗死体积减少(P＜0.05),神经功能缺陷评分降低(P＜0.05)。5-HD消除了七氟醚的保护作用(P＜0.05),但5-HD组与对照组相比神经功能缺陷评分和脑梗死体积没有差别(P＞0.05)。七氟醚预处理组及后处理组与行MCAO它组相比,bcl-2呈强表达,bax表达不明显。
结论七氟醚预处理及后处理对局灶性脑缺血再灌注损伤均有一定程度的保护作用,且其保护作用与mitoK_(ATP)通道的激活有关,并可能是通过调控凋亡相关基因bcl-2和bax的表达来实现的。
Objective In 1990 Kitagawa discovered the phenomenon of cerebral "ischemic preconditioning(IPC)." Since then ischemic postconditioning,pharmacological preconditioning and pharmacological postconditioning have been shown to mimic the most potent protective mechanism of IPC.Sevoflurane is a commonly used volatile anesthetics. Because of its low blood gas partition coefficients,induction and emergence from sevoflurane anesthesia is rapid.Sevoflurane has little influence on cardiovascular system and the incidence of arrhythmia and hypotension is low.In addition,sevoflurane in the canine model has no effect on intracranial pressure and the autonomic regulation of the central nervous system is well kept.The protective effect of sevoflurane preconditioning and postconditioning on oxygen-glucose deprivation injury in rat hippocampal slices and myocardial ischemia is generally acknowledged.Mitochondria is an important organelle that mediates cerebral ischemia-reperfusion injury,and mitochondrial ATP-sensitive-potassium channels(mitoK_(ATP))have a critical role in pharmacological preconditioning,including many volatile anesthetics. We investigated the relationship between the protective effect of sevoflurane preconditioning and postconditioning against focal cerebral ischemia-reperfusion injury and the roles of mitochondrial ATP-sensitive-potassium channels(mitoK_(ATP)).
Methods Fifty-six male SD rats weighting 250～280g were randomly allocated into seven groups(n=8).Rats were subjected to 2 hours of middle cerebral artery occlusion(MCAO)followed by 24 hours of reperfusion.The following protocols were used:1)preconditioning (S-Pre,achieved by 2.4%sevoflurane(1MAC)inhalation for 30min before MCAO);2)postconditoning(S-Post,2.4%sevoflurane given for 30min at the beginning of reperfusion).Protocols 1-2 were repeated in the presence of 5-hydroxydecanoate(5-HD),a specific mK_(ATP)-channel-blocker(S-Pre+5-HD,S-Post+5-HD).Eight rats served as sham operation group(Sham),untreated controls(CON)or received 5-HD alone(5-HD).Neurological deficit of the rats was assessed by Zea Longa's scoring system,infarct size was determined by TTC staining, and the expression of bcl-2 and bax in the frontal lobe of cerebral cortex was evaluated by immunohistochernistry.
Results Both S-Pre and S-Post reduced infarct size and neurologic deficit compared with CON.5-HD diminished the protection in all two sevoflurane treated groups,but given alone had no effect on infarct size and neurologic deficit.Sevoflurane preconditioning and postconditioning induce the expression of bcl-2 and relatively inhibit the expression of bax.
Conclusion Sevoflurane preconditioning and postconditioning protects against cerebral ischemia-reperfusion injury by regulating the expression of bcl-2 and bax protein,and is mediated,at least in part,by mitoK_(ATP)-channels.
方法雄性SD大鼠56只,随机分为假手术组、缺血再灌注组、七氟醚预处理组、七氟醚后处理组、5-HD组、5-HD干预七氟醚预处理组、5-HD干预七氟醚后处理组(n=8)。采用大脑中动脉线栓法阻断前脑血供2 h、再灌注24 h制备大鼠局灶性脑缺血再灌注(middlecerebral artery occlusion,MCAO)模型。七氟醚处理组于缺血前1h或恢复再灌注后立即经半密闭的吸入箱吸入七氟醚(呼吸末浓度维持2.4%),持续30min。5-HD干预组于缺血前或七氟醚预处理前经尾静脉注射mitoK_(ATP)通道阻断剂5-HD。再灌注24h后用Zea Longa评分法进行神经功能缺陷评分,TTC染色法测大鼠脑梗死体积,免疫组化法测定大脑皮质bcl-2和bax蛋白表达。
结果七氟醚预处理组和后处理组与对照组相比,脑梗死体积减少(P＜0.05),神经功能缺陷评分降低(P＜0.05)。5-HD消除了七氟醚的保护作用(P＜0.05),但5-HD组与对照组相比神经功能缺陷评分和脑梗死体积没有差别(P＞0.05)。七氟醚预处理组及后处理组与行MCAO它组相比,bcl-2呈强表达,bax表达不明显。
结论七氟醚预处理及后处理对局灶性脑缺血再灌注损伤均有一定程度的保护作用,且其保护作用与mitoK_(ATP)通道的激活有关,并可能是通过调控凋亡相关基因bcl-2和bax的表达来实现的。
Objective In 1990 Kitagawa discovered the phenomenon of cerebral "ischemic preconditioning(IPC)." Since then ischemic postconditioning,pharmacological preconditioning and pharmacological postconditioning have been shown to mimic the most potent protective mechanism of IPC.Sevoflurane is a commonly used volatile anesthetics. Because of its low blood gas partition coefficients,induction and emergence from sevoflurane anesthesia is rapid.Sevoflurane has little influence on cardiovascular system and the incidence of arrhythmia and hypotension is low.In addition,sevoflurane in the canine model has no effect on intracranial pressure and the autonomic regulation of the central nervous system is well kept.The protective effect of sevoflurane preconditioning and postconditioning on oxygen-glucose deprivation injury in rat hippocampal slices and myocardial ischemia is generally acknowledged.Mitochondria is an important organelle that mediates cerebral ischemia-reperfusion injury,and mitochondrial ATP-sensitive-potassium channels(mitoK_(ATP))have a critical role in pharmacological preconditioning,including many volatile anesthetics. We investigated the relationship between the protective effect of sevoflurane preconditioning and postconditioning against focal cerebral ischemia-reperfusion injury and the roles of mitochondrial ATP-sensitive-potassium channels(mitoK_(ATP)).
Methods Fifty-six male SD rats weighting 250～280g were randomly allocated into seven groups(n=8).Rats were subjected to 2 hours of middle cerebral artery occlusion(MCAO)followed by 24 hours of reperfusion.The following protocols were used:1)preconditioning (S-Pre,achieved by 2.4%sevoflurane(1MAC)inhalation for 30min before MCAO);2)postconditoning(S-Post,2.4%sevoflurane given for 30min at the beginning of reperfusion).Protocols 1-2 were repeated in the presence of 5-hydroxydecanoate(5-HD),a specific mK_(ATP)-channel-blocker(S-Pre+5-HD,S-Post+5-HD).Eight rats served as sham operation group(Sham),untreated controls(CON)or received 5-HD alone(5-HD).Neurological deficit of the rats was assessed by Zea Longa's scoring system,infarct size was determined by TTC staining, and the expression of bcl-2 and bax in the frontal lobe of cerebral cortex was evaluated by immunohistochernistry.
Results Both S-Pre and S-Post reduced infarct size and neurologic deficit compared with CON.5-HD diminished the protection in all two sevoflurane treated groups,but given alone had no effect on infarct size and neurologic deficit.Sevoflurane preconditioning and postconditioning induce the expression of bcl-2 and relatively inhibit the expression of bax.
Conclusion Sevoflurane preconditioning and postconditioning protects against cerebral ischemia-reperfusion injury by regulating the expression of bcl-2 and bax protein,and is mediated,at least in part,by mitoK_(ATP)-channels.
引文
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[9] Callaway CW, Tadler SC, Katz LM, et al.: Feasibility of external cranial cooling during out-of-hospital cardiac arrest. Resuscitation: 2002, 52:159-165.
[10]Hachimi-Idrissi S, Corne L, Ebinger G, et al.: Mild hypothermia induced by a helmet device: a clinical feasibility study. Resuscitation 2001, 51:275-281.
[11] Bernard SA, Gray TW, Buist MD, Jones BM, Silvester W, Gutteridge G, Smith K: Treatment of comatose survivors of out-of-hospital cardiac arrest with induced hypothermia. N Engl J Med 2002; 346:557-563.
[12] The Hypothennia after Cardiac Arrest Study Group: Mild therapeutic hypothermia to improve the neurologic outcome after cardiac arrest. N Engl J Med 2002; 346:549-556.
[13]Holzer M, Behringer W: Therapeutic hypothermia after cardiac arrest. Current Opinion in Anaesthesiology. 2005,18(2):163-168
[14] Fisher M, Dalton D: New Research in the Field of Stroke: Therapeutic Hypothermia after Cardiac Arrest. Stroke. 2003, 34(4) ;1051-1053
[15]Clifton GL, Miller ER, Choi SC, et al.: Lack of effect of induction of hypothermia after acute brain injury. N Engl J Med 2001, 344:556-563.
[16]Oddo M, Schaller M-D, Feihl F, et al: From evidence to clinical practice :Effective implementation of therapeutic hypothermia to improve patient outcome after cardiac arrest. Crit Care Med 2006; 34:1865-1873
[17] Sterz F, Holzer M, et al: Hypothermia after cardiac arrest: a treatment that works. Current Opinion in Critical Care. 2003, 9(3):205-210
[18]Rajek A, Greif R, Sessler DI, et al.: Core cooling by central venous infusion of ice-cold (4 degrees C and 20 degrees C) fluid: isolation of core and peripheral thermal compartments. Anesthesiology 2000,93:629-637.
[19]Bernard S, Buist M, Monteiro O, et al.: Induced hypothermia using large volume, ice-cold intravenous fluid in comatose survivors of out-of-hospital cardiac arrest: a preliminary report. Resuscitation 2003, 56:9-13.
[20] Safar P, Behringer W. Cerebral resuscitation from cardiac arrest. In: A textbook of neurointensive care. Layon AJ, Gabrielli A, Friedman WA, editors. Philadelphia, WB Saunders; in press.
[21]Battin MR, Penrice J, Gunn TR, Gunn AJ: Treatment of term infants with head cooling and mild systemic hypothermia (35.0[degrees]C and 34.5[degrees]C) after perinatal asphyxia. Pediatrics 2003; 111:244-251.
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[24]Negovsky VA: Postresuscitation disease. Crit Care Med 1988; 16:942-946.
[25]Broccard A: Therapeutic hypothermia for anoxic brain injury following cardiac arrest: A "cool" transition toward cardiopulmonary cerebral resuscitation. Critical Care Medicine. 2006, 34(7): 2008-2009
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[1] Morris, Marilyn C: Temperature regulation after cardiac arrest[horizontal ellipsis] Timing is everything! Critical Care Medicine. 2003, 31(2) :654-655
[2] Nozari A, Safar P: Mild hypothermia during prolonged cardiopulmonary cerebral resuscitation increases conscious survival in dogs. Critical Care Medicine. 2004, 32(10):2110-2116
[3] Safar P, Kochanek P: Therapeutic hypothermia after cardiac arrest. N Engl J Med 2002, 346:612-613.
[4] Karibe H, Sato K, Shimizu H, Tominaga T, Koshu K, Yoshimoto T: Intraoperative mild hypothermia ameliorates postoperative cerebral blood flow impairment in patients with aneurismal subarachnoidal hemorrhage. Neurosurgery 2000; 47:594-601.
[5] Eisenburger P, Sterz F, Holzer M, et al.: Therapeutic hypothermia after cardiac arrest. Curr Opin Crit Care 2001, 7:184-188.
[6] Nagao K, Hayashi N, Kanmatsuse K, et al.: Cardiopulmonary cerebral resuscitation using emergency cardiopulmonary bypass, coronary reperfusion therapy and mild hypothermia in patients with cardiac arrest outside the hospital. J Am Coll Cardiol 2000,36:776-783.
[7] Nozari A, Safar P: Mild hypothermia during prolonged cardiopulmonary cerebral resuscitation increases conscious survival in dogs. Critical Care Medicine. 2004, 32(10):2110-2116
[8] Yang X, Hachimi I: Effect of resuscitative mild hypothermia and oxygen concentration on the survival time during lethal uncontrolled haemorrhagic shock in mechanically ventilated rats. European Journal of Emergency Medicine. 2004, 11(4):210-216
[9] Callaway CW, Tadler SC, Katz LM, et al.: Feasibility of external cranial cooling during out-of-hospital cardiac arrest. Resuscitation: 2002, 52:159-165.
[10]Hachimi-Idrissi S, Corne L, Ebinger G, et al.: Mild hypothermia induced by a helmet device: a clinical feasibility study. Resuscitation 2001, 51:275-281.
[11] Bernard SA, Gray TW, Buist MD, Jones BM, Silvester W, Gutteridge G, Smith K: Treatment of comatose survivors of out-of-hospital cardiac arrest with induced hypothermia. N Engl J Med 2002; 346:557-563.
[12] The Hypothennia after Cardiac Arrest Study Group: Mild therapeutic hypothermia to improve the neurologic outcome after cardiac arrest. N Engl J Med 2002; 346:549-556.
[13]Holzer M, Behringer W: Therapeutic hypothermia after cardiac arrest. Current Opinion in Anaesthesiology. 2005,18(2):163-168
[14] Fisher M, Dalton D: New Research in the Field of Stroke: Therapeutic Hypothermia after Cardiac Arrest. Stroke. 2003, 34(4) ;1051-1053
[15]Clifton GL, Miller ER, Choi SC, et al.: Lack of effect of induction of hypothermia after acute brain injury. N Engl J Med 2001, 344:556-563.
[16]Oddo M, Schaller M-D, Feihl F, et al: From evidence to clinical practice :Effective implementation of therapeutic hypothermia to improve patient outcome after cardiac arrest. Crit Care Med 2006; 34:1865-1873
[17] Sterz F, Holzer M, et al: Hypothermia after cardiac arrest: a treatment that works. Current Opinion in Critical Care. 2003, 9(3):205-210
[18]Rajek A, Greif R, Sessler DI, et al.: Core cooling by central venous infusion of ice-cold (4 degrees C and 20 degrees C) fluid: isolation of core and peripheral thermal compartments. Anesthesiology 2000,93:629-637.
[19]Bernard S, Buist M, Monteiro O, et al.: Induced hypothermia using large volume, ice-cold intravenous fluid in comatose survivors of out-of-hospital cardiac arrest: a preliminary report. Resuscitation 2003, 56:9-13.
[20] Safar P, Behringer W. Cerebral resuscitation from cardiac arrest. In: A textbook of neurointensive care. Layon AJ, Gabrielli A, Friedman WA, editors. Philadelphia, WB Saunders; in press.
[21]Battin MR, Penrice J, Gunn TR, Gunn AJ: Treatment of term infants with head cooling and mild systemic hypothermia (35.0[degrees]C and 34.5[degrees]C) after perinatal asphyxia. Pediatrics 2003; 111:244-251.
[22]Siesjo BK: Pathophysiology and treatment of focal cerebral ischemia, II: mechanisms of damage and treatment. J Neurosurg 1992; 77:337-354.
[23]Lipton SA, Rosenberg PA: Excitatory amino acids as final common pathway for neurological disorders. N Engl J Med 1994; 330:613-622.
[24]Negovsky VA: Postresuscitation disease. Crit Care Med 1988; 16:942-946.
[25]Broccard A: Therapeutic hypothermia for anoxic brain injury following cardiac arrest: A "cool" transition toward cardiopulmonary cerebral resuscitation. Critical Care Medicine. 2006, 34(7): 2008-2009
[26]Kentner R, Rollwagen FM, Prueckner S, Behringer W, Wu X, Stezoski J, et al.: Effects of mild hypothermia on survival and serum cytokines in uncontrolled hemorrhagic shock in rats. Shock 2002; 17:521-526.
[27] Lin X, Zhi D, Zhang S: Inhibiting effect of moderate hypothermia on cell apoptosis after diffuse brain injury in rats. Chin J Traumatol 2001; 4:14-19.
[28]Nolan JP, Morley PT, Vanden Hoek TL, et al.: Therapeutic hypothermia after cardiac arrest. An advisory statement by the Advanced Life Support Task Force of the International Liaison Committee on Resuscitation. Resuscitation 2003;