法舒地尔对大鼠慢性脑缺血认知功能及皮层自由基水平的影响
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摘要
目的:观察法舒地尔对慢性脑缺血大鼠认知功能及皮层自由基水平的影响。
方法:采用双侧颈总动脉永久性阻断法(2VO)建立大鼠慢性脑缺血模型,大鼠随机分为假手术组、盐水-缺血组和法舒地尔-缺血组,缺血时间为3w、6w、9w,应用Morris水迷宫检测大鼠逃避潜伏期和游泳路径判断学习记忆能力,采用分光光度法检测大鼠额叶皮层超氧化物歧化酶(SOD)、过氧化氢酶(CAT)活性,硫代巴比妥酸(Thibabituric Acid,TAB)比色法检测丙二醛(MDA)含量。
结果:假手术组大鼠3w、6w、9w逃避潜伏期、游泳路径无显著性差异(P>0.05);盐水-缺血组3w大鼠逃避潜伏期延长,游泳路径延长,6w、9w时更加明显,与假手术组相比差异显著(P<0.05);法舒地尔干预3w,大鼠逃避潜伏期、游泳路径较盐水-缺血组明显缩短,差异显著(P<0.05),干预6w、9w后,与盐水-缺血组比也有显著差异(P<0.05)。
假手术组大鼠3w、6w、9w额叶皮层SOD、CAT活性、MDA含量无显著性差异(P>0.05);盐水-缺血组3w、6w、9w额叶皮层SOD、CAT活性降低、MDA含量升高,与假手术组相比差异显著(P<0.05);法舒地尔干预后,法舒地尔-缺血组在3w、6w、9w时额叶皮层SOD、CAT活性升高、MDA含量降低,与盐水-缺血组相比差异显著(P<0.05)。
结论:慢性脑缺血可致大鼠学习记忆能力及额叶皮层SOD、CAT活性和MDA含量改变,法舒地尔干预能明显减轻大鼠慢性脑缺血所致认知功能障碍,并可影响自由基水平,法舒地尔可能通过抑制Rho激酶活性影响自由基代谢减轻慢性脑缺血造成的神经元的损伤而改善认知功能。
Chronic cerebral ischemia is a common pathological condition. It is the lack of brain blood flow perfusion for a long time caused by a variety of reasons accompanying a variety of cerebrovascular diseases’pathological processes, such as chronic cerebral ischemia, Vascular Dementia, Alzheimer, Binswanger and arteriovenous malformation. The cardinal symptom of early chronic cerebral ischemia is cognitive impairment, finally, permanent cognitive impairment and neurological deficit will be led to. Many clinical and laboratory evidence show that chronic cerebral ischemia can lead to cognitive dysfunction. With the increasing aging population, prevention and treatment of chronic cerebral ischemia caused by age-related diseases have a major social significance. Prevention of chronic cerebral ischemia disease precedes acute cerebral ischemia disease in time. So there are attached great importance to the present chronic cerebral ischemia induced cognitive dysfunction prevention research. The pathogenesis of Chronic cerebral ischemia are currently considered as in cerebral blood flow to be less than lack of cerebral blood flow and Disturbance of energy metabolism and the output of oxygen free radical and superoxide dismutase activity decrease and so on. As a result of free radical attack on cell membrane polyunsaturated fatty acid peroxidation products of a large amount of malondialdehyde. Peroxidation toxic damage to cells and enzyme produced ischemia, cytokines, such as leukocytes and endothelial cells induced the expression of adhesion molecules. Leukocyte activation and T cells go into the brain parenchyma, which resulting inflammatory response to neuronal damage. At last result the cognitive dysfunction Fasudil is a Rho / Rock signaling pathway of selective protein kinase inhibitor, in patients with acute cerebral ischemia has been confirmed. But there is little seen in the role of chronic cerebral ischemia and its mechanism. The success of this experiment in a rat model of chronic cerebral ischemia on the basis of their cognitive function in rats and the effects of free radicals in cortical. Aims to chronic cerebral ischemia induced cognitive impairment to provide a new means of prevention and treatment, and is widely used in its clinical, prevention and treatment of chronic shortage of cerebral perfusion caused by the provision of old age-related diseases based on experimental evidence.
The author of this study performed Morris water maze tests before sampling to ensure that the rats can be randomly divided into sham operation group, ischemia group and Fasudil group on the premise of that there is no obvious difference in intelligence, 6 rats each group. Method we established rat chronic cerebral ischemia models is bilateral carotid communis artery occulusion with ligation. Within 48h after the operation, rats received intraperitoneal injection of 1.5ml normal saline (0.9%) at total dose of 3w. The sham operation group was blocked bilateral carotid artery without ligation. Fasudil–ischemia group received permanent bilateral carotid communis artery occulusion, as the same as chronic cerebral ischemia models, and received intraperitoneal injection of Fasudil at a dose of 7.5ml/kg every day, the total dose is 3w. The Morris water maze tests were performed to exam every group rats’learning and memory ability when the injection is at 3w, 6w and 9w, the SOD activity and CAT activity were tested by spectrophotometer, the content of MDA was tested by Thibabituric Acid TAB. The result shows that there is no obvious difference in escape latency and swim distance in sham operation group (p>0.05). When ischemia reached 3w in saline–Ischemia group, the escape latency and swim distance extended, when ischemia reached 6w and 9w, the change is obvious, which is obvious comparing that of sham operation group. When Fasudil intervene reached 3w, Fasudil–ischemia group rats’escape latency and swim distance shortened obviously than that of saline–Ischemia group (p<0.05), after intervene reached 6w and 9w, there is obvious difference between Fasudil–ischemia group and saline–Ischemia group. In sham operation group, there is no obvious difference in the activity of SOD and CAT, and the content of MDA when the intervene is at 3w, 6w and 9w (p>0.05). Ischemia led to the decrease of activity of SOD and CAT, the increase of the content of MDA in saline–Ischemia group, the difference is obvious comparing with the sham operation group. Fasudil–ischemia group rats’activity of SOD and CAT increase obviously, the content of MDA in saline–Ischemia group, the difference is obvious comparing with the sham operation group. Fasudil–ischemia group rats’activity of SOD and CAT increase obviously, the content of MDA decrease, difference is obvious (p<0.05).
Schemic cerebral damage is a complex pathological process. It is generally thought that cerebral sharp metabolism, too much amount consumed of oxygen and energy is very sensitive to ischemia and absence of oxygen. A short time ischemia may lead to the functional obstacle of brain wave and nerve. The emergence of free radical theory opens out oxygen free radical’s important role in some diseases’pathogenesis from molecular level. More and more research have shown that free radical takes part in damaging nerve cell in cerebral ischemia, while the most representative ones in the process of metabolism of free radical are SOD, CAT and MDA, whose activity and content reflects indirectly the change of the level of metabolism of free radical in the body.
This study is based on 2VO models, learning and memory ability of rats with chronic cerebral ischemia is tested at different time. The result has shown that bilateralcarotid communis artery occlusion with ligation will decrease every indices in the Morris water maze examination which reflects rats’spatial memory ability, as time went on, rats’learning and memory ability will decrease further, which shows that at the state of chronic low perfusion, the influence of the states of ischemia and absence of oxygen on learning and memory function is gradual. After applying Fasudil intervention, comparing with Saline-Ischemia group, rats’escape latency and swim distance shortened obviously, which showed that Fasudil may improve the cognitive obstacle of rats with chronic cerebral ischemia. Then, the level change of chronic cerebral ischemia rats’epidermis free radical was observed in this examination. The result shows that the activity of rats’cortex’s SOD and CAT decreased obviously, the content of MDA increased after 2VO. The activity of SOD increased at the different time, the content of MDA decreased in Fasudil-Ischemia group, the difference is more obvious than Saline-Ischemia group (p<0.05). The result of this study hints that free radical’s level change is more obvious at the early stage of ischemia, and Fasudil may ameliorate chronic cerebral low perfusion caused by 2VO, the oxidative damage then decreased the damage of nerve cell, which will improve rats’learning and memory ability. The above results show that after chronic cerebral ischemia rats receiving Fasudil protection, the production of oxygen free radical in the rats’brain tissue will be decreased or the elimination will be increased, the level of active oxygen will be decreased, so the aging and death of nerve cells are decreased and stared, which show that Fasudil possesses protecting function for chronic cerebral ischemia rats.
In conclusion, by medicament intervening to the rats with chronic cerebral ischemia and comparing different groups, the rats’escape latency and swim distance, and the level of free radical were tested and the conclusion is chronic cerebral ischemia will lead to the rat’s cognitive obstacle, and which can be ameliorated by using Fasudil. The activity of SOD and CAT in rats with chronic cerebral ischemia declined and the content of MDA increased. Fasudil will increase the activities of SOD and CAT, and decrease the content of MDA Fasudil can improve the level of cognitive function obstacle caused by chronic cerebral ischemia through influencing the level of free radical.
方法:采用双侧颈总动脉永久性阻断法(2VO)建立大鼠慢性脑缺血模型,大鼠随机分为假手术组、盐水-缺血组和法舒地尔-缺血组,缺血时间为3w、6w、9w,应用Morris水迷宫检测大鼠逃避潜伏期和游泳路径判断学习记忆能力,采用分光光度法检测大鼠额叶皮层超氧化物歧化酶(SOD)、过氧化氢酶(CAT)活性,硫代巴比妥酸(Thibabituric Acid,TAB)比色法检测丙二醛(MDA)含量。
结果:假手术组大鼠3w、6w、9w逃避潜伏期、游泳路径无显著性差异(P>0.05);盐水-缺血组3w大鼠逃避潜伏期延长,游泳路径延长,6w、9w时更加明显,与假手术组相比差异显著(P<0.05);法舒地尔干预3w,大鼠逃避潜伏期、游泳路径较盐水-缺血组明显缩短,差异显著(P<0.05),干预6w、9w后,与盐水-缺血组比也有显著差异(P<0.05)。
假手术组大鼠3w、6w、9w额叶皮层SOD、CAT活性、MDA含量无显著性差异(P>0.05);盐水-缺血组3w、6w、9w额叶皮层SOD、CAT活性降低、MDA含量升高,与假手术组相比差异显著(P<0.05);法舒地尔干预后,法舒地尔-缺血组在3w、6w、9w时额叶皮层SOD、CAT活性升高、MDA含量降低,与盐水-缺血组相比差异显著(P<0.05)。
结论:慢性脑缺血可致大鼠学习记忆能力及额叶皮层SOD、CAT活性和MDA含量改变,法舒地尔干预能明显减轻大鼠慢性脑缺血所致认知功能障碍,并可影响自由基水平,法舒地尔可能通过抑制Rho激酶活性影响自由基代谢减轻慢性脑缺血造成的神经元的损伤而改善认知功能。
Chronic cerebral ischemia is a common pathological condition. It is the lack of brain blood flow perfusion for a long time caused by a variety of reasons accompanying a variety of cerebrovascular diseases’pathological processes, such as chronic cerebral ischemia, Vascular Dementia, Alzheimer, Binswanger and arteriovenous malformation. The cardinal symptom of early chronic cerebral ischemia is cognitive impairment, finally, permanent cognitive impairment and neurological deficit will be led to. Many clinical and laboratory evidence show that chronic cerebral ischemia can lead to cognitive dysfunction. With the increasing aging population, prevention and treatment of chronic cerebral ischemia caused by age-related diseases have a major social significance. Prevention of chronic cerebral ischemia disease precedes acute cerebral ischemia disease in time. So there are attached great importance to the present chronic cerebral ischemia induced cognitive dysfunction prevention research. The pathogenesis of Chronic cerebral ischemia are currently considered as in cerebral blood flow to be less than lack of cerebral blood flow and Disturbance of energy metabolism and the output of oxygen free radical and superoxide dismutase activity decrease and so on. As a result of free radical attack on cell membrane polyunsaturated fatty acid peroxidation products of a large amount of malondialdehyde. Peroxidation toxic damage to cells and enzyme produced ischemia, cytokines, such as leukocytes and endothelial cells induced the expression of adhesion molecules. Leukocyte activation and T cells go into the brain parenchyma, which resulting inflammatory response to neuronal damage. At last result the cognitive dysfunction Fasudil is a Rho / Rock signaling pathway of selective protein kinase inhibitor, in patients with acute cerebral ischemia has been confirmed. But there is little seen in the role of chronic cerebral ischemia and its mechanism. The success of this experiment in a rat model of chronic cerebral ischemia on the basis of their cognitive function in rats and the effects of free radicals in cortical. Aims to chronic cerebral ischemia induced cognitive impairment to provide a new means of prevention and treatment, and is widely used in its clinical, prevention and treatment of chronic shortage of cerebral perfusion caused by the provision of old age-related diseases based on experimental evidence.
The author of this study performed Morris water maze tests before sampling to ensure that the rats can be randomly divided into sham operation group, ischemia group and Fasudil group on the premise of that there is no obvious difference in intelligence, 6 rats each group. Method we established rat chronic cerebral ischemia models is bilateral carotid communis artery occulusion with ligation. Within 48h after the operation, rats received intraperitoneal injection of 1.5ml normal saline (0.9%) at total dose of 3w. The sham operation group was blocked bilateral carotid artery without ligation. Fasudil–ischemia group received permanent bilateral carotid communis artery occulusion, as the same as chronic cerebral ischemia models, and received intraperitoneal injection of Fasudil at a dose of 7.5ml/kg every day, the total dose is 3w. The Morris water maze tests were performed to exam every group rats’learning and memory ability when the injection is at 3w, 6w and 9w, the SOD activity and CAT activity were tested by spectrophotometer, the content of MDA was tested by Thibabituric Acid TAB. The result shows that there is no obvious difference in escape latency and swim distance in sham operation group (p>0.05). When ischemia reached 3w in saline–Ischemia group, the escape latency and swim distance extended, when ischemia reached 6w and 9w, the change is obvious, which is obvious comparing that of sham operation group. When Fasudil intervene reached 3w, Fasudil–ischemia group rats’escape latency and swim distance shortened obviously than that of saline–Ischemia group (p<0.05), after intervene reached 6w and 9w, there is obvious difference between Fasudil–ischemia group and saline–Ischemia group. In sham operation group, there is no obvious difference in the activity of SOD and CAT, and the content of MDA when the intervene is at 3w, 6w and 9w (p>0.05). Ischemia led to the decrease of activity of SOD and CAT, the increase of the content of MDA in saline–Ischemia group, the difference is obvious comparing with the sham operation group. Fasudil–ischemia group rats’activity of SOD and CAT increase obviously, the content of MDA in saline–Ischemia group, the difference is obvious comparing with the sham operation group. Fasudil–ischemia group rats’activity of SOD and CAT increase obviously, the content of MDA decrease, difference is obvious (p<0.05).
Schemic cerebral damage is a complex pathological process. It is generally thought that cerebral sharp metabolism, too much amount consumed of oxygen and energy is very sensitive to ischemia and absence of oxygen. A short time ischemia may lead to the functional obstacle of brain wave and nerve. The emergence of free radical theory opens out oxygen free radical’s important role in some diseases’pathogenesis from molecular level. More and more research have shown that free radical takes part in damaging nerve cell in cerebral ischemia, while the most representative ones in the process of metabolism of free radical are SOD, CAT and MDA, whose activity and content reflects indirectly the change of the level of metabolism of free radical in the body.
This study is based on 2VO models, learning and memory ability of rats with chronic cerebral ischemia is tested at different time. The result has shown that bilateralcarotid communis artery occlusion with ligation will decrease every indices in the Morris water maze examination which reflects rats’spatial memory ability, as time went on, rats’learning and memory ability will decrease further, which shows that at the state of chronic low perfusion, the influence of the states of ischemia and absence of oxygen on learning and memory function is gradual. After applying Fasudil intervention, comparing with Saline-Ischemia group, rats’escape latency and swim distance shortened obviously, which showed that Fasudil may improve the cognitive obstacle of rats with chronic cerebral ischemia. Then, the level change of chronic cerebral ischemia rats’epidermis free radical was observed in this examination. The result shows that the activity of rats’cortex’s SOD and CAT decreased obviously, the content of MDA increased after 2VO. The activity of SOD increased at the different time, the content of MDA decreased in Fasudil-Ischemia group, the difference is more obvious than Saline-Ischemia group (p<0.05). The result of this study hints that free radical’s level change is more obvious at the early stage of ischemia, and Fasudil may ameliorate chronic cerebral low perfusion caused by 2VO, the oxidative damage then decreased the damage of nerve cell, which will improve rats’learning and memory ability. The above results show that after chronic cerebral ischemia rats receiving Fasudil protection, the production of oxygen free radical in the rats’brain tissue will be decreased or the elimination will be increased, the level of active oxygen will be decreased, so the aging and death of nerve cells are decreased and stared, which show that Fasudil possesses protecting function for chronic cerebral ischemia rats.
In conclusion, by medicament intervening to the rats with chronic cerebral ischemia and comparing different groups, the rats’escape latency and swim distance, and the level of free radical were tested and the conclusion is chronic cerebral ischemia will lead to the rat’s cognitive obstacle, and which can be ameliorated by using Fasudil. The activity of SOD and CAT in rats with chronic cerebral ischemia declined and the content of MDA increased. Fasudil will increase the activities of SOD and CAT, and decrease the content of MDA Fasudil can improve the level of cognitive function obstacle caused by chronic cerebral ischemia through influencing the level of free radical.
引文
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[18] Yagita Y, Kitagawa K, Sasaki T, et al. Rho-kinase activation in endothelial cells contributes to expansion of infarction after focal cerebral ischemia [J]. J Neurosci Res, 2007, 85(11):2460-2469.
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[22]Dong-Myung S, Jinmo K, Jongwon H, et al.Cystamine prevents ischemia–reperfusion injury by inhibiting polyamination of RhoA.Biochemical and Biophysical Research Comm- unications,2008,365(3):509-514.
[23]Kenji I, Hisayo F, Mariko H , et al.Trapidil inhibits platelet-derived growth factor-induced migration via protein kinase A and RhoA/Rho-associated kinase in rat vascular smooth muscle cells .European Journal of Pharmacology, 2005,515(1-3):28– 33.
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[25] Rajnicek AM, Foubister LE, McCaig CD. Temporally and spatially coordinated roles for Rho, Rac, Cdc42 and their effectors in growth cone guidance by a physiological electric field [J]. J Cell Sci, 2006, 119(Pt 9):1723-35.
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[29]Watanabe Y,Faraci FM,Heistad DD.Activation of Rho-associated kinase during augmented contraction of the basilar artery to serotonin after subarachnoid hemorrhage[J].Am J Physiol Heart Circ Physiol,2005,288(6):2653-2658.
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[36] Shimokawa H,Morishige K,Miyata K,et al.Long-term inhibition of Rho-kinase induces a regression of arteriosclerotic coronary lesions in a porcine model in vivo[J].Cardiovasc Res,2001,51(1):l69-l77.
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[15] Shirao S, Fujisawa H, Kudo A, et al.Inhibitory effects of eicosap- entaenoic acid on chronic cerebral vasospasm after subara-chnoid hemorrhage: possible involvement of a sphingosylphosph-orylcholine-rho-kinase pathway [J]. Cerebrovasc Dis, 2008, 26(1):30- 37.
[16] Li Q, Huang XJ, He W, et al. Neuroprotective potential of fasudil mesylate in brain ischemia-reperfusion injury of rats [J]. Cell Mol Neurobiol, 2009, 29(2):169-180.
[17] Yano K, Kawasaki K, Hattori T, et al. Demonstration of elevation and localization of Rho-kinase activity in the brain of a rat model of cerebral infarction [J]. Eur J Pharmacol, 2008, 594(1-3):77-83.
[18] Yagita Y, Kitagawa K, Sasaki T, et al. Rho-kinase activation in endothelial cells contributes to expansion of infarction after focal cerebral ischemia [J]. J Neurosci Res, 2007, 85(11):2460-2469.
[19] Wardle RL, Gu M, Ishida Y, et al. Rho kinase is an effector underlying Ca2+ desensitizing hypoxic relaxation in porcine coronary artery [J]. Am J Physiol Heart Circ Physiol, 2007, 293(1):H23-29.
[20] Shin HK, Salomone S, Potts EM, et al. Rho-kinase inhibition acutely augments blood flow in focal cerebral ischemia via endothelial mechanisms [J]. J Cereb Blood Flow Metab, 2007, 27(5):998-1009.
[21]Ziad Mallat, Hafid A, Alain T.Regulatory T-Cell Immunity in Atherosclerosis[J].Trends in Cardiovascular Medicine, 2007,17(4): 113-118.
[22]Dong-Myung S, Jinmo K, Jongwon H, et al.Cystamine prevents ischemia–reperfusion injury by inhibiting polyamination of RhoA.Biochemical and Biophysical Research Comm- unications,2008,365(3):509-514.
[23]Kenji I, Hisayo F, Mariko H , et al.Trapidil inhibits platelet-derived growth factor-induced migration via protein kinase A and RhoA/Rho-associated kinase in rat vascular smooth muscle cells .European Journal of Pharmacology, 2005,515(1-3):28– 33.
[24]Hiroaki S, Mamunur R.Development of Rho-kinase inhibitors for cardiovascular medicine .Trends in Pharmacological Sciences,2007,28(6): 296- 302.
[25] Rajnicek AM, Foubister LE, McCaig CD. Temporally and spatially coordinated roles for Rho, Rac, Cdc42 and their effectors in growth cone guidance by a physiological electric field [J]. J Cell Sci, 2006, 119(Pt 9):1723-35.
[26] Shin HK, Salomone S, Ayata C. Targeting cerebrovascular Rho-kinase in stroke [J]. Expert Opin Ther Targets, 2008, 12(12): 1547-1564.
[27]Melanie Yeoh,James A. Brock. Rho kinase inhibitors reduce neurally evoked contraction of the rat tail artery in vitro[J]. British Journal of Pharmacology,2005,146(6):854-861.
[28]Kumai T,Takeba Y,Matsumoto N,et al. Fasudil attenuates sympathetic nervous activity in the adrenal medulla of spontaneously hypertensive rats[J]. Life Sci,2007,81(15):1193-1198.
[29]Watanabe Y,Faraci FM,Heistad DD.Activation of Rho-associated kinase during augmented contraction of the basilar artery to serotonin after subarachnoid hemorrhage[J].Am J Physiol Heart Circ Physiol,2005,288(6):2653-2658.
[30] Kajimoto H,Hashimoto K,Bonnet SN,et al. Oxygen activates the Rho/Rho-kinase pathway and induces RhoB and ROCK-1 expression in human and rabbit ductus arteriosus by increasing mitochondria-derived reactive oxygen species: a newly recognized mechanism for sustaining ductal constriction[J]. Circulation,2007,115(13):1777-1788.
[31] Thorlacius K, Slotta JE, Laschke MW, et al. Protective effect of fasudil, a Rho-kinase inhibitor, on chemokine expression, leukocyte recruitment, and hepatocellular apoptosis in septic liver injury [J]. J Leukoc Biol, 2006, 79(5): 923-931.
[32] Kluytmans M, van der Grond J, van Everdingen KJ, et al. Cerebral hemodynamics in relation to patterns of collateral flow [J]. Stroke, 1999, 30(7): 1432-1439.
[33] Yamashita K, Kotani Y, Nakajima Y, et al. Fasudil, a Rho kinase (ROCK) inhibitor, protects against ischemic neuronal damage in vitro and in vivo by acting directly on neurons [J]. Brain Res, 2007, 1154: 215-224.
[34] Kanda T,Wakino S,Homma K,et al.Rho-kinase as a molecular target for insulin resistance and hypertension[J].FASEB J,2006,20(1):169-171.
[35] Shah DI,Singh M.Involvement of Rho-kinase in experimental vascular endothelial dysfunction[J].Mol cell Biochem,2006,283(1-2):191-199.
[36] Shimokawa H,Morishige K,Miyata K,et al.Long-term inhibition of Rho-kinase induces a regression of arteriosclerotic coronary lesions in a porcine model in vivo[J].Cardiovasc Res,2001,51(1):l69-l77.
[37] Miranda FJ,Alabadi JA,Torregrosa G,et al. Modulatory role of endothelial and nonendothelial nitric oxide in 5-hydroxytryptamine-induced contraction in cerebral arteries after subarachnoid hemorrhage[J]. Neurosurg, 1996,39(5):998-1004.
[38] Takemoto M,Sun J,Hiroki J,et al. Rho-kinase mediates hypoxia- induced downregulation of endothelial nitric oxide synthase[J]. Circulation, 2002, 106(1):57-62.
[39] Rikitake Y, Kim HH, Huang Z, et al. Inhibition of Rho kinase (ROCK) leads to increased cerebral blood flow and stroke protection [J]. Stroke, 2005, 36(10):2251-2257.
[40] Mallat Z, Gojova A, Sauzeau V, et al. Rho-associated protein kinase contributes to early atherosclerotic lesion formation in mice [J]. Circ Res, 2003, 93(9):884-888.
[41] Satoh S, Toshima Y, Ikegaki I, et al. Wide therapeutic time window for fasudil neuroprotection against ischemia-induced delayed neuronal death in gerbils [J]. Brain Res, 2007, 1128(1):175-180.
[42] Shibuya M, Hirai S, Seto M, et al. Effects of fasudil in acute ischemic stroke: results of a prospective placebo-controlled double-blind trial [J]. J Neurol Sci, 2005, 238(1-2):31-39.
[43] Lipton P, Lobner D. Mechanisms of intracellular calcium accumulation in the CA1 region of rat hippocampus during anoxia in vitro [J]. Stroke, 1990, 21(11 Suppl):III60-64.