Journal articles: 'Cerebral ischemia – Animal models'

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Umemura, Kazuo. "Experimental animal models of cerebral ischemia." Japanese Journal of Pharmacology 76 (1998): 39. http://dx.doi.org/10.1016/s0021-5198(19)40286-2.

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Takizawa, Shunya, and Antoine M. Hakim. "Animal Models of Cerebral Ischemia. 2. Rat Models." Cerebrovascular Diseases 1, no. 1 (1991): 16–21. http://dx.doi.org/10.1159/000108876.

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Ma, Rong, Qian Xie, Yong Li, Zhuoping Chen, Mihong Ren, Hai Chen, Hongyan Li, Jinxiu Li, and Jian Wang. "Animal models of cerebral ischemia: A review." Biomedicine & Pharmacotherapy 131 (November 2020): 110686. http://dx.doi.org/10.1016/j.biopha.2020.110686.

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Bacigaluppi, Marco. "Animal Models of Ischemic Stroke. Part Two: Modeling Cerebral Ischemia." Open Neurology Journal 4, no. 1 (August 31, 2010): 34–38. http://dx.doi.org/10.2174/1874205x01004010034.

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Traystman, R. J. "Animal Models of Focal and Global Cerebral Ischemia." ILAR Journal 44, no. 2 (January 1, 2003): 85–95. http://dx.doi.org/10.1093/ilar.44.2.85.

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O'Collins, Victoria E., Malcolm R. Macleod, Geoffrey A. Donnan, and David W. Howells. "Evaluation of Combination Therapy in Animal Models of Cerebral Ischemia." Journal of Cerebral Blood Flow & Metabolism 32, no. 4 (February 1, 2012): 585–97. http://dx.doi.org/10.1038/jcbfm.2011.203.

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Combination therapy has been identified as a promising strategy to improve stroke management. We conducted a systematic review and meta-analysis of evidence from animal models of ischemic stroke to determine whether combining treatments improved efficacy. Multiple databases were searched and data were extracted from focal ischemia experiments comparing control groups, single treatments, and combination treatments. Of 11,430 papers identified, 142 met the inclusion criteria; these tested 126 treatments in 373 experiments using 8,037 animals ( I2 = 85 to 96%). Taken together, single treatments reduced infarct size by 20% and improved neurological score by 12% compared with control; a second therapy improved efficacy by an additional 18% and 25%, respectively. Publication bias may affect combination efficacy for infarct size but not neurological score. Combining thrombolysis with other therapies may extend the time window from 4.4 to 8 hours in animal models, although testing beyond 6 hours is required to confirm this. Benefits of additional therapy decreased as the efficacy of the primary treatment increased, with combination efficacy reaching a ceiling at 60% to 80% protection. Combining treatments may bring benefits and extend the time window for treatment. More evidence is needed due to potential publication bias and heterogeneity.

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Schweizer, Sophie, Andreas Meisel, and Stefanie Märschenz. "Epigenetic Mechanisms in Cerebral Ischemia." Journal of Cerebral Blood Flow & Metabolism 33, no. 9 (June 12, 2013): 1335–46. http://dx.doi.org/10.1038/jcbfm.2013.93.

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Treatment efficacy for ischemic stroke represents a major challenge. Despite fundamental advances in the understanding of stroke etiology, therapeutic options to improve functional recovery remain limited. However, growing knowledge in the field of epigenetics has dramatically changed our understanding of gene regulation in the last few decades. According to the knowledge gained from animal models, the manipulation of epigenetic players emerges as a highly promising possibility to target diverse neurologic pathologies, including ischemia. By altering transcriptional regulation, epigenetic modifiers can exert influence on all known pathways involved in the complex course of ischemic disease development. Beneficial transcriptional effects range from attenuation of cell death, suppression of inflammatory processes, and enhanced blood flow, to the stimulation of repair mechanisms and increased plasticity. Most striking are the results obtained from pharmacological inhibition of histone deacetylation in animal models of stroke. Multiple studies suggest high remedial qualities even upon late administration of histone deacetylase inhibitors (HDACi). In this review, the role of epigenetic mechanisms, including histone modifications as well as DNA methylation, is discussed in the context of known ischemic pathways of damage, protection, and regeneration.

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Handayani, Ety S., Titis Nurmasitoh, Syaefudin Ali Akhmad, Afifah Nur Fauziah, Rizky Rizani, Rika Yulita Rahmawati, and Angga Afriandi. "Effect of BCCAO Duration and Animal Models Sex on Brain Ischemic Volume After 24 Hours Reperfusion." Bangladesh Journal of Medical Science 17, no. 1 (January 11, 2018): 129–37. http://dx.doi.org/10.3329/bjms.v17i1.35293.

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Background: Literature study shows, there are several variations regarding BCCAO duration and duration of reperfusion after BCCAO that can cause cerebral ischemia. Duration of BCCAO techniques varies between 10 to 30 minutes, while the duration of reperfusion period ranging between 45 minutes to 72 hours. Differences in the duration of occlusion, duration of BCCAO reperfusion and the sex of animal model could lead to different responses to ischemia conditions.Objective. This study aims to determine whether the duration BCCAO and sex of the animal models influences the volume of cerebral ischemia after 24 hours reperfusion.Method: This study uses post-test only study group design. The subjects are 20 female and 20 male Wistar rat that being divided into 8 groups which are male rat with occlusion duration of 5 minutes, 10 minutes and 20 minute, also the female rat with occlusion duration of 5 minutes, 10 minutes, 20 minutes respectively. BCCAO occlusion then followed by 24 hour reperfusion. Rat decapitation and brain extraction are done after reperfusion. Brain tissue sliced into 2 mm size and stained with 0.05% TTC solution for 30 minutes. Ischemic brain volume are being observed using Cavalieri method. Statistical data are being analyzed using One Way Anova.Result: There are significant difference in male rat cerebral ischemia volume between 5 minutes and 10 minutes occlusion (p<0.006). Meanwhile, there are no significant difference at cerebral ischemia volume between 10 and 20 minutes occlusion group (p=0.377). There are significant differences in the volume of brain ischemia between the 5, 10 and 20 minutes ischemia group (p<0.05). Post-hoc test showed no significant differences between the male and female rat (p>0.05).Conclusion: Duration of the bilateral common carotid artery occlusion for 5 and 10 minutes affect the volume of cerebral ischemia in male rat after 24 hour reperfusion. The occlusion of bilateral common carotid artery for 5,10 and 20 minutes also affect the volume of cerebral ischemia in female rat after 24 hour reperfusion. No significant differences of cerebral ischemia volume between the sexes after 5, 10 and 20 minutes occlusion.Bangladesh Journal of Medical Science Vol.17(1) 2018 p.129-137

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Cirillo, Carla, Nabila Brihmat, Evelyne Castel-Lacanal, Alice Le Friec, Marianne Barbieux-Guillot, Nicolas Raposo, Jérémie Pariente, et al. "Post-stroke remodeling processes in animal models and humans." Journal of Cerebral Blood Flow & Metabolism 40, no. 1 (October 23, 2019): 3–22. http://dx.doi.org/10.1177/0271678x19882788.

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After cerebral ischemia, events like neural plasticity and tissue reorganization intervene in lesioned and non-lesioned areas of the brain. These processes are tightly related to functional improvement and successful rehabilitation in patients. Plastic remodeling in the brain is associated with limited spontaneous functional recovery in patients. Improvement depends on the initial deficit, size, nature and localization of the infarction, together with the sex and age of the patient, all of them affecting the favorable outcome of reorganization and repair of damaged areas. A better understanding of cerebral plasticity is pivotal to design effective therapeutic strategies. Experimental models and clinical studies have fueled the current understanding of the cellular and molecular processes responsible for plastic remodeling. In this review, we describe the known mechanisms, in patients and animal models, underlying cerebral reorganization and contributing to functional recovery after ischemic stroke. We also discuss the manipulations and therapies that can stimulate neural plasticity. We finally explore a new topic in the field of ischemic stroke pathophysiology, namely the brain-gut axis.

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Hossmann, Konstantin-A. "Animal Models of Cerebral Ischemia. 1. Review of Literature." Cerebrovascular Diseases 1, no. 1 (1991): 2–15. http://dx.doi.org/10.1159/000108875.

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Wang, Peng-Fei, Yu Zhou, Huang Fang, Sen Lin, Yan-Chun Wang, Yong Liu, Jun Xia, Guy D. Eslick, and Qing-Wu Yang. "Treatment of acute cerebral ischemia using animal models: a meta-analysis." Translational Neuroscience 6, no. 1 (January 1, 2015): 47–58. http://dx.doi.org/10.1515/tnsci-2015-0006.

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AbstractBackground: There are numerous potential treatments assessed for acute cerebral ischemia using animal models. This study aimed to assess the effect of these treatments in terms of infarct size and neurobehavioral change. This meta-analysis was conducted to determine if any of these treatments provide a superior benefit so that they might be used on humans. Methods: A systematic search was conducted using several electronic databases for controlled animal studies using only nonsurgical interventions for acute cerebral ischemia. A random-effects model was used. Results: After an extensive literature search, 145 studies were included in the analysis. These studies included 1408 treated animals and 1362 control animals. Treatments that had the most significant effect on neurobehavioral scales included insulin, various antagonists, including N-methyl-Daspartate (NMDA) receptor antagonist ACEA1021, calmodulin antagonist DY-9760e, and α-amino-3-hydroxy-5- methyl-4-isoxazolepropionic acid (AMPA) receptor antagonist YM872, and antiviral agents. Treatments providing the greatest effect on infarct size included statins, sphingosine-1-phosphate agonist (fingolimod), alcohol, angiotensin, and leukotrienes. Treatments offering the greatest reduction in brain water content included various agonists, including sphingosine-1-phosphate agonist fingolimod, statins, and peroxisome proliferator-activated receptor gamma (PPAR-γ). Treatment groups with more than one study all had high heterogeneity (I2 > 80%), however, using meta-regression we determined several sources of heterogeneity including sample size of the treatment and control groups, the occlusion time, but not the year when the study was conducted. Conclusions: Some treatments stand out when compared to others for acute cerebral ischemia in animals. Greater replication of treatment studies is required before any treatments are selected for future human trials.

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Meng, Wei, Xiaoying Wang, Minoru Asahi, Tsuneo Kano, Kazuko Asahi, Robert H. Ackerman, and Eng H. Lo. "Effects of Tissue Type Plasminogen Activator in Embolic versus Mechanical Models of Focal Cerebral Ischemia in Rats." Journal of Cerebral Blood Flow & Metabolism 19, no. 12 (December 1999): 1316–21. http://dx.doi.org/10.1097/00004647-199912000-00004.

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Tissue type plasminogen activator (tPA) can be effective therapy for embolic stroke by restoring cerebral perfusion. However, a recent experimental study showed that tPA increased infarct size in a mouse model of transient focal ischemia, suggesting a possible adverse effect of tPA on ischemic tissue per se. In this report, the effects of tPA in two rat models of cerebral ischemia were compared. In experiment 1, rats were subjected to focal ischemia via injection of autologous clots into the middle cerebral artery territory. Two hours after clot injection, rats were treated with 10 mg/kg tPA or normal saline. Perfusion-sensitive computed tomography scanning showed that tPA restored cerebral perfusion in this thromboembolic model. Treatment with tPA significantly reduced ischemic lesion volumes measured at 24 hours by >60%. In experiment 2, three groups of rats were subjected to focal ischemia via a mechanical approach in which a silicon-coated filament was used intraluminally to occlude the origin of the middle cerebral artery. In two groups, the filament was withdrawn after 2 hours to allow for reperfusion, and then rats were randomly treated with 10 mg/kg tPA or normal saline. In the third group, rats were not treated and the filament was not withdrawn so that permanent focal ischemia was present. In this experiment, tPA did not significantly alter lesion volumes after 2 hours of transient focal ischemia. In contrast, permanent ischemia significantly increased lesion volumes by 55% compared with transient ischemia. These results indicate that in these rat models of focal cerebral ischemia, tPA did not have detectable negative effects. Other potentially negative effects of tPA may be dependent on choice of animal species and model systems.

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Bigdeli, Mohammad Reza. "Neuroprotection Caused by Hyperoxia Preconditioning in Animal Stroke Models." Scientific World JOURNAL 11 (2011): 403–21. http://dx.doi.org/10.1100/tsw.2011.23.

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Ischemic tolerance induced by hyperoxia (HO) can protect against brain injury and neurodegenerative diseases. Although multiple studies demonstrate neuroprotection by HO, the exact mechanism(s) of HO neuroprotection has not been elucidated. Here, I first review related mechanisms of brain ischemia and then data evaluating the neuroprotective effects of HO in focal and global ischemic animal models. I clearly establish that the cerebrovascular, extracellular matrix, plasma membrane, endoplasmic reticulum, mitochondrial, and lysosomal reactions are critical in neuroprotection induced by HO in focal ischemia. In rats and mice, the middle cerebral artery occlusion (MCAO) model was used to represent cerebrovascular stroke. Neuroprotection induced by HO exhibits specific adaptation responses that involve a number of cellular and biochemical alterations, including metabolic homeostasis and reprogramming of gene expression. The changes in the metabolic pathways are generally short lived and reversible, while the consequences of gene expression are a long-term process and may lead to the permanent alteration in the pattern of gene expression. The neuroprotection provided by HO may have important clinical implications. Therefore, it is important to assess the benefits and risks of HO therapy in noninfarcted tissue.

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Tamura, Akira. "Animal models of cerebral ischemia. How to select the model." Nosotchu 30, no. 6 (2008): 857–61. http://dx.doi.org/10.3995/jstroke.30.857.

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Hoehn, Mathias, Klaas Nicolay, Claudia Franke, and Boudewijn van der Sanden. "Application of magnetic resonance to animal models of cerebral ischemia." Journal of Magnetic Resonance Imaging 14, no. 5 (2001): 491–509. http://dx.doi.org/10.1002/jmri.1213.

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Handayani, Ety Sari, Rina Susilowati, Ismail Setyopranoto, and Ginus Partadiredja. "Transient Bilateral Common Carotid Artery Occlusion (tBCCAO) of Rats as a Model of Global Cerebral Ischemia." Bangladesh Journal of Medical Science 18, no. 3 (May 30, 2019): 491–500. http://dx.doi.org/10.3329/bjms.v18i3.41616.

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Background: Transient bilateral common carotid artery occlusion (tBCCAO) has been performed in rats as a model of global ischemia. However, the technique varied between laboratories and produced difficulties in the comparison of results. Variations such as rat strain, age, ischemic and reperfusion duration could affect the results. This review aims to provide a general overview of the variation of animal strains, duration of tBCCAO, reported cerebral ischemic area produced by tBCCAO, use of TTC staining for measurement of volume of brain ischemia and functional neurological tests. Method: The data of this review were obtained from abstracts in PubMed database and Google Scholars and were not limited by publication time. Keywords used to search the abstracts were (BCCAO OR “bilateral common carotid artery occlusion” OR “stroke” OR “cerebral ischemia” OR “brain ischemia”) AND (rat OR rats). The research method of each study was identified from the collected abstracts. The abstracts were chosen for further study on the basis that they met the inclusion criteria which were English language articles; original research article; animal model used were adolescent, adult, and elderly rats; ischemic finding in rats’ cerebrum by BCCAO technique was presented; ischemic size were assessed and the result was described; studies that had control group; and studies that induced transient global ischemic to the rats’ cerebrum. Data that were extracted to the datasheet were references; animal model strain; ischemic duration; reperfusion duration; ischemic area; 2,3,5 Triphenyltetrazolium Chloride (TTC) staining; Cavalieri method; and rats’ neurological functional tests. Results and Conclusions: There were differences in the ischemic area between Wistar and Sprague-Dawley rats after transient BCCAO. There were differences in the TTC staining solution concentration that was used to identify ischemic area of the brain following transient BCCAO. There was a very limited number of studies using Cavalieri method for the quantification of ischemic volume of rats’ brain after transient BCCAO. Neurological functional tests in animal models post transient BCCAO did not include sensory and memory functions tests. Bangladesh Journal of Medical Science Vol.18(3) 2019 p.491-500

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Kitagawa, Kazuo, Masayasu Matsumoto, Gongming Yang, Takuma Mabuchi, Yoshiki Yagita, Masatsugu Hori, and Takehiko Yanagihara. "Cerebral Ischemia after Bilateral Carotid Artery Occlusion and Intraluminal Suture Occlusion in Mice: Evaluation of the Patency of the Posterior Communicating Artery." Journal of Cerebral Blood Flow & Metabolism 18, no. 5 (May 1998): 570–79. http://dx.doi.org/10.1097/00004647-199805000-00012.

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Cerebral ischemia models using mice have drawn increasing attention, particularly because of the availability of transgenic animals. However, the variability of intracranial vasculature at the circle of Willis in mice can influence the degree of ischemia in both the bilateral common carotid artery (CCA) occlusion and intraluminal suture occlusion models. We have developed a method to predict the extent of the anastomosis between carotid and vertebrobasilar circulation in three mouse strains (C57BL/6, CBA, and DBA/2) by measuring cortical microperfusion with laser Doppler flowmetry during a 1-minute occlusion of both CCA. When animals showed residual cortical microperfusion of less than 12% during bilateral CCA occlusion, the mice showed absence of functional anastomosis, developed ATP depletion in the frontal cortex during occlusion, and had ischemic neuronal death in the hippocampus and caudoputamen after occlusion for 15 minutes and recirculation for 7 days. Furthermore, those mice exhibited decreased local cerebral blood flow and associated ischemic neuronal death in the hippocampus, within the territory supplied by the posterior cerebral artery, with the intraluminal suture occlusion model. The current study demonstrates the need for assessment of intracranial vasculature in each animal by measuring cortical microperfusion during temporary occlusion of both CCA, no matter whether cerebral ischemia is produced by bilateral CCA occlusion or intraluminal suture occlusion in transgenic mice.

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Ahad, Mohamad Anuar, Kesevan Rajah Kumaran, Tiang Ning, Nur Izzati Mansor, Mohamad Azmeer Effendy, Thenmoly Damodaran, Kamilla Lingam, et al. "Insights into the neuropathology of cerebral ischemia and its mechanisms." Reviews in the Neurosciences 31, no. 5 (July 28, 2020): 521–38. http://dx.doi.org/10.1515/revneuro-2019-0099.

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AbstractCerebral ischemia is a result of insufficient blood flow to the brain. It leads to limited supply of oxygen and other nutrients to meet metabolic demands. These phenomena lead to brain damage. There are two types of cerebral ischemia: focal and global ischemia. This condition has significant impact on patient’s health and health care system requirements. Animal models such as transient occlusion of the middle cerebral artery and permanent occlusion of extracranial vessels have been established to mimic the conditions of the respective type of cerebral ischemia and to further understand pathophysiological mechanisms of these ischemic conditions. It is important to understand the pathophysiology of cerebral ischemia in order to identify therapeutic strategies for prevention and treatment. Here, we review the neuropathologies that are caused by cerebral ischemia and discuss the mechanisms that occur in cerebral ischemia such as reduction of cerebral blood flow, hippocampal damage, white matter lesions, neuronal cell death, cholinergic dysfunction, excitotoxicity, calcium overload, cytotoxic oedema, a decline in adenosine triphosphate (ATP), malfunctioning of Na+/K+-ATPase, and the blood-brain barrier breakdown. Altogether, the information provided can be used to guide therapeutic strategies for cerebral ischemia.

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Sysoev, Yuriy I., Veronika A. Prikhodko, Dmitry Y. Ivkin, and Sergey Okovity. "Rabbit models of ischemic stroke in biomedical research." Pharmacy Formulas 1, no. 1 (December 12, 2019): 10–21. http://dx.doi.org/10.17816/phf18514.

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The development of experimental models of ischemic stroke allowing for effective translation of results from animal studies to humans is an important task of modern neuropharmacology. Due to the fact that new drugs with neuroprotective properties that have shown activity in rodents most often turn out to be not effective enough in humans, the use of larger laboratory animals may become a viable solution. Among the latter, rabbits are the most accessible species for laboratories. Since they have gyrencephalic brains and a significant amount of white matter, they can be considered to be highly similar to humans. In the present review, we discussed the main methods of ischemic stroke modelling in rabbits. The breed, age and sex of the animals, anesthesia methods as well as criteria for functional state assessment after cerebral ischemia are the issues that should be addressed before the start of the study.

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Rosen, Charles L., Vincent A. Dinapoli, Tomoaki Nagamine, and Todd Crocco. "Influence of age on stroke outcome following transient focal ischemia." Journal of Neurosurgery 103, no. 4 (October 2005): 687–94. http://dx.doi.org/10.3171/jns.2005.103.4.0687.

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Object. More than 100 clinical trials based on animal models have failed to identify a clinically effective neuroprotectant for stroke. Current models of stroke do not account adequately for aging nor do they incorporate the use of female animals. The authors evaluated the pathological and physiological differences in stroke in young, adult, and elderly female rats. Methods. Three groups of female Sprague—Dawley rats were studied. Nine rats were divided into three groups: young (3 months); adult (9 months); and elderly (18 months). Intraluminal filament occlusion was performed for 120 minutes while cerebral blood flow was monitored. Physiological parameters were assessed. Infarction volumes were quantified at 24 hours. The mean arterial pressure increased in the young animals (103 ± 3.51 mm Hg; p < 0.001) during occlusion and decreased in the elderly group (65.56 ± 3.03 mm Hg; p < 0.01). Cortical and striatal infarction volumes in the elderly animals were substantially larger (p < 0.05). Young animals exhibited a lesser decrement in cerebral blood flow (p < 0.05) during ischemia. Conclusions. This study reinforces the importance of using older animals for the researching and treatment of stroke. Elderly animals show differences in response mechanisms, ischemic consequences, and histological changes. These differences may partially explain the current lack of success involved in using young-animal models to predict the clinical efficacy of neuroprotective agents.

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Barber, Philip A., Roland N. Auer, Alastair M. Buchan, and Garnette R. Sutherland. "Understanding and managing ischemic stroke." Canadian Journal of Physiology and Pharmacology 79, no. 3 (March 1, 2001): 283–96. http://dx.doi.org/10.1139/y00-125.

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Transient or permanent focal brain injury following acute thromboembolic occlusion develops from a complex cascade of pathophysiological events. The processes of excitotoxicity, peri-infarct depolarisation, inflammation, and apoptosis within the ischemic penumbra are proposed. While the translation of therapeutic agents from the animal models to human clinical trials have been disappointing, there remains an atmosphere of optimism as a result of the development of new diagnostic and therapeutic approaches, which include physiological, as opposed to pharmacological, intervention. This article provides an insight into the understanding of cerebral ischemia, together with current and future treatment strategies.Key words: cerebral ischemia, stroke, pathophysiology.

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MAGGIONI, A. "Activity of ?-dihydroergocryptine in some animal models of cerebral anoxia and ischemia." Pharmacological Research 26 (September 1992): 69. http://dx.doi.org/10.1016/1043-6618(92)90848-6.

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Washida, Kazuo, Yorito Hattori, and Masafumi Ihara. "Animal Models of Chronic Cerebral Hypoperfusion: From Mouse to Primate." International Journal of Molecular Sciences 20, no. 24 (December 7, 2019): 6176. http://dx.doi.org/10.3390/ijms20246176.

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Vascular cognitive impairment (VCI) or vascular dementia occurs as a result of brain ischemia and represents the second most common type of dementia after Alzheimer’s disease. To explore the underlying mechanisms of VCI, several animal models of chronic cerebral hypoperfusion have been developed in rats, mice, and primates. We established a mouse model of chronic cerebral hypoperfusion by narrowing the bilateral common carotid arteries with microcoils, eventually resulting in hippocampal atrophy. In addition, a mouse model of white matter infarct-related damage with cognitive and motor dysfunction has also been established by asymmetric common carotid artery surgery. Although most experiments studying chronic cerebral hypoperfusion have been performed in rodents because of the ease of handling and greater ethical acceptability, non-human primates appear to represent the best model for the study of VCI, due to their similarities in much larger white matter volume and amyloid β depositions like humans. Therefore, we also recently developed a baboon model of VCI through three-vessel occlusion (both the internal carotid arteries and the left vertebral artery). In this review, several animal models of chronic cerebral hypoperfusion, from mouse to primate, are extensively discussed to aid in better understanding of pathophysiology of VCI.

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Han, Xue Mei, Hong Tao Wei, and Song Yan Liu. "Functional Role of HIF-1α in Hypoxic Preconditioning-Induced Neuroprotection against Focal Cerebral Ischemia." Advanced Materials Research 554-556 (July 2012): 1762–67. http://dx.doi.org/10.4028/www.scientific.net/amr.554-556.1762.

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Objective To investigate the expression of HIF-1α after permenent focal cerebral ischemia and to explore the role of HIF-1α in hypoxic preconditioning-induced neuroprotection. Methods Rat focal cerebral ischemia model and hypoxic preconditioning models were established. Animals were randomly divided into four groups: healthy control, hypoxic preconditioning (3 h of 8% O2/92% N2 treatment), focal cerebral ischemia (6 h, 1 d, 3 d or 7 d) and hypoxic preconditioning + focal cerebral ischemia (6 h, 1 d, 3 d or 7 d). The expression of HIF-1α after different treatments was determined by histological examination, immunohistochemistry and in situ hybridization. Results The mRNA and protein expressions of HIF-1α could be detected in survival and necrotic neurons, glia as well as vascular endothelial cells. Hypoxic preconditioning significantly promoted the expression of HIF-1α after focal cerebral ischemia, especially in ischemic peripheral zone (P < 0.05).

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Mages, Bianca, Thomas Fuhs, Susanne Aleithe, Alexandra Blietz, Constance Hobusch, Wolfgang Härtig, Stefan Schob, Martin Krueger, and Dominik Michalski. "The Cytoskeletal Elements MAP2 and NF-L Show Substantial Alterations in Different Stroke Models While Elevated Serum Levels Highlight Especially MAP2 as a Sensitive Biomarker in Stroke Patients." Molecular Neurobiology 58, no. 8 (May 1, 2021): 4051–69. http://dx.doi.org/10.1007/s12035-021-02372-3.

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AbstractIn the setting of ischemic stroke, the neurofilament subunit NF-L and the microtubule-associated protein MAP2 have proven to be exceptionally ischemia-sensitive elements of the neuronal cytoskeleton. Since alterations of the cytoskeleton have been linked to the transition from reversible to irreversible tissue damage, the present study investigates underlying time- and region-specific alterations of NF-L and MAP2 in different animal models of focal cerebral ischemia. Although NF-L is increasingly established as a clinical stroke biomarker, MAP2 serum measurements after stroke are still lacking. Therefore, the present study further compares serum levels of MAP2 with NF-L in stroke patients. In the applied animal models, MAP2-related immunofluorescence intensities were decreased in ischemic areas, whereas the abundance of NF-L degradation products accounted for an increase of NF-L-related immunofluorescence intensity. Accordingly, Western blot analyses of ischemic areas revealed decreased protein levels of both MAP2 and NF-L. The cytoskeletal alterations are further reflected at an ultrastructural level as indicated by a significant reduction of detectable neurofilaments in cortical axons of ischemia-affected areas. Moreover, atomic force microscopy measurements confirmed altered mechanical properties as indicated by a decreased elastic strength in ischemia-affected tissue. In addition to the results from the animal models, stroke patients exhibited significantly elevated serum levels of MAP2, which increased with infarct size, whereas serum levels of NF-L did not differ significantly. Thus, MAP2 appears to be a more sensitive stroke biomarker than NF-L, especially for early neuronal damage. This perspective is strengthened by the results from the animal models, showing MAP2-related alterations at earlier time points compared to NF-L. The profound ischemia-induced alterations further qualify both cytoskeletal elements as promising targets for neuroprotective therapies.

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Zhou, An, Manabu Minami, Xiaoman Zhu, Sylvia Bae, John Minthorne, Jingquan Lan, Zhi-gang Xiong, and Roger P. Simon. "Altered Biosynthesis of Neuropeptide Processing Enzyme Carboxypeptidase E after Brain Ischemia: Molecular Mechanism and Implication." Journal of Cerebral Blood Flow & Metabolism 24, no. 6 (June 2004): 612–22. http://dx.doi.org/10.1097/01.wcb.0000118959.03453.17.

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In this study, using both in vivo and in vitro ischemia models, the authors investigated the impact of brain ischemia on the biosynthesis of a key neuropeptide-processing enzyme, carboxypeptidase E (CPE). The response to brain ischemia of animals that lacked an active CPE was also examined. Combined in situ hybridization and immunocytochemical analyses for CPE showed reciprocal changes of CPE mRNA and protein, respectively, in the same cortical cells in rat brains after focal cerebral ischemia. Western blot analysis revealed an accumulation of the precursor protein of CPE in the ischemic cortex in vivo and in ischemic cortical neurons in vitro. Detailed metabolic labeling experiments on ischemic cortical neurons showed that ischemic stress caused a blockade in the proteolytic processing of CPE. When mice lacking an active CPE protease were subjected to a sublethal episode of focal cerebral ischemia, abundant TUNEL-positive cells were seen in the ischemic cortex whereas only a few were seen in the cortex of wild-type animals. These findings suggest that ischemia has an adverse impact on the neuropeptide-processing system in the brain and that the lack of an active neuropeptide-processing enzyme exacerbates ischemic brain injury.

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Lv, Xianli, Chen Li, and Weijian Jiang. "The intracranial vasculature of canines represents a model for neurovascular ischemia and training residents and fellows in endovascular neurosurgery." Neuroradiology Journal 33, no. 4 (May 5, 2020): 292–96. http://dx.doi.org/10.1177/1971400920920787.

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Background We describe use of a canine model to evaluate physiological effects and neuroprotective strategies in the setting of cerebral ischemia and endovascular neurosurgery training. Methods We performed transfemoral digital subtraction cerebral and cervical angiography on eight anesthetized dogs. Angiographic images of cerebral arteries were obtained following cannulation of the femoral artery. Cerebral ischemia models were made after angiography. Results The canine cerebral vasculature exhibited extensive tortuosity of the carotid and vertebral arteries. Conversely, the bilateral anterior spinal arteries were easily catheterized using microcatheters and microguidewires. The basilar artery and its branches were facilely cannulable. Circle of Willis continuity sans hypoplasia or aplasia of its constitutive segments was appreciated in all animals. The middle cerebral arteries could be easily accessed via the posterior communicating arteries. We generated an empirically evaluable therapeutically interventional experimental animal model of cerebral ischemia by occluding the middle cerebral artery using small coils for a duration between 15 and 60 min. Conclusion Unique amenability of the canine intracranial vasculature to selective and microcatheter cannulation renders experimentally induced cerebral, cerebellar, and brainstem via occlusion of the supratentorial and infratentorial arteries a simple matter. The neural vasculature irrigating the canine cerebrum, brainstem, and cerebellum may consequently prove useful in helping young and nascent endovascular neurosurgeons in developing and refining their skills of microcatheter navigation and manipulation and deployment of therapeutic devices to achieve effective occlusion of aneurysms, arteriovenous malformations, arteriovenous fistulas, and neoplasms of the intracranial cavity.

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Li, Le, and Creed M. Stary. "Targeting Glial Mitochondrial Function for Protection from Cerebral Ischemia: Relevance, Mechanisms, and the Role of MicroRNAs." Oxidative Medicine and Cellular Longevity 2016 (2016): 1–11. http://dx.doi.org/10.1155/2016/6032306.

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Astrocytes and microglia play crucial roles in the response to cerebral ischemia and are effective targets for stroke therapy in animal models. MicroRNAs (miRs) are important posttranscriptional regulators of gene expression that function by inhibiting the translation of select target genes. In astrocytes, miR expression patterns regulate mitochondrial function in response to oxidative stressviatargeting of Bcl2 and heat shock protein 70 family members. Mitochondria play an active role in microglial activation, and miRs regulate the microglial neuroinflammatory response. As endogenous miR expression patterns can be altered with exogenous mimics and inhibitors, miR-targeted therapies represent a viable intervention to optimize glial mitochondrial function and improve clinical outcome following cerebral ischemia. In the present article, we review the role that astrocytes and microglia play in neuronal function and fate following ischemic stress, discuss the relevance of mitochondria in the glial response to injury, and present current evidence implicating miRs as critical regulators in the glial mitochondrial response to cerebral ischemia.

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Selakovic, V., Lj Arsenijevic, M. Jovanovic, S. Sivcev, N. Jovanovic, M. Leontijevic, M. Stojanovic, M. Radenkovic, P. Andjus, and L. Radenovic. "Functional and pharmacological analysis of agmatine administration in different cerebral ischemia animal models." Brain Research Bulletin 146 (March 2019): 201–12. http://dx.doi.org/10.1016/j.brainresbull.2019.01.005.

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Vinall, Phillip E., Michael S. Kramer, Lynn A. Heinel, and Robert H. Rosenwasser. "Temporal changes in sensitivity of rats to cerebral ischemic insult." Journal of Neurosurgery 93, no. 1 (July 2000): 82–89. http://dx.doi.org/10.3171/jns.2000.93.1.0082.

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Object. Experimental rat models are often used to study cerebral ischemia, yet rats are nocturnal animals that have activity cycles that are the opposite of those of humans. In the following study the authors examined the circadian rhythm of sensitivity to an ischemic insult in rats by using an intraluminal thread technique to produce reversible middle cerebral artery occlusion.Methods. Ischemia (2 hours of blockage followed by 22 hours of reperfusion) was induced in rats according to the 24-hour clock at either 100, 400, 700, 1000, 1300, 1600, 1900, or 2200 hours (11–14 rats per time period). The rat brains were removed, coronally sectioned, stained with 2,3,5-triphenyltetrazolium chloride and analyzed using commercially available software. Analysis of variance and cosinor-rhythmometry statistical tests were used for analysis of data. The time of day when the ischemic infarct was induced had a significant (p = 0.011) influence on the volume of the lesion. The volume of total brain infarct produced at 400 hours (7.65 ± 1.31%) was more than three times greater than the volume produced at 1600 hours (2.1 ± 0.34%). Cosinor-rhythm analysis indicated a peak occurrence of infarct volume at 6:02 (95% confidence interval 5:49–6:16). The size of the infarct correlated with core body temperature rhythms, which varied by 1.3 ± 0.62°C (mean ± standard deviation).Conclusions. Circadian rhythms, as well as the reversed natural body rhythms of the rat compared with humans, should be considered when extrapolating data to human or other animal studies. Temporal rhythms may also provide information concerning the cascading disease processes associated with cerebral ischemia.

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Liu, Mengting, Liying Tang, Xin Liu, Jing Fang, Hao Zhan, Hongwei Wu, and Hongjun Yang. "An Evidence-Based Review of Related Metabolites and Metabolic Network Research on Cerebral Ischemia." Oxidative Medicine and Cellular Longevity 2016 (2016): 1–12. http://dx.doi.org/10.1155/2016/9162074.

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In recent years, metabolomics analyses have been widely applied to cerebral ischemia research. This paper introduces the latest proceedings of metabolomics research on cerebral ischemia. The main techniques, models, animals, and biomarkers of cerebral ischemia will be discussed. With analysis help from the MBRole website and the KEGG database, the altered metabolites in rat cerebral ischemia were used for metabolic pathway enrichment analyses. Our results identify the main metabolic pathways that are related to cerebral ischemia and further construct a metabolic network. These results will provide useful information for elucidating the pathogenesis of cerebral ischemia, as well as the discovery of cerebral ischemia biomarkers.

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Yin, Bo, Yang Xu, Ruili Wei, and Benyan Luo. "Ginkgo biloba on Focal Cerebral Ischemia: A Systematic Review and Meta-Analysis." American Journal of Chinese Medicine 42, no. 04 (January 2014): 769–83. http://dx.doi.org/10.1142/s0192415x14500499.

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Gingko biloba extract (EGB) has been used in traditional medicines for centuries, and although its application to cerebral ischemia has been of great interest in recent years, high quality evidence-based clinical trials have not been carried out. This systematic review and meta-analysis aimed to examine the neuroprotective effect of EGB on focal cerebral ischemia in animal models. A systematic literature search was performed using five databases spanning January 1980–July 2013. The outcome was assessed using the effect size, which was based on infarct size and/or neurological score. A total of 42 studies with 1,232 experimental animals matched our inclusion criteria. The results revealed that EGB improved the effect size by 34% compared to the control group. The animal species, the method and time to measure outcome, and the route and dosage of EGB administration affected the variability of the effect size. Mechanisms of EGB neuroprotection were reported as anti-apoptotic, anti-oxidative, and anti-inflammatory. In conclusion, EGB exerts a significant protective effect on experimental focal cerebral ischemia. However, possible experimental bias should be taken into account in future clinical studies.

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Fukuda, S., and G. J. del Zoppo. "Models of Focal Cerebral Ischemia in the Nonhuman Primate." ILAR Journal 44, no. 2 (January 1, 2003): 96–104. http://dx.doi.org/10.1093/ilar.44.2.96.

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Wei, Rui-li, Hai-juan Teng, Bo Yin, Yang Xu, Yue Du, Fang-pin He, Ke-tan Chu, Ben-yan Luo, and Guo-qing Zheng. "A Systematic Review and Meta-Analysis of Buyang Huanwu Decoction in Animal Model of Focal Cerebral Ischemia." Evidence-Based Complementary and Alternative Medicine 2013 (2013): 1–13. http://dx.doi.org/10.1155/2013/138484.

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Buyang Huanwu Decoction (BHD) is a well-known Chinese herbal prescription for ischemic stroke. The objective of this systematic review and meta-analysis is to provide the current evidence for neuroprotective effects of BHD and its possible mechanisms in animal models of focal ischemia. A systematic literature search, through October 2012, was performed using six databases. The outcome measures assessed were infarct size and/or neurological score. Fifty-six studies with 1270 animals that met the inclusion criteria were identified. The median score for methodological quality was 3 with a range of 2 to 6. Compared with vehicle or no treatment controls, BHD gave a 37% improvement in outcome for all doses ranging from 1.0 g/kg to 60 g/kg at each time point that BHD was administered (P<0.01). Efficacy was higher in mouse models that utilized suture occlusion and temporary ischemia. The neuroprotective effects of BHD are involved in multiple mechanisms and act upon multiple cell types. In conclusion, BHD possesses substantial neuroprotective effects in experimental stroke probably as a result of the multitarget therapy strategy typically utilized in traditional Chinese medicine. Future research should examine the presence of possible experimental bias and an in-depth study of herbal compound preparations.

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Kirino, Takaaki. "Ischemic Tolerance." Journal of Cerebral Blood Flow & Metabolism 22, no. 11 (November 2002): 1283–96. http://dx.doi.org/10.1097/01.wcb.0000040942.89393.88.

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A brief period of cerebral ischemia confers transient tolerance to a subsequent ischemic challenge in the brain. This phenomenon of ischemic tolerance has been confirmed in various animal models of forebrain ischemia and focal cerebral ischemia. Since the ischemic tolerance afforded by preceding ischemia can bring about robust protection of the brain, the mechanism of tolerance induction has been extensively studied. It has been elucidated that ischemic tolerance protects neurons, and at the same time, it preserves brain function. Further experiments have shown that metabolic and physical stresses can also induce cross-tolerance to cerebral ischemia, but the protection by cross-tolerance is relatively modest. The underlying mechanism of ischemic tolerance still is not fully understood. Potential mechanisms may be divided into two categories: (1) A cellular defense function against ischemia may be enhanced by the mechanisms inherent to neurons. They may arise by posttranslational modification of proteins or by expression of new proteins via a signal transduction system to the nucleus. These cascades of events may strengthen the influence of survival factors or may inhibit apoptosis. (2) A cellular stress response and synthesis of stress proteins may lead to an increased capacity for health maintenance inside the cell. These proteins work as cellular “chaperones” by unfolding misfolded cellular proteins and helping the cell to dispose of unneeded denatured proteins. Recent experimental data have demonstrated the importance of the processing of unfolded proteins for cell survival and cell death. The brain may be protected from ischemia by using multiple mechanisms that are available for cellular survival. If tolerance induction can be manipulated and accelerated by a drug treatment that is safe and effective enough, it could greatly improve the treatment of stroke.

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Li, T. Q., Z. G. Chen, and T. Hindmarsh. "Diffusion-weighted MR imaging of acute cerebral ischemia." Acta Radiologica 39, no. 5 (September 1998): 460–73. http://dx.doi.org/10.1080/02841859809172209.

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Diffusion-weighted MR imaging has been used in studies on experimental animal models and on patients with acute cerebral ischemia. Compared with CT and conventional MR techniques, diffusion-weighted imaging can provide earlier and more precise detection of the location and the extent of an ischemic lesion during the critical first few hours after the onset of stroke Quantitative apparent diffusion coefficient (ADC) mapping of the brain water can also be carried out by recording a series of diffusion-weighted images with different amplitudes of the displacement encoding gradients. ADC maps can provide important information about the extra- and intracellular water homeostasis. ADC reduction of the tissue water is one of the early signals of the pathophysiological cascade resulting from ischemic tissue injury. Diffusion MR imaging has become a valuable tool in stroke research. It may also prove a valuable tool in monitoring the efficiency of therapeutic effects in stroke patients It is our intention to provide an overview of the recent development in this area with emphasis on the diffusion-weighted MR techniques, and to discuss the possible underlying biophysical mechanisms responsible for the contrast of diffusion-weighted imaging

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Howells, David W., Michelle J. Porritt, Sarah SJ Rewell, Victoria O'Collins, Emily S. Sena, H. Bart van der Worp, Richard J. Traystman, and Malcolm R. Macleod. "Different Strokes for Different Folks: The Rich Diversity of Animal Models of Focal Cerebral Ischemia." Journal of Cerebral Blood Flow & Metabolism 30, no. 8 (May 19, 2010): 1412–31. http://dx.doi.org/10.1038/jcbfm.2010.66.

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No single animal model is able to encompass all of the variables known to affect human ischemic stroke. This review highlights the major strengths and weaknesses of the most commonly used animal models of acute ischemic stroke in the context of matching model and experimental aim. Particular emphasis is placed on the relationships between outcome and underlying vascular variability, physiologic control, and use of models of comorbidity. The aim is to provide, for novice and expert alike, an overview of the key controllable determinants of experimental stroke outcome to help ensure the most effective application of animal models to translational research.

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Boltze, Johannes, Annette Förschler, Björn Nitzsche, Daniela Waldmin, Anke Hoffmann, Christiane M. Boltze, Antje Y. Dreyer, et al. "Permanent Middle Cerebral Artery Occlusion in Sheep: A Novel Large Animal Model of Focal Cerebral Ischemia." Journal of Cerebral Blood Flow & Metabolism 28, no. 12 (August 13, 2008): 1951–64. http://dx.doi.org/10.1038/jcbfm.2008.89.

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As effective stroke treatment by thrombolysis is bound to a narrow time window excluding most patients, numerous experimental treatment strategies have been developed to gain new options for stroke treatment. However, all approaches using neuroprotective agents that have been successfully evaluated in rodents have subsequently failed in clinical trials. Existing large animal models are of significant scientific value, but sometimes limited by ethical drawbacks and mostly do not allow for long-term observation. In this study, we are introducing a simple, but reliable stroke model using permanent middle cerebral artery occlusion in sheep. This model allows for control of ischemic lesion size and subsequent neurofunctional impact, and it is monitored by behavioral phenotyping, magnetic resonance imaging, and positron emission tomography. Neuropathologic and (immuno)-histologic investigations showed typical ischemic lesion patterns whereas commercially available antibodies against vascular, neuronal, astroglial, and microglial antigens were feasible for ovine brain specimens. Based on absent mortality in this study and uncomplicated species-appropriate housing, long-term studies can be realized with comparatively low expenditures. This model could be used as an alternative to existing large animal models, especially for longitudinal analyses of the safety and therapeutic impact of novel therapies in the field of translational stroke research.

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Ma, Rong, Xiao Ma, Jianxia Wen, Jian Wang, Qian Xie, Nian Chen, and Taiwei Dong. "Preclinical Evidence and Mechanism of Xingnaojing Injection for Cerebral Ischemia: A Systematic Review and Meta-Analysis of Animal Studies." Evidence-Based Complementary and Alternative Medicine 2018 (November 15, 2018): 1–12. http://dx.doi.org/10.1155/2018/9624175.

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Objectives. Cerebral ischemia can cause severe harm to people’s health with the characteristics of high incidence, high disability, and high mortality. Xingnaojing injection (XNJI) is widely used in the treatment of cerebral ischemia. The aim of this review is to evaluate the efficacy and mechanism of XNJI in animal models of cerebral ischemia. Methods. Total seven electronic databases in English or Chinese (CNKI, Wanfang, VMIS, PubMed, MEDLINE, Embase, and the Cochrane Library) about most experiments and studies which came out before June 2018 of XNJI for cerebral ischemia have been searched. Data extraction, quality assessment, and meta-analysis are conducted according to the Cochrane standards and RevMan 5.3 software. Results. We have identified 23 eligible studies and made a meta-analysis based on these studies. Meta-analysis shows that XNJI contributes significantly to reduction in neurological deficit score (P = 0.0002, MD = −1.25, 95% CI: −1.92, −0.58) compared with the control group of cerebral ischemia. Subgroup analytic results demonstrate that XNJI has been more effective in animal model of cerebral ischemia-reperfusion injury (P = 0.009, MD = −1.35, 95%CI: −2.36, −0.34) than that of permanent cerebral ischemia (P = 0.0002, MD = −1.08, 95%CI: −1.66, −0.51). Compared with control group, XNJI could remarkably reduce cerebral infarction area (P < 0.00001, MD = −14.98, 95%CI: −21.36, −8.59), brain edema (P < 0.00001, MD = −4.64, 95%CI: −5.38, −3.90), and neuronal cell apoptosis (P < 0.0001, MD = −12.21, 95%CI: 18.05, −6.37). Meanwhile, the meta-analysis shows that XNJI has a significant anti-inflammatory effect, and the levels of TNF-α, IL-6, and IL-1β are significantly reduced by XNJI (P = 0.001, MD = −4.13, 95%CI:−6.68, −1.58; P < 0.00001, MD = −119.23, 95%CI: −138.04, −100.43; P = 0.21, MD = −228.69, 95% CI: −586.20, 128.83). Additionally, XNJI could raise the body's antioxidant function and the level of SOD and GSH-Px (P = 0.002, MD = 53.02, 95% CI: −20.52, 85.78; P = 0.01, MD = 8.65, 95% CI: 1.77, 15.48) and decrease the level of MDA (P < 0.00001, MD = −4.16, 95% CI: −5.50, −2.82). Conclusion. XNJI might be effective in cerebral ischemia by regulating oxidative stress and inflammatory reaction.

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Felberg, Robert A., W. Scott Burgin, and James C. Grotta. "Neuroprotection and the Ischemic Cascade." CNS Spectrums 5, no. 3 (March 2000): 52–58. http://dx.doi.org/10.1017/s1092852900012967.

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AbstractBrain ischemia is a process of delayed neuronal cell death, not an instantaneous event. The concept of neuroprotection is based on this principle. Diminished cerebral blood flow initiates a series of events (the “ischemic cascade”) that lead to cell destruction. This ischemic cascade is akin to a spreading epidemic starting from a hypothesized core of ischemia and radiating outward. If intervention occurs early, the process may be halted.Interventions have been directed toward salvaging the ischemic penumbra. Hypothermia decreases the size of the ischemic insult in both anecdotal clinical and laboratory reports. In addition, a wide variety of agents have been shown to reduce infant volume in animal models. Pharmacologic interventions that involve thrombolysis, calcium channel blockade, and cell membrane receptor antagonism have been studied and have been found to be beneficial in animal cortical stroke models. Human trials of neuroprotective therapies have been disappointing. Other than thrombolytics, no agents, have shown an unequivocal benefit. The future of neuroprotection will require a logical extension of what has been learned in the laboratory and previous human trials. A sensible approach to the use of multiple-agent cocktails used in combination with thrombolytics is likely to offer the highest chance for benefit.

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Kamp, Marcel A., Maxine Dibué, Toni Schneider, Hans-Jakob Steiger, and Daniel Hänggi. "Calcium and Potassium Channels in Experimental Subarachnoid Hemorrhage and Transient Global Ischemia." Stroke Research and Treatment 2012 (2012): 1–8. http://dx.doi.org/10.1155/2012/382146.

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Healthy cerebrovascular myocytes express members of several different ion channel families which regulate resting membrane potential, vascular diameter, and vascular tone and are involved in cerebral autoregulation. In animal models, in response to subarachnoid blood, a dynamic transition of ion channel expression and function is initiated, with acute and long-term effects differing from each other. Initial hypoperfusion after exposure of cerebral vessels to oxyhemoglobin correlates with a suppression of voltage-gated potassium channel activity, whereas delayed cerebral vasospasm involves changes in other potassium channel and voltage-gated calcium channels expression and function. Furthermore, expression patterns and function of ion channels appear to differ between main and small peripheral vessels, which may be key in understanding mechanisms behind subarachnoid hemorrhage-induced vasospasm. Here, changes in calcium and potassium channel expression and function in animal models of subarachnoid hemorrhage and transient global ischemia are systematically reviewed and their clinical significance discussed.

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Pike, Brian R., Jeremy Flint, Jitendra R. Dave, X. C. May Lu, Kevin K. K. Wang, Frank C. Tortella, and Ronald L. Hayes. "Accumulation of Calpain and Caspase-3 Proteolytic Fragments of Brain-Derived αII-Spectrin in Cerebral Spinal Fluid after Middle Cerebral Artery Occlusion in Rats." Journal of Cerebral Blood Flow & Metabolism 24, no. 1 (January 2004): 98–106. http://dx.doi.org/10.1097/01.wcb.0000098520.11962.37.

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Preclinical studies have identified numerous neuroprotective drugs that attenuate brain damage and improve functional outcome after cerebral ischemia. Despite this success in animal models, neuroprotective therapies in the clinical setting have been unsuccessful. Identification of biochemical markers common to preclinical and clinical cerebral ischemia will provide a more sensitive and objective measure of injury severity and outcome to facilitate clinical management and treatment. However, there are currently no effective biomarkers available for assessment of stroke. Nonerythroid αII-spectrin is a cytoskeletal protein that is cleaved by calpain and caspase-3 proteases to signature αII-spectrin breakdown products (αII-SBDPs) after cerebral ischemia in rodents. This investigation examined accumulation of calpain- and caspase-3-cleaved αII-SBDPs in cerebrospinal fluid (CSF) of rodents subjected to 2 hours of transient focal cerebral ischemia produced by middle cerebral artery occlusion (MCAO) followed by reperfusion. After MCAO injury, full-length αII-spectrin protein was decreased in brain tissue and increased in CSF from 24 to 72 hours after injury. Whereas αII-SBDPs were undetectable in sham-injured control animals, calpain but not caspase-3 specific αII-SBDPs were significantly increased in CSF after injury. However, caspase-3 αII-SBDPS were observed in CSF of some injured animals. These results indicate that αII-SBDPs detected in CSF after injury, particularly those mediated by calpain, may be useful diagnostic indicators of cerebral infarction that can provide important information about specific neurochemical events that have occurred in the brain after acute stroke.

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Ma, Di, Liangshu Feng, Fang Deng, and Jia-Chun Feng. "Overview of Experimental and Clinical Findings regarding the Neuroprotective Effects of Cerebral Ischemic Postconditioning." BioMed Research International 2017 (2017): 1–12. http://dx.doi.org/10.1155/2017/6891645.

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Research on attenuating the structural and functional deficits observed following ischemia-reperfusion has become increasingly focused on the therapeutic potential of ischemic postconditioning. In recent years, various methods and animal models of ischemic postconditioning have been utilized. The results of these numerous studies have indicated that the mechanisms underlying the neuroprotective effects of ischemic postconditioning may involve reductions in the generation of free radicals and inhibition of calcium overload, as well as the release of endogenous active substances, alterations in membrane channel function, and activation of protein kinases. Here we review the novel discovery, mechanism, key factors, and clinical application of ischemic postconditioning and discuss its implications for future research and problem of clinical practice.

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Okami, Nobuya, Purnima Narasimhan, Hideyuki Yoshioka, Hiroyuki Sakata, Gab Seok Kim, Joo Eun Jung, Carolina M. Maier, and Pak H. Chan. "Prevention of JNK Phosphorylation as a Mechanism for Rosiglitazone in Neuroprotection after Transient Cerebral Ischemia: Activation of Dual Specificity Phosphatase." Journal of Cerebral Blood Flow & Metabolism 33, no. 1 (October 3, 2012): 106–14. http://dx.doi.org/10.1038/jcbfm.2012.138.

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Rosiglitazone, a synthetic peroxisome proliferator-activated receptor-γ (PPARγ) agonist, prevents cell death after cerebral ischemia in animal models, but the underlying mechanism has not been clarified. In this study, we examined how rosiglitazone protects neurons against ischemia. Mice treated with rosiglitazone were subjected to 60 minutes of focal ischemia followed by reperfusion. Rosiglitazone reduced infarct volume after ischemia and reperfusion. We show that this neuroprotective effect was reversed with a PPARgM antagonist. Western blot analysis showed a significant increase in expression of phosphorylated stress-activated protein kinases (c-Jun N-terminal kinase (JNK) and p38) in ischemic brain tissue. Rosiglitazone blocked this increase. Furthermore, we observed that rosiglitazone increased expression of the dual-specificity phosphatase 8 (DUSP8) protein and messenger RNA in ischemic brain tissue. Dual-specificity phosphatase 8 is a mitogen-activated protein kinase phosphatase that can dephosphorylate JNK and p38. Another key finding of the present study was that knockdown of DUSP8 in primary cultured cortical neurons that were subjected to oxygen–glucose deprivation diminished rosiglitazone's effect on downregulation of JNK phosphorylation. Thus, rosiglitazone's neuroprotective effect after ischemia is mediated by blocking JNK phosphorylation induced by ischemia via DUSP8 upregulation.

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Cheng, Jian, Nabil J. Alkayed, and Patricia D. Hurn. "Deleterious Effects of Dihydrotestosterone on Cerebral Ischemic Injury." Journal of Cerebral Blood Flow & Metabolism 27, no. 9 (February 21, 2007): 1553–62. http://dx.doi.org/10.1038/sj.jcbfm.9600457.

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Outcome from cerebral ischemia is sexually dimorphic in many experimental models. Male animals display greater sensitivity to ischemic injury than do their female counterparts; however, the underlying mechanism is unclear. The present study determined if the potent and nonaromatizable androgen, dihydrotestosterone (DHT), exacerbates ischemic damage in the male rat and alters postischemic gene expression after middle cerebral artery occlusion. At 22 h reperfusion, removal of androgens by castration provided protection from ischemic injury in both cortex and striatum (2,3,5-triphenyltetrazolium chloride (TTC) histology), whereas DHT replacement (50 mg subcutaneous implant) restored infarction volume to that of the intact male; testosterone (50 mg) had similar but less potent effects. We utilized microarray and real-time quantitative polymerase chain reaction (PCR) to identify genes differentially expressed at 6 h reperfusion in periinfarct cortex from castrated rats with or without DHT replacement. We identify, for the first time, a number of gene candidates that are induced by DHT with or without ischemia, many of which could account for cell death through enhanced inflammation, dysregulation of blood–brain barrier and the extracellular matrix, apoptosis, and ionic imbalance. Our data suggest that androgens are important mediators of ischemic damage in male brain and that transcriptional mechanisms should be considered as we seek to understand innate male sensitivity to cerebral ischemia.

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Harston, George WJ, Brad A. Sutherland, James Kennedy, and Alastair M. Buchan. "The Contribution of L-Arginine to the Neurotoxicity of Recombinant Tissue Plasminogen Activator following Cerebral Ischemia: A Review of rtPA Neurotoxicity." Journal of Cerebral Blood Flow & Metabolism 30, no. 11 (August 25, 2010): 1804–16. http://dx.doi.org/10.1038/jcbfm.2010.149.

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Alteplase is the only drug licensed for acute ischemic stroke, and in this formulation, the thrombolytic agent recombinant tissue plasminogen activator (rtPA) is stabilized in a solution of L-arginine. Improved functional outcomes after alteplase administration have been shown in clinical trials, along with improved histological and behavioral measures in experimental models of embolic stroke. However, in animal models of mechanically induced ischemia, alteplase can exacerbate ischemic damage. We have systematically reviewed the literature of both rtPA and L-arginine administration in mechanical focal ischemia. The rtPA worsens ischemic damage under certain conditions, whereas L-arginine can have both beneficial and deleterious effects dependent on the time of administration. The interaction between rtPA and L-arginine may be leading to the production of nitric oxide, which can cause direct neurotoxicity, altered cerebral blood flow, and disruption of the neurovascular unit. We suggest that alternative formulations of rtPA, in the absence of L-arginine, would provide new insight into rtPA neurotoxicity, and have the potential to offer more efficacious thrombolytic therapy for ischemic stroke patients.

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Bowes, Mark P., Steven Swanson, and Justin A. Zivin. "The AMPA Antagonist LY293558 Improves Functional Neurological Outcome following Reversible Spinal Cord Ischemia in Rabbits." Journal of Cerebral Blood Flow & Metabolism 16, no. 5 (September 1996): 967–72. http://dx.doi.org/10.1097/00004647-199609000-00021.

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Glutamate (Glu) neurotoxicity is an important element of a number of neurological disorders including central nervous system (CNS) ischemia. We evaluated the effects of the novel AMPA Glu antagonist LY293558 on functional neurological outcome in two rabbit stroke models. In the reversible spinal cord ischemia model, ischemia of the caudal lumbar spinal cord was produced by temporary occlusion of the abdominal aorta. LY293558 was administered 5 min after recirculation as a 16 mg/kg i.v. bolus followed by 2.2 mg/kg infused over 1 h. Control animals received saline. LY293558 significantly increased the duration of ischemia required to produce paraplegia, from 30.5 ± 15.8 min (mean ± SD) controls to 50.1 ± 11.5 in treated animals ( p < 0.01). In an irreversible model of cerebral ischemia, 50 μm plastic microspheres were injected into the carotid artery and lodged in the cerebral microvasculature. LY293558 did not significantly reduce neurological damage in this model. These data suggest that LY293558 may have therapeutic benefit following some types of ischemic injury.

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Koehler, Raymond C., Zeng-Jin Yang, Jennifer K. Lee, and Lee J. Martin. "Perinatal hypoxic-ischemic brain injury in large animal models: Relevance to human neonatal encephalopathy." Journal of Cerebral Blood Flow & Metabolism 38, no. 12 (August 28, 2018): 2092–111. http://dx.doi.org/10.1177/0271678x18797328.

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Perinatal hypoxia-ischemia resulting in death or lifelong disabilities remains a major clinical disorder. Neonatal models of hypoxia-ischemia in rodents have enhanced our understanding of cellular mechanisms of neural injury in developing brain, but have limitations in simulating the range, accuracy, and physiology of clinical hypoxia-ischemia and the relevant systems neuropathology that contribute to the human brain injury pattern. Large animal models of perinatal hypoxia-ischemia, such as partial or complete asphyxia at the time of delivery of fetal monkeys, umbilical cord occlusion and cerebral hypoperfusion at different stages of gestation in fetal sheep, and severe hypoxia and hypoperfusion in newborn piglets, have largely overcome these limitations. In monkey, complete asphyxia produces preferential injury to cerebellum and primary sensory nuclei in brainstem and thalamus, whereas partial asphyxia produces preferential injury to somatosensory and motor cortex, basal ganglia, and thalamus. Mid-gestational fetal sheep provide a valuable model for studying vulnerability of progenitor oligodendrocytes. Hypoxia followed by asphyxia in newborn piglets replicates the systems injury seen in term newborns. Efficacy of post-insult hypothermia in animal models led to the success of clinical trials in term human neonates. Large animal models are now being used to explore adjunct therapy to augment hypothermic neuroprotection.

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Khan, Mohd Muazzam, Badruddeen, Mohd Mujahid, Juber Akhtar, Mohammad Irfan Khan, and Usama Ahmad. "An Overview of Stroke: Mechanism, In vivo Experimental Models Thereof, and Neuroprotective Agents." Current Protein & Peptide Science 21, no. 9 (December 11, 2020): 860–77. http://dx.doi.org/10.2174/1389203721666200617133903.

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Background: Stroke is one of the causes of death and disability globally. Brain attack is because of the acute presentation of stroke, which highlights the requirement for decisive action to treat it. Objective: The mechanism and in-vivo experimental models of stroke with various neuroprotective agents are highlighted in this review. Method: The damaging mechanisms may proceed by rapid, nonspecific cell lysis (necrosis) or by the active form of cell death (apoptosis or necroptosis), depending upon the duration and severity and of the ischemic insult. Results: Identification of injury mediators and pathways in a variety of experimental animal models of global cerebral ischemia has directed to explore the target-specific cytoprotective strategies, which are critical to clinical brain injury outcomes. Conclusion: The injury mechanism, available encouraging medicaments thereof, and outcomes of natural and modern medicines for ischemia have been summarized. In spite of available therapeutic agents (thrombolytics, calcium channel blockers, NMDA receptor antagonists and antioxidants), there is a need for an ideal drug for strokes.

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Hao, Jiukuan, and Ulrich Bickel. "Transferrin Receptor Mediated Brain Uptake During Ischemia and Reperfusion." Journal of Pharmacy & Pharmaceutical Sciences 16, no. 4 (September 16, 2013): 541. http://dx.doi.org/10.18433/j3b303.

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Abstract:

Purpose. Drug delivery by transferrin receptor-mediated transport at the blood-brain barrier has shown beneficial effects in animal models of stroke, but it is unclear whether receptor mediated uptake remains functional in the ischemic tissue. The present study addressed that question in a mouse model of brain focal ischemia, permanent or transient middle cerebral artery occlusion (MCAO). Methods. Brain accumulation of 125I-labeled 8D3, a mouse-specific transferrin receptor antibody, or of the isotype control UPC-10 used as vascular marker, was measured autoradiographically by phosphorimaging in the core ischemic region on cryostat brain sections up to 24h after ischemia or reperfusion. Cerebral blood flow was quantitatively determined in the same animals after administration of 99mTc-ECD (Neurolite). Results. Apparent volume of distribution obtained with UPC-10 indicated no significant nonspecific leakage of the blood-brain barrier at any time point. Although brain uptake of 8D3 gradually declined compared to healthy tissue under MCAO, VD remained significantly higher than VD of UPC-10 up to 5h. In transient MCAO the brain uptake recovered to levels as in healthy tissue immediately after reperfusion. Conclusion. Transferrin receptor-mediated brain uptake, which is an energy dependent vesicular transport process, is sensitive to reduction in blood supply but remains partially functional for several hours after onset of ischemia. The uptake shows complete recovery after reperfusion. These results support the use of transferrin receptor-mediated brain drug delivery in the early phase of ischemia and in the phase when blood flow is restored. This article is open to POST-PUBLICATION REVIEW. Registered readers (see “For Readers”) may comment by clicking on ABSTRACT on the issue’s contents page.

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Journal articles on the topic 'Cerebral ischemia – Animal models'

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