丙泊酚对脑出血大鼠脑保护作用及其机制的实验研究
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摘要
背景与目的:脑出血(Intracerebral hemorrhage, ICH)是指由血管破裂引起的急性脑实质内出血。脑出血是临床的常见病、多发病,具有起病急、病情危重、死亡率和致残率高的特点,严重威胁了人类的预期寿命和健康。病情的恶化往往与ICH后继发的脑水肿、血肿周围组织能量代谢紊乱及氧自由基的损伤有关。目前脑出血的治疗主要有药物治疗和外科手术治疗等。
丙泊酚(2,6-二异丙基酚)是一种脂溶性的静脉麻醉药,广泛用于临床各科手术麻醉。有研究显示,丙泊酚在体内、体外脑缺血模型中均具有脑保护作用,其脑保护作用可能与丙泊酚的抗氧化性,降低脑水肿以及抑制缺血后的细胞调亡有关。通过对丙泊酚脑保护作用机制及ICH病理生理机制的分析,我们推测丙泊酚可能对ICH损伤也具有一定的脑保护作用。
本研究旨在通过在体动物实验,从神经行为学、神经病理学及神经生物化学三个方面,研究丙泊酚对实验性ICH损伤的保护作用及其可能的相关作用机制。
方法:采用立体定位技术,以左侧尾状核注射Ⅶ型胶原酶0.5 U(1 U·μL ~(-1))诱导大鼠ICH模型。ICH术前10min腹腔注射给予三个不同剂量丙泊酚(分别为15 mg·kg~(-1)、30 mg·kg~(-1)和100 mg·kg~(-1)),观察丙泊酚对大鼠ICH后神经行为学评分、脑含水量(BWC)及脑组织病理形态学改变的影响;同时还观察了丙泊酚对ICH大鼠脑组织超氧化物歧化酶(SOD)活性、丙二醛(MDA)含量、血清乳酸脱氢酶(LDH)和肌酸激酶(CK)水平、脑组织Caspase-3蛋白表达的影响。主要结果与结论:
研究结果表明:
(1)丙泊酚(30 mg·kg~(-1)和100 mg·kg~(-1))可不同程度地缓解ICH后大鼠的神经行为学障碍、降低神经行为学评分、减轻ICH后脑水肿程度。同时,丙泊酚还能减轻大鼠ICH后脑组织的病理形态学损伤,表明丙泊酚对胶原酶诱导的大鼠ICH损伤具有一定的保护作用。
(2)丙泊酚(30 mg·kg~(-1)和100 mg·kg~(-1))可明显增高ICH后大鼠脑组织的SOD活性、降低MDA含量;降低ICH后大鼠血清LDH、CK水平。同时,三个剂量丙泊酚(15,30,100 mg·kg~(-1))可呈剂量依赖性地抑制Caspase-3在ICH大鼠脑组织中的表达。结果提示,丙泊酚可升高脑组织抗氧化酶SOD的活性,使脑组织的抗氧化水平增高,拮抗ICH时产生的氧自由基对细胞的损伤;丙泊酚可抑制脂质过氧化反应的发生,减少ICH损伤对细胞膜结构的破坏,提高脑细胞在脑出血时的存活率;同时抑制ICH诱导的细胞调亡的发生。
综上所述,本研究结果显示:丙泊酚对实验性ICH损伤具有一定的脑保护作用。丙泊酚的脑保护作用可能与其化学结构有关:1)在自由基反应体系中,丙泊酚含有的酚结构可以提供一个氢原子,自身转变成为苯氧基团,其中芳香环的共轭效应可降低苯氧基团活性,抑制脂质过氧化反应的发生;2)丙泊酚还可直接与氧自由基或单态氧反应,生成稳定的2,6-二异丙基苯氧基团,减轻后者引发的脂质过氧化级联反应;3)丙泊酚的脂溶性强,更容易积聚在细胞脂质双分子层上,可进一步提高细胞抗氧化损伤的能力。
Background and Objective: Intracerebral hemorrhage (ICH) indicates an acute extravasation of blood into the brain parenchyma due to vessel rupture. ICH is generally characterized by acute onset, rapid progress, considerable morbidity and mortality. After ICH, except direct tissue destruction of the space-occupying effect of hematoma, the secondary injuries in adjacent tissue including brain edema, abnormal energy metabolism and formation of oxygen free radicals (OFR) are the most important factors that induce the neurological deficits. Until recently, medical and surgical therapies are the main treatments for ICH.
Propofol (2, 6-diisopropyl phenol) is a lipid-soluble intravenous anesthetic, commonly used during operations in various clinical departments and out-patient department. The neuroprotective effect of propofol has been investigated in vivo and in vitro models of cerebral ischemia. It reveals that propofol can protect the brain tissue by exerting antioxidant effects, diminishing brain edema, and inhibiting cell apoptosis. It is strongly suggested that this anesthetic agent may serve as a neuropretective agent to combat ICH.
Although propofol is widely used in clinical anesthesia, it is still uncertain whether it could protect the brain from ICH injury. In this study, the protective effect of propofol against ICH was investigated in rats. Methods: ICH was induced in rats by infusion of collagenase (TypeⅦ) 0.5 U (1 U·μL ~(-1)) into the left caudate nucleus with stereotaxic apparatus. Three doses of propofol (15mg·kg~(-1), 30mg·kg~(-1) and 100mg·kg~(-1)) were given intraperitoneally (ip) 10 min before collagenase infusion, respectively. Effects of propofol on neurological behavioral scores, brain water content (BWC), pathomorphological changes of brain tissue, activity of superoxide dismutase (SOD) and content of malondialdehyde (MDA) in brain tissue, levels of lactate dehydrogenase (LDH) and creatine kinase (CK) in serum, expression level of Caspase-3 were studied.
Results and Conclusion:
(1) In propofol groups (30 mg·kg~(-1) and 100 mg·kg~(-1)), the neurological behavioral score and BWC were significantly lower than those in ICH group. Pathomorphological changes of the brain tissue were relieved to different degrees in propofol groups (30mg·kg~(-1) and 100mg·kg~(-1)).
(2) In propofol groups (30 mg·kg~(-1) and 100mg·kg~(-1)), the content of MDA, LDH and CK were significantly lower than those in ICH group, whereas the activity of SOD was higher than that in ICH group. Meanwhile, propofol (15, 30 and 100 mg·kg~(-1)) inhibited the Caspase-3 expression in a dose-dependent manner.
The study indicated that brain damages caused by ICH in rats can be alleviated by propofol, which mechanism might be attributed to its chemical structure. 1) In free radical reactions, the phenolic group of Propofol can react with OFR to form a phenoxyl group. The conjugation effect might decrease the activity of phenoxyl group, which make it impossible to induce the lipid peroxidation. 2) Propofol can also react with other oxidizing species such as singlet oxygen. 3) Meanwhile, the liposolubility of propofol makes it easy to gather on cell lipid bilayer to increase the antioxidant ability of cells.
丙泊酚(2,6-二异丙基酚)是一种脂溶性的静脉麻醉药,广泛用于临床各科手术麻醉。有研究显示,丙泊酚在体内、体外脑缺血模型中均具有脑保护作用,其脑保护作用可能与丙泊酚的抗氧化性,降低脑水肿以及抑制缺血后的细胞调亡有关。通过对丙泊酚脑保护作用机制及ICH病理生理机制的分析,我们推测丙泊酚可能对ICH损伤也具有一定的脑保护作用。
本研究旨在通过在体动物实验,从神经行为学、神经病理学及神经生物化学三个方面,研究丙泊酚对实验性ICH损伤的保护作用及其可能的相关作用机制。
方法:采用立体定位技术,以左侧尾状核注射Ⅶ型胶原酶0.5 U(1 U·μL ~(-1))诱导大鼠ICH模型。ICH术前10min腹腔注射给予三个不同剂量丙泊酚(分别为15 mg·kg~(-1)、30 mg·kg~(-1)和100 mg·kg~(-1)),观察丙泊酚对大鼠ICH后神经行为学评分、脑含水量(BWC)及脑组织病理形态学改变的影响;同时还观察了丙泊酚对ICH大鼠脑组织超氧化物歧化酶(SOD)活性、丙二醛(MDA)含量、血清乳酸脱氢酶(LDH)和肌酸激酶(CK)水平、脑组织Caspase-3蛋白表达的影响。主要结果与结论:
研究结果表明:
(1)丙泊酚(30 mg·kg~(-1)和100 mg·kg~(-1))可不同程度地缓解ICH后大鼠的神经行为学障碍、降低神经行为学评分、减轻ICH后脑水肿程度。同时,丙泊酚还能减轻大鼠ICH后脑组织的病理形态学损伤,表明丙泊酚对胶原酶诱导的大鼠ICH损伤具有一定的保护作用。
(2)丙泊酚(30 mg·kg~(-1)和100 mg·kg~(-1))可明显增高ICH后大鼠脑组织的SOD活性、降低MDA含量;降低ICH后大鼠血清LDH、CK水平。同时,三个剂量丙泊酚(15,30,100 mg·kg~(-1))可呈剂量依赖性地抑制Caspase-3在ICH大鼠脑组织中的表达。结果提示,丙泊酚可升高脑组织抗氧化酶SOD的活性,使脑组织的抗氧化水平增高,拮抗ICH时产生的氧自由基对细胞的损伤;丙泊酚可抑制脂质过氧化反应的发生,减少ICH损伤对细胞膜结构的破坏,提高脑细胞在脑出血时的存活率;同时抑制ICH诱导的细胞调亡的发生。
综上所述,本研究结果显示:丙泊酚对实验性ICH损伤具有一定的脑保护作用。丙泊酚的脑保护作用可能与其化学结构有关:1)在自由基反应体系中,丙泊酚含有的酚结构可以提供一个氢原子,自身转变成为苯氧基团,其中芳香环的共轭效应可降低苯氧基团活性,抑制脂质过氧化反应的发生;2)丙泊酚还可直接与氧自由基或单态氧反应,生成稳定的2,6-二异丙基苯氧基团,减轻后者引发的脂质过氧化级联反应;3)丙泊酚的脂溶性强,更容易积聚在细胞脂质双分子层上,可进一步提高细胞抗氧化损伤的能力。
Background and Objective: Intracerebral hemorrhage (ICH) indicates an acute extravasation of blood into the brain parenchyma due to vessel rupture. ICH is generally characterized by acute onset, rapid progress, considerable morbidity and mortality. After ICH, except direct tissue destruction of the space-occupying effect of hematoma, the secondary injuries in adjacent tissue including brain edema, abnormal energy metabolism and formation of oxygen free radicals (OFR) are the most important factors that induce the neurological deficits. Until recently, medical and surgical therapies are the main treatments for ICH.
Propofol (2, 6-diisopropyl phenol) is a lipid-soluble intravenous anesthetic, commonly used during operations in various clinical departments and out-patient department. The neuroprotective effect of propofol has been investigated in vivo and in vitro models of cerebral ischemia. It reveals that propofol can protect the brain tissue by exerting antioxidant effects, diminishing brain edema, and inhibiting cell apoptosis. It is strongly suggested that this anesthetic agent may serve as a neuropretective agent to combat ICH.
Although propofol is widely used in clinical anesthesia, it is still uncertain whether it could protect the brain from ICH injury. In this study, the protective effect of propofol against ICH was investigated in rats. Methods: ICH was induced in rats by infusion of collagenase (TypeⅦ) 0.5 U (1 U·μL ~(-1)) into the left caudate nucleus with stereotaxic apparatus. Three doses of propofol (15mg·kg~(-1), 30mg·kg~(-1) and 100mg·kg~(-1)) were given intraperitoneally (ip) 10 min before collagenase infusion, respectively. Effects of propofol on neurological behavioral scores, brain water content (BWC), pathomorphological changes of brain tissue, activity of superoxide dismutase (SOD) and content of malondialdehyde (MDA) in brain tissue, levels of lactate dehydrogenase (LDH) and creatine kinase (CK) in serum, expression level of Caspase-3 were studied.
Results and Conclusion:
(1) In propofol groups (30 mg·kg~(-1) and 100 mg·kg~(-1)), the neurological behavioral score and BWC were significantly lower than those in ICH group. Pathomorphological changes of the brain tissue were relieved to different degrees in propofol groups (30mg·kg~(-1) and 100mg·kg~(-1)).
(2) In propofol groups (30 mg·kg~(-1) and 100mg·kg~(-1)), the content of MDA, LDH and CK were significantly lower than those in ICH group, whereas the activity of SOD was higher than that in ICH group. Meanwhile, propofol (15, 30 and 100 mg·kg~(-1)) inhibited the Caspase-3 expression in a dose-dependent manner.
The study indicated that brain damages caused by ICH in rats can be alleviated by propofol, which mechanism might be attributed to its chemical structure. 1) In free radical reactions, the phenolic group of Propofol can react with OFR to form a phenoxyl group. The conjugation effect might decrease the activity of phenoxyl group, which make it impossible to induce the lipid peroxidation. 2) Propofol can also react with other oxidizing species such as singlet oxygen. 3) Meanwhile, the liposolubility of propofol makes it easy to gather on cell lipid bilayer to increase the antioxidant ability of cells.
引文
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[15]何爱霞,李立环.异丙酚对脑缺血缺氧性损伤保护作用的分子机制[J].国外医学,麻醉学与复苏分册,2005,26(6):355-358
[16] Hollrigel G.S.,Toth K,Soltesz I.Neuroprotection by propofol in acute mechanical injury: role of GABAergic inhibition[J].J Neurophysiol,1996,76(4):2412-2422
[17] Mantz J,Lechamy JB,Laudenbach V,et al.Anesthetics Affect the Uptake but Not the Depolarization-evoked Release of GABA in Rat Striatal Synaptosomes [J].Anesthesiology,1995,82(2):502-511
[18] Hutchinson P J,O'Connell M T,Al-Rawi P G,et al.Increases in GABA concentrations during cerebral ischaemia:a microdialysis study of extracellular amino acids[J].J Neurol Neurosurg and Psychiatry,2002,72:99-105
[19] Chen RM,Chen TG,Liu ll,et al.Anti-inflammatory and antioxidative of effects of propofol on lipopolysaccharide-activated macrophages[J].Ann NY Acad Sci,2005,1042:262-271
[20]夏瑞,杨光,郑利民,等.异丙酚对家兔脑缺血/再灌注期血清白介素-8的影响[J].中华麻醉学杂志,2000,20(4):233-235
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[23]冯春生,麻海春,岳云,张永谦,曲向东.异丙酚酚对大鼠局灶性脑缺血再灌注时核因子κB的活化和炎症因子表达的影响[J].中华医学杂志,2004,84(24):2110-2114
[24] Shibakawa YS, Sasaki Y, Goshima Y,et al.Effects of ketamine and propofol on inflammatory response of primary glial cell cultures stimulated with lipopolysaccharide[J]. British Journal of Anaesthesia, 2005,95(6):803-810
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[1] Engelhard K, Werner C, Eberspacher E, et al.Influence of propofol on neuronal damage and apoptotic factors after incomplete cerebral ischemia and reperfusion in rats: a long-term observation[J].Anesthesiology,2004, 101(4):912-917.
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[3] Adembri C, Venturi L, Tani A,et a1.Neuroprotective Effects of Propofol in Models of Cerebral Ischemia: Inhibition of Mitochondrial Swelling as a Possible Mechanism[J].Anesthesiology,2006,104(1):80-89
[4] Velly LJ,Guillet BA,Masmejean FM,et a1.Neuroprotective effects of propofol in a model of ischemic cortical cell cultures: role of glutamate and its transporters[J].Anesthesiology,2003,99(2):368-375.
[5]薛庆生,于布为,王泽剑,等.四种静脉麻醉药物对大鼠皮层脑片缺氧缺糖损伤的作用[J].中华麻醉学杂志,2003,23(9):681-684
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[7]王宁,邹元杰,汪小海,等.异丙酚治疗老年脑出血术后患者的疗效观察[J].临床神经病学杂志,2002,15(6):375-376
[8]陈煜,朱明,王顺民.硫喷妥钠与异丙酚在心脏手术深低温停循环期间对脑代谢影响的观察[J].中华麻醉学杂志,2002,22(10):603-605
[9] Kokita N,Hara A.Propofol attenuates rat heart peroxide-induced mechanical and metabolic derangements in the isolated rat heart[J].Anesthsiology,1996,84(1):117-127
[10]陈冀衡,王迪芬,安裕文,高巨.异丙酚预处理对脑缺血再灌注损伤的保护作用[J].中华麻醉学杂志,2001,24(6):355-357
[11]贾东林,褚晓玉,张利萍.丙泊酚对自由基引起的大鼠脑皮质线粒体损伤的保护作用[J].中国临床药理学与治疗学,2007,12(7):763-765
[12] WU XJ, ZHENG YJ,CUI YY,et a1.Propofol attenuates oxidative stress-induced PC12 cell injury via p38 MAP kinase dependent pathway[J].Acta Pharmacol Sin,2007,28(8):1123- 1128.
[13] Chang KSK , Davis RF . Propofol produces endothelium-independent vasodilation and may act as a Ca2+ channel blocker[J].Anesth Analg,1993,76(1):24-32
[14] Tsujiguchi N,Yamakage M,Namiki A.Mechanisms of direct inhibitory acton of propofol on uterine smooth muscle contraction in pregnant rats[J].Anesthesiology,2001,95(5):1245-1255
[15]何爱霞,李立环.异丙酚对脑缺血缺氧性损伤保护作用的分子机制[J].国外医学,麻醉学与复苏分册,2005,26(6):355-358
[16] Hollrigel G.S.,Toth K,Soltesz I.Neuroprotection by propofol in acute mechanical injury: role of GABAergic inhibition[J].J Neurophysiol,1996,76(4):2412-2422
[17] Mantz J,Lechamy JB,Laudenbach V,et al.Anesthetics Affect the Uptake but Not the Depolarization-evoked Release of GABA in Rat Striatal Synaptosomes [J].Anesthesiology,1995,82(2):502-511
[18] Hutchinson P J,O'Connell M T,Al-Rawi P G,et al.Increases in GABA concentrations during cerebral ischaemia:a microdialysis study of extracellular amino acids[J].J Neurol Neurosurg and Psychiatry,2002,72:99-105
[19] Chen RM,Chen TG,Liu ll,et al.Anti-inflammatory and antioxidative of effects of propofol on lipopolysaccharide-activated macrophages[J].Ann NY Acad Sci,2005,1042:262-271
[20]夏瑞,杨光,郑利民,等.异丙酚对家兔脑缺血/再灌注期血清白介素-8的影响[J].中华麻醉学杂志,2000,20(4):233-235
[21] Taniguchi T,Yamamoto K,Ohomto N,et al.Effect of propofol on hemodynamic and inflammatory responses to endotoxemia in rats[J].Cirt Care Med,2000,28(4):1101-1106
[22] Taniguchi T,Kanakura H,Yamamoto K,et al.Effects of post-treatment with propofol on mortality and cytokine responses to endotoxin-induced shock in rats[J].Cirt Care Med,2002,30:904-907
[23]冯春生,麻海春,岳云,张永谦,曲向东.异丙酚酚对大鼠局灶性脑缺血再灌注时核因子κB的活化和炎症因子表达的影响[J].中华医学杂志,2004,84(24):2110-2114
[24] Shibakawa YS, Sasaki Y, Goshima Y,et al.Effects of ketamine and propofol on inflammatory response of primary glial cell cultures stimulated with lipopolysaccharide[J]. British Journal of Anaesthesia, 2005,95(6):803-810
[25] Engelhard K, Werner C, Ebersp?cher E,et al.Sevoflurane and propofol influence the expression of apoptosis-regulating proteins after cerebral ischaemia and reperfusion in rats[J]. Eur J Anaesthesiol 2004,21:530-537
[26]冯春生,麻海春,岳云,于洋,王云.异丙酚对大鼠局灶性脑缺血再灌注时NF-κB的活化和Bcl-2、Caspase-3基因表达的影响[J].中华麻醉学杂志,2006,26(5):456-459