共查询到20条相似文献,搜索用时 31 毫秒
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Candelario-Jalil E Alvarez D González-Falcón A García-Cabrera M Martínez-Sánchez G Merino N Giuliani A León OS 《European journal of pharmacology》2002,453(2-3):189-195
Cyclooxygenase-2 is involved in the inflammatory component of the ischemic cascade, playing an important role in the delayed progression of the brain damage. The present study evaluated the pharmacological effects of the selective cyclooxygenase-2 inhibitor nimesulide on delayed neuronal death of hippocampal CA1 neurons following transient global cerebral ischemia in gerbils. Administration of therapeutically relevant doses of nimesulide (3, 6 and 12 mg/kg; i.p.) 30 min before ischemia and at 6, 12, 24, 48 and 72 h after ischemia significantly (P<0.01) reduced hippocampal neuronal damage. Treatment with a single dose of nimesulide given 30 min before ischemia also resulted in a significant increase in the number of healthy neurons in the hippocampal CA1 sector 7 days after ischemia. Of interest is the finding that nimesulide rescued CA1 pyramidal neurons from ischemic death even when treatment was delayed until 24 h after ischemia (34+/-9% protection). Neuroprotective effect of nimesulide is still evident 30 days after the ischemic episode, providing the first experimental evidence that cyclooxygenase-2 inhibitors confer a long-lasting neuroprotection. Oral administration of nimesulide was also able to significantly reduce brain damage, suggesting that protective effects are independent of the route of administration. The present study confirms the ability of cyclooxygenase-2 inhibitors to reduce brain damage induced by cerebral ischemia and indicates that nimesulide can provide protection when administered for up to 24 h post-ischemia. 相似文献
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Protein transduction technology offers novel therapeutic approach for brain ischemia 总被引:8,自引:0,他引:8
Transient or permanent reduction in cerebral blood flow following ischemia can lead to severe and irreversible tissue damage to the brain. Emerging biochemical evidence suggests a role for apoptosis in neuronal death following cerebral ischemia. Despite the abundance of studies on the subject, therapeutic interventions for ischemia-related cell injury have so far proved disappointing in clinical trials. Recently, four new, exciting studies reported the use of protein transduction technology to deliver anti-apoptotic molecules to protect neuronal cells following ischemic stroke in vivo. These studies offer new avenues for the treatment and prevention of cell death following brain injuries. 相似文献
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Stroke is one of the most important causes of mortality and morbidity in the world. Prevention and effective treatment of stroke is of the utmost importance. Cerebral ischemia causes disturbances in a variety of cellular and molecular mechanisms, including oxidative phosphorylation, membrane function, neurotransmitter release, and free radical generation. It has been years since tissue-type plasminogen activator (t-PA) became the first medication approved by the FDA for the management of stroke, with limited success. Thrombolytic therapy is the most effective therapeutic strategy for the prevention of brain injury and reduction of mortality in patients with cerebral infarction. However, a combination of established thrombolytic therapy and effective neuronal protection therapy may have more beneficial effects for patients with cerebral infarction. Because clinical trials of pharmacological neuroprotective strategies in stroke have been disappointing, attention has turned towards approaches which include herbal drugs that can be used in limiting the neurological damage associated with stroke. Herbal drugs may be used as prophylactic treatment in patients with high risk of stroke. Herbals drugs have been described in ancient systems of medicine for the treatment of various ailments associated with stroke and have more recently been reported to be beneficial in treating stroke. However, the strength of evidence to support the use of these herbal drugs is unclear. This review focuses on putative mechanisms underlying the beneficial effects of herbal drugs in patients with stroke and on the possibility of herbal drugs to increase the therapeutic time window in patients with cerebral ischemia. 相似文献
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Neuroinflammation is one of the key pathological events involved in the progression of brain damage caused by cerebral ischemia. Metabolism of arachidonic acid through cyclooxygenase (COX) enzymes is known to be actively involved in the neuroinflammatory events leading to neuronal death after ischemia. Two isoforms of COX, termed COX-1 and COX-2, have been identified. Unlike COX-1, COX-2 expression is dramatically induced by ischemia and appears to be an effector of tissue damage. This review article will focus specifically on the involvement of COX isozymes in brain ischemia. We will discuss issues related to the biochemistry and selective pharmacological inhibition of COX enzymes, and further refer to their expression in the brain under normal conditions and following excitotoxicity and ischemic cerebral injury. We will review present knowledge of the relative contribution of each COX isoform to the brain ischemic pathology, based on data from investigations utilizing selective COX-1/COX-2 inhibitors and genetic knockout mouse models. The mechanisms of neurotoxicity associated with increased COX activity after ischemia will also be examined. Finally, we will provide a critical evaluation of the therapeutic potential of COX inhibitors in cerebral ischemia and discuss new targets downstream of COX with potential neuroprotective ability. 相似文献
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目的:探索依达拉奉注射液的治病机制,以期为临床合理使用提供理论依据和参考。方法:以"依达拉奉注射液"或"edaravone injection"为检索词,检索近年来国内、外医药文献发表的大量临床试验和研究,并对依达拉奉注射液的药理作用和临床应用等研究结果进行分析、总结和评价。结果与结论:依达拉奉对缺血再灌注损伤具有保护作用,能清除自由基、抑制脂质过氧化、有效降低高血压脑出血患者血浆ET值,升高CGRP及SPECT值,改善局部脑血流,达到保护脑细胞的作用。随着依达拉奉的药理作用和作用机制的深入研究,目前已广泛应用于临床,且其适应证也在逐步拓宽。 相似文献
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当归基于功效物质基础的抗脑缺血药理作用研究进展 总被引:1,自引:0,他引:1
目的总结当归与功效物质基础相关的抗缺血性脑损伤药理作用研究现状,明确当归抗脑缺血物质基础、药理特点及分子机制,为进一步研究当归抗缺血性脑损伤与功效、物质基础间的相关性提供文献依据和思路。方法对近十几年来国内外发表的相关文献进行分析、整理和归纳。结果当归具有多种生物活性成分和广泛的药理作用,临床上用于缺血性脑血管病治疗取得较好疗效。结论目前对于当归功效物质基础研究多局限于单一成分的药效学研究和机制探讨,缺少多个有效成分之间药理学研究与机制探讨;中药化学成分复杂,具有非单一效应,因此,应结合其功效加强当归有效单体成分、有效成分群、有效部位、有效部位群之间的药效学研究及其作用靶点和联合保护机制研究,为阐明当归临床疗效及功效作用机理提供理论依据,以便更好地指导临床合理用药和创新药物研发。 相似文献
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Fengling Pu Kyoko Motohashi Tomohiro Kaneko Yurika Tanaka Naomi Manome Keiichi Irie Jirou Takata Nobuaki Egashira Ryozo Oishi Takuya Okamoto Yasuo Sei Takako Yokozawa Kenichi Mishima Katsunori Iwasaki Michihiro Fujiwara 《Journal of pharmacological sciences》2009,109(3):424-430
In the present study, we investigated the neuroprotective effects of Kangen-karyu (KGK) in a repeated cerebral ischemia model (2 × 10 min, 1-h interval). A 21-day pre- and postischemic treatment with KGK (10 – 300 mg/kg) and aspirin (5 mg/kg) improved the spatial memory impairment and neuronal death in the hippocampal CA1 region induced by repeated cerebral ischemia. However, a 7-day post-ischemic treatment with KGK did not attenuate the spatial memory impairment and neuronal death in this model. To determine the mechanism of action of KGK, we investigated the effects of a 14-day pre-ischemic treatment with KGK on cerebral blood flow in the hippocampal area of the repeated cerebral ischemia model using laser Doppler flowmetry. The 14-day pre-ischemic treatment with KGK increased the cerebral blood flow during reperfusion. These results suggest that a 21-day pre- and post-ischemic treatment with KGK can protect against brain damage caused by cerebral ischemia by increasing the cerebral blood flow in the hippocampal area. 相似文献
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Zausinger S 《IDrugs : the investigational drugs journal》2003,6(10):970-975
Bradykinin, an endogenous nonapeptide produced by activation of the kallikrein-kinin system, promotes neuronal tissue damage as well as disturbances in blood-brain barrier function, mainly through the activation of B2 receptors. Both cerebral ischemia and trauma are associated with an activation of the kallikrein-kinin system, resulting in a sustained production of kinins. This is strong evidence supporting an involvement of bradykinin-mediated secondary brain damage following cerebral ischemia and trauma. Accordingly, specific inhibition of bradykinin B2 receptors attenuates brain swelling and limits tissue damage, indicating its potential in patients with acute cerebral ischemia and trauma. 相似文献
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Honokiol suppresses the development of post-ischemic glucose intolerance and neuronal damage in mice
Harada S Kishimoto M Kobayashi M Nakamoto K Fujita-Hamabe W Chen HH Chan MH Tokuyama S 《Journal of natural medicines》2012,66(4):591-599
Honokiol, a constituent of Magnolia obovata, has various pharmacological effects, including protection against cerebral ischemia. However, few studies have been conducted to evaluate the possible neuroprotective effects of honokiol against cerebral ischemia. We recently reported that cerebral ischemic neuronal damage could be triggered by glucose intolerance that develops after the onset of ischemic stress (i.e., post-ischemic glucose intolerance). In addition, suppression of post-ischemic glucose intolerance significantly ameliorated ischemic neuronal damage. Here, we investigated the effects of honokiol on the development of post-ischemic glucose intolerance and neuronal damage. Mice were subjected to middle cerebral artery occlusion (MCAO) for 2?h. The development of post-ischemic glucose intolerance on day 1 and neuronal damage on day 3 after MCAO were significantly reduced by intraperitoneal administration of honokiol (10?mg/kg) compared with the vehicle-treated group. Honokiol did not affect serum insulin or adiponectin levels. However, honokiol significantly decreased the expression of phosphoenolpyruvate carboxykinase and increased the expression of 5'-AMP-activated protein kinase (AMPK) on day 1 after MCAO, compared with the vehicle-treated MCAO group. The results of this study suggest that honokiol could prevent post-ischemic glucose intolerance in an AMPK-dependent manner, which may be involved in the neuroprotective effects of honokiol against cerebral ischemia. 相似文献
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Takano H Sugimura M Kanazawa Y Uchida T Morishima Y Shirasaki Y 《Biological & pharmaceutical bulletin》2004,27(11):1788-1791
An excessive elevation of intracellular Ca(2+) levels is known to play a key role in the pathological events following cerebral ischemia. DY-9760e, 3-[2-[4-(3-chloro-2-methylphenylmethyl)-1-piperazinyl]ethyl]-5,6-dimethoxy-1-(4-imidazolylmethyl)-1H-indazole dihydrochloride 3.5 hydrate, is a potent calmodulin antagonist that attenuates brain damage in focal ischemia models. In the present study, we investigated the effect of DY-9760e on neuronal cell death induced by a variety of cell-toxic stimuli that increase intracellular Ca(2+). Cell death was induced by the exposure of primary cultured neurons to excitotoxic agents such as glutamate and N-methyl-D-aspartate, membrane-depolarizing agents such as veratridine and high KCl, or thapsigargin an endoplasmic reticulum Ca(2+)-ATPase inhibitor. Treatment with DY-9760e resulted in a dose-dependent prevention of neuronal cell death elicited by excitotoxicity, voltage-gated channel opening, and inhibition of endoplasmic reticulum Ca(2+)-ATPase. These results indicate that DY-9760e can rescue neurons from various types of cell-toxic stimuli, which may contribute to attenuation of brain injury after cerebral ischemia. 相似文献
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Emodin-8-O-beta-D-glucoside extracted from the traditional Chinese medicinal herb Polygonum cuspidatum Sieb. et Zucc is widely used to treat acute hepatitis possibly by antioxidative mechanisms. The present study was designed to investigate whether emodin-8-O-beta-D-glucoside exerted neuroprotective effects on the focal cerebral injury induced by ischemia and reperfusion in vivo and on the neuronal damage induced by glutamate in vitro, and to study the possible mechanisms. Male Wistar rats were used to establish the model of ischemia and reperfusion. The behavioral test was performed and the cerebral infarction area was assessed in the brain slices stained with 2% 2,3,5-triphenyl tetrazolium chloride to evaluate the neuroprotective effects of emodin-8-O-beta-D-glucoside. Superoxide dismutase (SOD) activity, total antioxidative capability and malondialdehyde (MDA) level in the brain tissue were determined with spectrophotometrical methods to probe the primary mechanisms of emodin-8-O-beta-D-glucoside. In vitro, the neuroprotective effects of emodin-8-O-beta-D-glucoside were tested in the cultured cortical cells of fetal rats exposed to glutamate. Emodin-8-O-beta-D-glucoside concentration in plasma and brain tissue was also measured to examine distribution of emodin-8-O-beta-D-glucoside in the brain. The results showed that the treatment of rats with emodin-8-O-beta-D-glucoside reduced the neurological deficit score and the cerebral infarction area, increased SOD activity and total antioxidative capability, and decreased MDA level in the brain tissue in dose-dependent way. Emodin-8-O-beta-D-glucoside also inhibited the neuronal damage induced by glutamate. Besides, emodin-8-O-beta-D-glucoside was able to penetrate blood-brain barrier and distribute in the brain tissue. These findings demonstrate that emodin-8-O-beta-D-glucoside is able to provide neuroprotection against cerebral ischemia-reperfused injury and glutamate induced neuronal damage through exerting antioxidative effects and inhibiting glutamate neurotoxicity. 相似文献
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侧脑室注射血管内皮生长因子抗体加重短暂性脑缺血后脑损伤 总被引:25,自引:0,他引:25
AIM: To clarify the role of vascular endothelial growth factor (VEGF) in neuronal damage induced by cerebral ischemia. METHODS: Expression of VEGF in adult rat brain was measured by immunohistochemistry. Transient middle cerebral artery occlusion (MCAO) model was induced by placing a nylon thread in the lumen of the internal carotid artery. The infarct volume was shown with 2,3,5-triphenyltetrazolium chloride (TTC) staining and quantitated by computer image analyzer with and without VEGF antibody treatment. RESULTS: VEGF expression was widely distributed in neuronal cells besides vascular endothelial cells, and the neuronal distribution of VEGF was specific. After intraventricular treatment with VEGF antibody (0.1 g.L-1 daily, for 7 d following the ischemia), infarct volume in the antibody treatment was increased versus vehicle-treated rats [(21.6 +/- 2.7 vs 16 +/- 6) mm3, P < 0.05] respectively. CONCLUSION: Intraventricular injection of VEGF antibody increased the infarct volume after focal cerebral ischemia in rats, suggesting that expression of neuronal VEGF may be one of neuronal protective mechanisms. 相似文献
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A Ravati V Junker M Kouklei B Ahlemeyer C Culmsee J Krieglstein 《European journal of pharmacology》1999,373(1):21-33
Angiotensin-converting enzyme inhibitors have been demonstrated to protect spontaneously hypertensive rats from cerebral ischemia. The present study investigated the protective effect of enalapril and moexipril in models of permanent focal cerebral ischemia in normotensive mice and rats. To elucidate the mechanism of neuroprotection the influence of these angiotensin-converting enzyme inhibitors on glutamate-, staurosporine- or Fe2+/3+-induced generation of reactive oxygen species and neuronal cell death in primary cultures from chick embryo telencephalons was studied. Treatment with moexipril or enalapril dose-dependently reduced the percentage of damaged neurons, as well as mitochondrial reactive oxygen species generation induced by glutamate, staurosporine or Fe2+/3+. Furthermore, moexipril and enalapril attenuated staurosporine-induced neuronal apoptosis as determined by nuclear staining with Hoechst 33258. In mice, 1 h pretreatment with enalapril (0.03 mg/kg) or moexipril (0.3 mg/kg) significantly reduced brain damage after focal ischemia as compared to control animals. Additionally, moexipril (0.01 mg/kg) was able to reduce the infarct volume in the rat model after focal cerebral ischemia. The results of the present study indicate that the angiotensin-converting enzyme inhibitors enalapril and moexipril promote neuronal survival due to radical scavenging properties. 相似文献
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Poly(ADP-ribosyl)ation and stroke. 总被引:5,自引:0,他引:5
Alberto Chiarugi 《Pharmacological research》2005,52(1):15-24
Over the past decade, poly(ADP-ribosyl)ation has emerged as a crucial event in the pathogenesis of ischemic stroke. A large body of evidence unambiguously demonstrates that activity of poly(ADP-ribose) polymerase-1 (PARP-1) significantly increases during brain ischemia, and that inhibition of this enzymatic activity affords substantial neuroprotection from ischemic brain injury. This review strictly focuses on literature on poly(ADP-ribosyl)ation and ischemic stroke, highlighting the pathogenetic role of poly(ADP-ribose) in ischemic neuronal death, and the therapeutic relevance of drugs modulating its metabolism to pharmacological treatment of cerebral ischemia. 相似文献