右甲吗喃对脑缺血的实验治疗研究

目的和方法：在沙土鼠通过夹闭双侧颈总动脉复制短暂性脑缺血神经元迟发性坏死,以海马ＣＡ１区神经元坏死为指标;在大鼠采用凝闭大脑中动脉复制局部脑缺血,以缺血区脑组织钠、水、钙含量及梗塞面积为指标;观察非竞争性、低亲和力兴奋性氨基酸拮抗剂右甲吗喃对抗脑缺血的作用。结果：右甲吗喃能提高沙土鼠脑缺血后海马ＣＡ１区神经元存活数;能降低大鼠大脑中动脉闭塞后缺血区水、钠及钙含量,缩小梗塞面积。结论：右甲吗喃能减轻脑缺血后神经元死亡（即凋亡）;并通过减轻脑水肿,缩小梗塞面积,改善大鼠局部脑缺血时缺血性脑损伤。     

Antiedematous effect of the preparation Polyosm in brain ischemia

The effect of the preparation Polyosm (polyethylene oxide 400) on cerebral edema (impedance measurements) and cerebral circulation is studied in brain ischemia caused by ligation of the left common carotid artery and reduction of blood flow through the right common carotid artery to 25% of the original level. The preparation markedly reduces cerebral edema and induces transient improvements in cerebral circulation. Translated fromByulleten' Eksperimental'noi Biologii i Meditsiny, Vol. 122, No. 10, pp. 410–412, October, 1996     

Antiedematous activity of cerebrocrastin cerebral ischemia

The effect of a course of cerebrocrast, a 1,4-dihydropyridine derivative, on brain edema (as shown by impedometry) and cerebral tissue microvascularization in ischemia caused by ligation of the left common carotid artery and 50% restriction of the bloodflow in the right common carotid artery is studied in Wistar rats. Cerebrocrast is found to appreciably limit the development of brain tissue edema and to improve the status of microvessels by reducing the number of sharply constricted nonfunctioning capillaries and increasing the number of capillaries of 4 μ and more in diameter. Pronounced antioxidative effects of cerebrocrast in transitory cerebral ischemia are demonstrated. Translated fromByulleten' Eksperimental'noi Biologii i Meditsiny, Vol. 119, No. 3, pp. 291–293, March, 1995 Presented by E. D. Gol'dberg, Member of the Russian Academy of Medical Sciences.     

Ligation of lateral carotid artery attenuates disturbance of brain function caused by subsequent cerebral ischemia in rabbits

The effects of right carotid artery ligation on the subsequent cerebral ischemia, induced by iron particle injection, in rabbits, were evaluated by recording somatosensory evoked potentials (SEPs) and cerebral blood flow (CBF) using laser Doppler flowmetry. Iron particle injection decreased CBF over 120 min and delayed SEP onset latency in rabbits with no previous carotid artery ligation (control group). In rabbits with a carotid ligation 3 days before, iron particle injection induced the decrease of CBF, as in the control group, but did not prolong the latency of SEP. Injection of iron particles induced only a transient decrease of CBF (less than 10 min) followed by an abrupt recovery, and no prolongation of SEP latency was observed in rabbits with a carotid ligation 6 days before. These results suggest that carotid artery ligation induces a beneficial effect on cerebral function during the subsequent ischemia, which is independent on the CBF changes.     

Effect of hemoglobin vesicle,a cellular-type artificial oxygen carrier,on middle cerebral artery occlusion- and arachidonic acid-induced stroke models in rats

Hemoglobin vesicle (HbV), which is also called liposome-encapsulated hemoglobin, functions as a hemoglobin-based oxygen carrier and is expected to be utilized in emergency situations including hemorrhagic shock and several kinds of ischemic diseases. In the present study, we evaluated the efficacy of HbV for improving stroke-related symptoms induced by middle cerebral artery (MCA) occlusion/reperfusion and an intra-internal carotid arterial injection of arachidonic acid (AA) in rats. When HbV (10 mL/kg, i.v.) was administered to rats immediately after the MCA occlusion, it reduced the cerebral infarct volumes of the cortex and total of the cortex plus sub-cortex significantly as compared with saline as a vehicle. In AA-induced stroke model, HbV (10 mL/kg, i.v.) improved the motor dysfunction score and inhibited the increase in cerebral water content suggesting it could suppress cerebral edema. These results strongly suggest that HbV would provide a novel beneficial option for the treatment of stroke, especially acute ischemic stroke.     

Reversible myocardial damage in gerbil brain ischaemia and its prevention by beta-adrenergic blockade.

Acute cerebral infarction in gerbils, produced by unilateral carotid ligation, was used as a model to investigate secondary myocardial changes. The extent of the myocardial damage revealed by succinic dehydrogenase (SDH) histochemistry and by release of myocardial creatine phosphokinase (MB-CK) was measured in gerbils sacrificed from 3 to 48 h after either carotid ligation, carotid isolation only or skin incision only. For technical reasons dead animals were excluded from analysis. Of surviving ligated animals 74% developed neurological deficits related to brain ischaemia. A significant weight increase in the ipsilateral hemisphere was found at 6-10 h, and maximal histological damage at 16 h, both partially reversible thereafter. Non-ligated animals did not develop neurological changes, and showed neither brain swelling nor cerebral histopathology. Extensive cardiac damage was shown by the SDH method from 3 h postoperatively, and confirmed by the elevated serum levels of MB-CK in the carotid-ligated group. The SDH changes were identical with those described in the hearts of patients with acute intracranial lesions, and appeared to be reversible. The effect of beta-adrenergic blockade was assessed in this model. Metoprolol tartrate injected intraperitoneally 3 h before and 1 h after carotid ligation (10 mg/kg each dose) significantly decreased the extent of myocardial damage as estimated both with SDH histochemistry and MB-CK serum levels. It had no effect on the ischaemic brain changes. These results strongly support the concept of catecholamine mediation of myocardial injury resulting from acute brain lesions.     

Reversible myocardial damage in gerbil brain ischaemia and its prevention by beta-adrenergic blockade

Acute cerebral infarction in gerbils, produced by unilateral carotid ligation, was used as a model to investigate secondary myocardial changes. The extent of the myocardial damage revealed by succinic dehydrogenase (SDH) histochemistry and by release of myocardial creatine phosphokinase (MB-CK) was measured in gerbils sacrificed from 3 to 48 h after either carotid ligation, carotid isolation only or skin incision only. For technical reasons dead animals were excluded from analysis. Of surviving ligated animals 74% developed neurological deficits related to brain ischaemia. A significant weight increase in the ipsilateral hemisphere was found at 6-10 h, and maximal histological damage at 16 h, both partially reversible thereafter. Non-ligated animals did not develop neurological changes, and showed neither brain swelling nor cerebral histopathology. Extensive cardiac damage was shown by the SDH method from 3 h postoperatively, and confirmed by the elevated serum levels of MB-CK in the carotid-ligated group. The SDH changes were identical with those described in the hearts of patients with acute intracranial lesions, and appeared to be reversible. The effect of beta-adrenergic blockade was assessed in this model. Metoprolol tartrate injected intraperitoneally 3 h before and 1 h after carotid ligation (10 mg/kg each dose) significantly decreased the extent of myocardial damage as estimated both with SDH histochemistry and MB-CK serum levels. It had no effect on the ischaemic brain changes. These results strongly support the concept of catecholamine mediation of myocardial injury resulting from acute brain lesions.     

山莨菪硷对家兔不完全性脑缺血的影响

急性结扎兔双侧颈总动脉及左侧椎动脉造成了实验性不完全脑缺血模型。此模型可用于探讨缺血性脑病的发病机制及实验治疗。于脑缺血后30及60分钟分别注入654-2(山莨菪硷),可见:(1)654-2治疗组脑血流量下降率明显低于空白对照组(P<0.01)及生理盐水组(P<0.01)。(2)血浆中TXB_2含量明显低于空白对照组(P<0.01)及盐水组(P<0.01)。表明山莨菪硷可以改善局部脑循环和抑制血浆中TXB_2的形成、大脑皮层无明显脑水肿发生。本实验结果提示664-2可用于脑卒中急性期。     

蒙古沙土鼠完全性脑缺血模型的研究

用４０只蒙古种沙土鼠，经双侧颈总动脉血流阻断后，采用ＪＩ－２００激光微循环动态分析仪、ＬＭＢ－１型激光微循环显微镜及其录像系统双重观察，计算机同步记录。结果显示：３８例沙土鼠脑膜微循环血流完全停止，脑局部血流量几乎降到０。但是仍有２例尚有血流，有异于一些论著有关蒙古沙土鼠“阻断双侧颈总动脉，肯定造成双侧大脑半球的完全性缺血”的报导。提示：为了保障完全性脑缺血模型的成功制作，上述现象必须引起重视。     

Methylprednisolone and vitamin E therapy in perinatal hypoxic-ischemic brain damage in rats.

To study the efficacy of methylprednisolone/vitamin E in reducing cerebral edema and improving the ultimate neuropathological outcome in perinatal cerebral hypoxia-ischemia, 40 seven-day postnatal rats were subjected to right common carotid artery ligation followed by exposure to 8% oxygen at 37 degrees C for 3 h. The animals were divided into groups. Twenty rat pups received an intraperitoneal injection of 30 mg/kg body weight methylprednisolone and vitamin E (100 U/kg) immediately following cerebral hypoxia-ischemia. Control animals received either no therapy (n = 10) or an equivalent volume of normal saline (n = 10). After 72 h of recovery from hypoxia-ischemia, the animals were killed and their brains were examined to measure the water contents in the right and left hemispheres (29 rat pups), whereas the others were killed at 21 days for neuropathological examination. Methylprednisolone/vitamin E-treated rats had significantly less water content in the right hemisphere (87.08 +/- 0.28%, mean +/- S.E.M.) than saline-treated animals (89.07 +/- 0.37%, mean +/- S.E.M., P < 0.0001). Methylprednisolone/vitamin E significantly reduced water content in the right hemisphere of the brain. Neuropathological study was performed on nine rat pups. The brains of four methylprednisolone/vitamin E- and five saline-treated pups were examined at the end of the 21-day recovery period. Two groups of the right cerebral cortex included thinning of the cortex. Significantly less damage was seen in the methylprednisolone/vitamin E-treated pups. Our study suggests that trials of methylprednisolone/vitamin E might be effective if they are given to the mother at risk of fetal hypoxia during labor or to the hypoxic infant right after delivery in preventing hypoxic brain damage.     

Effect of blocking angiotensin receptors on cerebral blood flow in the post-ischemic period in hypertensive rats

Acute experiments on anesthetized rats have been conducted to study the effect of lozartan (5 mg/kg i.p.) on cerebral circulation and its autoregulation in hypertensive animals (a vasorenal model) in postischemic period. Transitory ischemia was induced by bilateral compression of the carotid arteries for 12 minutes, continued--by ligation of the carotid arteries. It was found that blockade of angiotensin receptors by lazartan provoked lowering of systemic arterial pressure. Changes in cerebral circulation were unstable, depended on arterial pressure and vascular cerebral resistance. The lower limit of autoregulation of the brain flow shifted to higher arterial pressure in hypertensive animals before brain ischemia and disorder after ischemia. Lozartan promoted recovery of the autoregulatory reactions of the brain vessels and raised survival of rats in continuous ligation of the carotid arteries.     

Study of cellular changes induced by moderate cerebral ischemia achieved through internal carotid artery ligation

Reduced cerebral blood flow beyond the compensatory mechanisms leads to cerebral hypoxia. Hypoxia causes various lesions of neurons, glial cells and cerebral blood vessels, depending on its duration and intensity. In our study, we reduced cerebral blood flow in the experience animal on average by 30%, by right internal carotid artery ligation. Fifteen days after the onset of hypoxia, by histology and immunohistochemical studies, we identified neuronal, glial and vascular damage. Lesions of nerve and glial cells ranged from changes of cytoplasmic tinting with the development of "red neurons", to neuronal and glial cytolysis with areas of focal necrosis. Vascular lesions were represented by the collapse, fragmentation and discontinuity of capillaries, always associated with a marked perivascular edema.     

早期动脉瘤模型大鼠形成过程中血管壁基质结构蛋白的表达

背景：基质蛋白是构成血管壁的必不可少的重要成分,为血管壁的完整性和血管壁细胞发挥生理功能提供了必要的框架,并参与对细胞和平滑肌的调控。 目的：构建早期动脉瘤模型大鼠评价基质结构蛋白在形成过程中的表达差异性。 方法：将28只健康雄性SD大鼠随机分为2组：对照组(n=8)和模型组(n=20)。模型组大鼠以结扎左侧颈总动脉和右侧肾肾动脉致高血压方法建立脑动脉瘤模型;对照组大鼠仅暴露左侧颈动脉分叉和双侧颈动脉。模型组大鼠分别于造模后15,30 d处死,取大鼠右侧大脑前动脉和嗅动脉的分叉处部分组织进行免疫组化染色,分析纤维连接蛋白、α-平滑肌肌动蛋白和Ⅲ型胶原蛋白的表达。 结果与结论：与对照组相比,造模后30 d时模型组大鼠右侧大脑前动脉和嗅动脉的分叉处部分中纤维连接蛋白表达水平差异无显著性意义(P > 0.05),而Ⅲ型胶原和α-平滑肌肌动蛋白表达明显减少(P < 0.05)。提示大鼠早期脑动脉瘤形成过程中的结构蛋白表达存在差异性并发生动态变化,血管壁基质结构蛋白降解是动脉瘤形成主要机制之一。 中国组织工程研究杂志出版内容重点：肾移植;肝移植;移植;心脏移植;组织移植;皮肤移植;皮瓣移植;血管移植;器官移植;组织工程全文链接：     

A Model of Cerebral Circulation Disorders Created by Staged Ligation of the Common Carotid Arteries

A model of brain ischemia induced by staged ligation of the left and right common carotid arteries has been developed in experiments on rats. The use to this model led to reduction of animal mortality. On days 2-5 after the second ligature, the animals lost weight, the level of their CNS vulnerability increased, the volume of perceived information reduced, adaptation to environmental conditions and reproduction of conditioned reflexes were disordered. Focal and diffuse destructive changes in the nerve and glia cells were found in the cerebral cortex, hippocampus, and thalamic nuclei. The severity of disorders in the blood supply to the brain depended on the interval between ligation of the carotid arteries. This recommends this model for evaluation of the efficiency of drugs of various pharmacological groups.     

Tetramethylpyrazine reduces ischemic brain injury in rats

Tetramethylpyrazine (TMP), which is widely used in the treatment of ischemic stroke by Chinese herbalists, is one of the most important active ingredients of the traditional Chinese herbal medicine, Ligusticum wallichii Franchat (Chung Xiong). However, the mechanism by which TMP protects the brain is still not clear. We examined neuroprotective effects of TMP after transient focal cerebral ischemia using common carotid artery and middle cerebral artery occlusion model in rats and evaluated the involvement of anti-inflammation. TMP administrated intraperitoneally significantly protected the brain against ischemic insult as evidenced by the reduction in infarction volume, preservation of neurons, and decrease in brain edema. TMP markedly reduced cerebral ischemia/reperfusion-induced inflammatory cell activation and proinflammatory mediator production. Moreover, TMP suppressed lipopolysaccharide/interferon-gamma-induced inflammation and prostaglandin E(2) production in cultured glial cells. Our findings suggest that one of neuroprotective effects of TMP against ischemic brain injury might involve its anti-inflammatory potential.     

NITRIC OXIDE (NO), CITRULLINE - NO CYCLE ENZYMES,GLUTAMINE SYNTHETASE AND OXIDATIVE STRESS IN ANOXIA (HYPOBARIC HYPOXIA) AND REPERFUSION IN RAT BRAIN

Nitric oxide is postulated to be involved in the pathophysiology of neurological disorders due to hypoxia/ anoxia in brain due to increased release of glutamate and activation of N-methyl-D-aspartate receptors. Reactive oxygen species have been implicated in pathophysiology of many neurological disorders and in brain function. To understand their role in anoxia (hypobaric hypoxia) and reperfusion (reoxygenation), the nitric oxide synthase, argininosuccinate synthetase, argininosuccinate lyase, glutamine synthetase and arginase activities along with the concentration of nitrate /nitrite, thiobarbituric acid reactive substances and total antioxidant status were estimated in cerebral cortex, cerebellum and brain stem of rats subjected to anoxia and reperfusion. The results of this study clearly demonstrated the increased production of nitric oxide by increased activity of nitric oxide synthase. The increased activities of argininosuccinate synthetase and argininosuccinate lyase suggest the increased and effective recycling of citrulline to arginine in anoxia, making nitric oxide production more effective and contributing to its toxic effects. The decreased activity of glutamine synthetase may favor the prolonged availability of glutamic acid causing excitotoxicity leading to neuronal damage in anoxia. The increased formation of thiobarbituric acid reactive substances and decreased total antioxidant status indicate the presence of oxidative stress in anoxia and reperfusion. The increased arginase and sustained decrease of GS activity in reperfusion group likely to be protective.     

The administration of cobra venom factor reduces post-ischemic cerebral injury in adult and neonatal rats

The role of complement in post-ischemic cerebral injury is incompletely understood. Therefore, experiments were designed to test the effect of complement depletion on cerebral infarct volume in adult rats and cerebral atrophy in neonatal rats. Cerebral infarcts were induced in adult rats by transient filamentous occlusion of the right middle cerebral artery (MCAO). Cerebral atrophy was induced by subjecting 7-day-old rats to ligation of the right common carotid artery followed by 2.5h of hypoxia (8% O2). Forty-eight hours after MCAO, coronal sections of adult brains were obtained and stained with 2,3,5-triphenyl tetrazolium chloride. The infant rat brains were removed for analysis 6 weeks after the hypoxic-ischemic insult. Volumes of infarcts and normal hemispheric parenchyma were quantified by computer-based planimetry. Twenty-four hours prior to MCAO (adults) or hypoxia-ischemia (neonates), each animal received an i.p. injection of either 1 mcg/g body weight cobra venom factor (CVF; adult n=11; neonatal n=20) or normal saline (adult n=12; neonatal n=24). In the neonates, a second dose of CVF or saline was administered 2 days after hypoxia-ischemia. The administration of CVF significantly reduced: (1) post-ischemic cerebral infarct volume in the adults and (2) post-hypoxic-ischemic cerebral atrophy in the neonates. Therefore, complement activation augmented post-ischemic cerebral injury in adult and neonatal rats. Complement depletion induced by CVF significantly reduced post-ischemic cerebral infarct volume and atrophy in adult and neonatal rats.     

降钙素基因相关肽对脑缺血大鼠脑血流的影响

大鼠侧脑室注入降钙素基因相关肽（ＣＧＲＰ）或等体积甘露醇为对照，用非损伤阻抗法测定一侧颈总动脉结扎后ＣＧＲＰ对脑血流的影响。结果表明，一侧颈总动脉结扎后，脑血流量降低３４％，此时侧脑室给予ＣＧＲＰ即刻使脑血流图波幅增加，５分钟时达高峰，比注药前平均增加６５％，与甘露醇对照相比差别非常显著（Ｐ＜０．０１），４０分钟时作用开始减弱，１００分钟后作用消失。与颈总动脉结扎前相比，在脑血供不足时，ＣＧＲＰ增     

中药羌菖合剂对脑缺血大鼠外周血细胞的影响

目的 观察中药羌菖合剂对实验性脑缺血大鼠外周血细胞、血清生化指标的影响。方法 采用颈总动脉结扎法建立脑缺血模型。动物分为羌菖合剂3d、7d组;假手术3d、7d组;生理盐水3d、7d组。用称重法测定脑含水量,常规测定各组外周血细胞与生化指标。结果 中药3d、7d组右脑含水量明显低于相应对照组（P＜0．05）,中药3d组外周血WBC明显低于对照组3d组（P＜0．01）,MPV与P－LCR明显高于对照组（P＜0．01）,而生化指标各组间无明显差别。结论 羌菖合剂能明显降低实验大鼠脑缺血时水肿程度,并在早期有减低白细胞应激性升高与血小板活性增强的作用,对机体无明显损伤。