Journal articles on the topic 'Stroke; animal models; middle cerebral artery occlusion'
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1
Golubev, A. M. "Models of Ischemic Stroke (Review)." General Reanimatology 16, no. 1 (March 2, 2020): 59–72. http://dx.doi.org/10.15360/1813-9779-2020-1-59-72.
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The incidence of ischemic stroke remains high in many countries, despite a declining trend in the incidence of brain circulation disorders. Limited knowledge of the pathogenesis, diagnosis, clinical presentation, and treatment of this life-threatening disease can be complemented by modelling of ischemic stroke on animals, particularly, in rodents (rats, mice).The aim of review: to provide a rationale for choosing an optimal model of human ischemic stroke.Among more than 300 primary literature sources from various databases (Scopus, Web of science, RSCI, etc.), 84 sources were selected for evaluation, of which 72 were published in the recent years (2015–2019). The criteria for exclusion of sources were low relevance and outdated data.The review examined six experimental models of acute cerebrovascular events including middle cerebral artery occlusion, embolic stroke model; phototrombosis; models using thrombin, endothelin-1 and electrocoagulation of the middle cerebral artery.The review outlines the factors influencing reliability and reproducibility of research results, related to adherence to the rules of animal accommodation and acclimatization, nutrition and care, selection of anesthesia and pain relief methods, compliance with aseptic techniques, monitoring of basic physiological parameters at all stages of the ischemic stroke modeling experiment, with humane withdrawal of animals from the experiment.It was concluded that the model of ischemic stroke, based on the occlusion of the middle cerebral artery, is most promising as being the closest to features of human ischemic stroke and enabling to obtain reproducible results in the experiment.
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Liu, Fudong, and Louise D. McCullough. "Middle Cerebral Artery Occlusion Model in Rodents: Methods and Potential Pitfalls." Journal of Biomedicine and Biotechnology 2011 (2011): 1–9. http://dx.doi.org/10.1155/2011/464701.
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A variety of animal models have been developed for modeling ischemic stroke. The middle cerebral artery occlusion (MCAO) model has been utilized extensively, especially in rodents. While the MCAO model provides stroke researchers with an excellent platform to investigate the disease, controversial or even paradoxical results are occasionally seen in the literature utilizing this model. Various factors exert important effects on the outcome in this stroke model, including the age and sex of the animal examined. This paper discusses emerging information on the effects of age and sex on ischemic outcomes after MCAO, with an emphasis on mouse models of stroke.
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Percie du Sert, Nathalie, Alessio Alfieri, Stuart M. Allan, Hilary VO Carswell, Graeme A. Deuchar, Tracy D. Farr, Paul Flecknell, et al. "The IMPROVE Guidelines (Ischaemia Models: Procedural Refinements Of in Vivo Experiments)." Journal of Cerebral Blood Flow & Metabolism 37, no. 11 (August 11, 2017): 3488–517. http://dx.doi.org/10.1177/0271678x17709185.
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Most in vivo models of ischaemic stroke target the middle cerebral artery and a spectrum of stroke severities, from mild to substantial, can be achieved. This review describes opportunities to improve the in vivo modelling of ischaemic stroke and animal welfare. It provides a number of recommendations to minimise the level of severity in the most common rodent models of middle cerebral artery occlusion, while sustaining or improving the scientific outcomes. The recommendations cover basic requirements pre-surgery, selecting the most appropriate anaesthetic and analgesic regimen, as well as intraoperative and post-operative care. The aim is to provide support for researchers and animal care staff to refine their procedures and practices, and implement small incremental changes to improve the welfare of the animals used and to answer the scientific question under investigation. All recommendations are recapitulated in a summary poster (see supplementary information).
4
Mauler, Frank, and Ervin Horváth. "Neuroprotective Efficacy of Repinotan HCl, a 5-HT1A Receptor Agonist, in Animal Models of Stroke and Traumatic Brain Injury." Journal of Cerebral Blood Flow & Metabolism 25, no. 4 (January 26, 2005): 451–59. http://dx.doi.org/10.1038/sj.jcbfm.9600038.
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Repinotan is a highly potent 5-HT1A receptor agonist with strong neuroprotective efficacy in animal models of middle cerebral artery occlusion and traumatic brain injury. In this study, we characterized the time window for neuroprotective effects of repinotan in animal models. In the permanent middle cerebral artery occlusion model, repinotan showed neuroprotective efficacy when administered as a triple bolus injection (0.3–100 μg/kg) or an intravenous infusion (0.3–100 μg/kg per hour). A 73% reduction in infarct volume was observed with a 3 μg/kg intravenous bolus, and a 65% reduction was observed with a 3 and 10 μg/kg per hour intravenous infusion. When delayed until 5 hours after occlusion, repinotan (10 μg/kg per hour) reduced infarct volume by 43%. In the transient middle cerebral artery occlusion model, repinotan (10 μg/kg per hour) administered immediately after occlusion reduced infarct volume by 97%, and a delay to 5 hours reduced infarct volume by 81%. In the acute subdural hematoma model, repinotan (3 and 10 μg/kg per hour) reduced infarct volume by 65%. In this model, repinotan (3 μg/kg per hour) administered 5 hours after occlusion reduced infarct volume by 54%. The favorable neuroprotective efficacy, broad dose–response curve, and prolonged therapeutic window observed in all models strongly suggest that repinotan is a promising candidate for treating acute ischemic stroke in humans.
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Ramli, Yetty, Ahmad S. Alwahdy, Mohammad Kurniawan, Berry Juliandi, Puspita E. Wuyung, and Yayi D. B. Susanto. "Permanent flame-blunted monofilament of middle cerebral artery occlusion technique for ischemia stroke induction in animal models." Medical Journal of Indonesia 26, no. 3 (November 27, 2017): 183–9. http://dx.doi.org/10.13181/mji.v26i3.1645.
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Background: Rat is the most frequently used animal for ischemic stroke studies. Recently, middle cerebral artery occlusion (MCAO) by introducing various types of surgical monofilament intraluminally has been widely used, with their advantages and disadvantages. For permanent occlusion, problems with mortality in rats are higher than transient. In this study, we used permanent occlusion using modified monofilament by flaming on its tip which may reduce mortality rate, so that chronic phase of stroke can be learned extensively.Methods: Three male Sprague-Dawley rats underwent permanent MCAO. The flame-blunted monofilament was introduced through common carotid artery. Hematoxylin eosin histopathology confirmation and functional assessment post-stroke induction were then evaluated.Results: Evaluation was conducted on 3 rats in different time post-stroke induction (48 hours, 72 hours, and 3 weeks). Using histopathological examination, the infarction was proved in all 3 rats showing red neurons, perivascular edema and neutrophil spongiosis, in infarct and peri-infarct area. The changes in histopathology showed spongiosis were more dominant in 3 week-post-MCAO rats. On the other hand, red neurons and perivascular edema were less compared to 48 and 72-hour-post-MCAO rats.Conclusion: Flame–blunted monofilament showed its efficacy in producing infarct area. The advantages of this technique are easy to perform with simple and less expensive modification of the monofilament. Conducting successful permanent occlusion with less mortality rate will give chances to do further research on stroke in chronic phase and its effect on novel treatment.
6
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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Leon, Rachel L., Xinlan Li, Jason D. Huber, and Charles L. Rosen. "Worsened Outcome from Middle Cerebral Artery Occlusion in Aged Rats Receiving 17β-Estradiol." Endocrinology 153, no. 7 (May 11, 2012): 3386–93. http://dx.doi.org/10.1210/en.2011-1859.
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Although estrogens are neuroprotective in young adult animal models of stroke, clinical trials demonstrate that estrogens increase the incidence and severity of stroke in aged women. We have previously shown that experimental stroke pathophysiology differs between young adult and aged rats. The aim of this study was to determine the effects of 17β-estradiol after middle cerebral artery occlusion and reperfusion in young adult and aged female rats. Focal embolic stroke was performed by middle cerebral artery occlusion with fibrin clot followed by reperfusion with iv human recombinant tissue plasminogen activator. Histological and functional outcomes were measured at 24 h after middle cerebral artery occlusion with fibrin clot. Aged rats treated with 17β-estradiol had significantly increased infarct volumes compared with placebo-treated aged rats. Young adult rats treated with 17β-estradiol had significantly decreased infarct volumes and improved functional outcome compared with ovariectomized young adult rats. Our results suggest that 17β-estradiol may act in an age-dependent manner in the postischemic rat brain. In young adult rats, it is neuroprotective; chronic treatment with 17β-estradiol during aging leads to worsened ischemic brain injury in aged female rats.
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Krueger, Martin, Wolfgang Härtig, Clara Frydrychowicz, Wolf C. Mueller, Andreas Reichenbach, Ingo Bechmann, and Dominik Michalski. "Stroke-induced blood–brain barrier breakdown along the vascular tree – No preferential affection of arteries in different animal models and in humans." Journal of Cerebral Blood Flow & Metabolism 37, no. 7 (October 1, 2016): 2539–54. http://dx.doi.org/10.1177/0271678x16670922.
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Stroke-induced blood–brain barrier breakdown promotes complications like cerebral edema and hemorrhagic transformation, especially in association with therapeutical recanalization of occluded vessels. As arteries, capillaries and veins display distinct functional and morphological characteristics, we here investigated patterns of blood–brain barrier breakdown for each segment of the vascular tree in rodent models of embolic, permanent, and transient middle cerebral artery occlusion, added by analyses of human stroke tissue. Twenty-four hours after ischemia induction, loss of blood–brain barrier function towards FITC-albumin was equally observed for arteries, capillaries, and veins in rodent brains. Noteworthy, veins showed highest ratios of leaky vessels, whereas capillaries exhibited the most and arteries the least widespread perivascular tracer extravasation. In contrast, human autoptic stroke tissue exhibited pronounced extravasations of albumin around arteries and veins, while the pericapillary immunoreactivity appeared only faint. Although electron microscopy revealed comparable alterations of the arterial and capillary endothelium throughout the applied animal models, structural loss of arterial smooth muscle cells was only observed in the translationally relevant model of embolic middle cerebral artery occlusion. In light of the so far available concepts of stroke treatment, the consideration of a differential vascular pathophysiology along the cerebral vasculature is likely to allow development of novel effective treatment strategies.
9
Brown, Aliza, Sean Woods, Robert Skinner, Jeff Hatton, John Lowery, Paula Roberson, Leah Hennings, and William C. Culp. "Neurological Assessment Scores in Rabbit Embolic Stroke Models." Open Neurology Journal 7, no. 1 (October 31, 2013): 38–43. http://dx.doi.org/10.2174/1874205x01307010038.
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Background: Neurological outcomes and behavioral assessments are widely used in animal models of stroke, but assessments in rabbit models are not fully validated. The wryneck model of neurological assessment scores (NAS) was compared to percent infarct volume (%IV) values (infarct volume is a proven clinical indicator of stroke severity) and arterial occlusion localization in three rabbit angiographic stroke models. Hypothesis: NAS values will correlate with percent infarct volume values. Methods: Anesthetized New Zealand White rabbits (N=131, 4-5 kg) received internal carotid artery emboli by angiographic catheter introduced into the femoral artery and occlusions were characterized. Rabbits were evaluated at 24 hours post embolism using the NAS test of 0 (normal) to 10 (death). Deficit criteria included neck twist, righting reflex, extension reflex in hind paw and forepaw, and posture. Brain sections stained with triphenyltetrazolium chloride (TTC) were analyzed for %IV. Volume of the infarct was measured and calculated as a percent of the total brain volume. Results: The aggregate correlation for NAS values vs. %IV values was R=0.61, p<0.0001, a strong positive relationship, while correlations of the NAS components ranged from R=0.28-0.46. Occlusionsof the posterior cerebral artery vs. the middle cerebral artery alone produced significantly greater deficit scores at p<0.0001. Conclusions: These positive results validate the NAS system in the rabbit angiographic embolic stroke model.
10
Rewell, Sarah SJ, John A. Fernandez, Susan F. Cox, Neil J. Spratt, Lisa Hogan, Elena Aleksoska, Leena van Raay, Gabriel T. Liberatore, Peter E. Batchelor, and David W. Howells. "Inducing Stroke in Aged, Hypertensive, Diabetic Rats." Journal of Cerebral Blood Flow & Metabolism 30, no. 4 (January 13, 2010): 729–33. http://dx.doi.org/10.1038/jcbfm.2009.273.
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Animal models of ischemic stroke often neglect comorbidities common in patients. This study shows the feasibility of inducing stroke by 2 h of thread occlusion of the middle cerebral artery in aged (56 week old) spontaneously hypertensive rats (SHRs) with both acute (2 weeks) and chronic (36 weeks) diabetes. After modifying the streptozotocin dosing regimen to ensure that old SHRs survived the induction of diabetes, few died after induction of stroke. Induction of stroke is feasible in rats with multiple comorbidities. Inclusion of such comorbid animals may improve translation from the research laboratory to the clinic.
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Chen, Yong, John M. Hallenbeck, Christl Ruetzler, David Bol, Karen Thomas, Nancy E. J. Berman, and Stefanie N. Vogel. "Overexpression of Monocyte Chemoattractant Protein 1 in the Brain Exacerbates Ischemic Brain Injury and is Associated with Recruitment of Inflammatory Cells." Journal of Cerebral Blood Flow & Metabolism 23, no. 6 (June 2003): 748–55. http://dx.doi.org/10.1097/01.wcb.0000071885.63724.20.
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Brain cells produce cytokines and chemokines during the inflammatory process after stroke both in animal models and in patients. Monocyte chemoattractant protein 1 (MCP-1), one of the proinflammatory chemokines, can attract monocytes to the tissue where MCP-1 is overexpressed. However, the role of MCP-1 elevation in stroke has not been explored in detail. The authors hypothesized that elevated MCP-1 levels would lead to increased influx of monocytes and increased brain infarction size in stroke induced by middle cerebral artery occlusion with partial reperfusion. There were no differences in blood pressure, blood flow, or vascular architecture between wild-type mice and transgenic MBP-JE mice. Twenty-four to 48 hours after middle cerebral artery occlusion, brain infarction volumes after ischemia were significantly larger in MBP-JE mice than in wild-type controls and were accompanied by increased local transmigration and perivascular accumulation of macrophages and neutrophils. These results indicate that MCP-1 can contribute to inflammatory injury in stroke.
12
Bingham, Deborah, I. Mhairi Macrae, and Hilary V. Carswell. "Detrimental Effects of 17β-Oestradiol after Permanent Middle Cerebral Artery Occlusion." Journal of Cerebral Blood Flow & Metabolism 25, no. 3 (January 12, 2005): 414–20. http://dx.doi.org/10.1038/sj.jcbfm.9600031.
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Oestrogen is a complex hormone whose role as a neuroprotectant in experimental stroke has been published in numerous studies. However, although some clinical studies report a reduction in stroke incidence by oestrogen replacement therapy in postmenopausal women, others have found increased mortality and morbidity after stroke. Diathermy occlusion of the proximal middle cerebral artery (MCAO), one of the most reproducible rodent stroke models, has consequently been employed to investigate physiologic and supraphysiologic doses of 17β-oestradiol on ischaemic brain damage. Lister Hooded rats were ovariectomised (OVX) and a 21-day release pellet (placebo, 0.025 or 0.25 mg 17β-oestradiol) implanted in the neck. At 2 weeks after OVX, animals underwent MCAO and were perfusion fixed 24 hours later. Neuronal perikaryal damage was assessed from haematoxylin and eosin-stained sections and in adjacent sections, axonal pathology was assessed with amyloid precursor protein and Neurofilament 200 (NF-200) immunohistochemistry. 17β-Oestradiol induced a dose-dependent increase in neuronal perikaryal damage, 0.025 and 0.25 mg 17β-oestradiol increased damage by 20% ( P<0.05) and 27.5% ( P<0.01) compared with placebo. 17β-Oestradiol did not influence axonal pathology compared with placebo. Our results suggest that 17β-oestradiol treatment can exacerbate brain damage in experimental stroke. Thus, further investigation into the role of oestrogen and the mechanisms which mediate its effects in stroke is required.
13
Cheng, Quancheng, Xuhao Chen, Jiayi Ma, Xingyuan Jiang, Jiahui Chen, Mengqin Zhang, Yejun Wu, Weiguang Zhang, and Chunhua Chen. "Effect of Methylene Blue on White Matter Injury after Ischemic Stroke." Oxidative Medicine and Cellular Longevity 2021 (February 2, 2021): 1–10. http://dx.doi.org/10.1155/2021/6632411.
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Methylene blue, the FDA-grandfathered drug was proved to be neuroprotective in ischemic stroke in rat. However, the mechanism of the protective effect was unknown. In this study, we used different animal models to investigate the effect of MB administration given within and beyond the therapeutic time window on behavioral deficits and infarct volume and related mechanism about the white matter protection. Middle cerebral artery occlusion and reperfusion (MCAO) and photothrombotic middle cerebral artery occlusion (PT-MCAO) models were used. Behavioral deficits and infarct volume were measured by foot fault test, Garcia neurological score, and TTC staining. Black gold staining and western blot were used to evaluate the brain white matter injury. We found that intraperitoneal administration of MB immediately or 24 h after the MCAO or PT-MCAO surgery reduced infarct volume, improved the neurological deficits, and reduced the white matter injury via myelin basic protein (BMP) protection. These findings suggested that MB relieved the white matter injury besides neuronal protection and has potential therapeutic effects on ischemic stroke.
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Dong, Chao, Jiawei Li, Ming Zhao, Lin Chen, Xiaochen Zhai, Lingling Song, Jin Zhao, Qiang Sun, Jie Wu, and Xiaolu Xie. "Pharmacological Effect of Panax notoginseng Saponins on Cerebral Ischemia in Animal Models." BioMed Research International 2022 (August 4, 2022): 1–12. http://dx.doi.org/10.1155/2022/4281483.
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Panax notoginseng saponins (PNS), bioactive compounds, are commonly used to treat ischemic heart and cerebral diseases in China and other Asian countries. Most previous studies of PNS have focused on the mechanisms underlying their treatment of ischemic cardiovascular diseases but not cerebral ischemic diseases. This study sought to explore the pharmacological mechanisms underlying the effectiveness of PNS in treating cerebral ischemic diseases. Different experimental cerebral ischemia models (including middle cerebral artery occlusion (MCAO) and the blockade of four arteries in rats, collagen-adrenaline-induced systemic intravascular thrombosis in mice, thrombosis of carotid artery-jugular vein blood flow in the bypass of rats, and hypoxia tolerance in mice) were used to investigate the mechanisms underlying the actions of PNS on cerebral ischemia. The results indicated that (1) PNS improved neurological function and reduced the cerebral ischemia infraction area in MCAO rats; (2) PNS improved motor coordination function in rats with complete cerebral ischemia (blockade of four arteries), decreased Ca2+ levels, and ameliorated energy metabolism in the brains of ischemia rats; (3) PNS reduced thrombosis in common carotid artery-jugular vein blood flow in the bypass of rats; (4) PNS provided significant promise in antistroke hemiplegia and hypoxia tolerance in mice. In conclusion, PNS showed antagonistic effects on ischemic stroke, and pharmacological mechanisms are likely to be associated with the reduction of cerebral pathological damage, thrombolysis, antihypoxia, and improvement in the intracellular Ca2+ overload and cerebral energy metabolism.
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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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Trueman, Rebecca C., Claris Diaz, Tracy D. Farr, David J. Harrison, Anna Fuller, Paweł F. Tokarczuk, Andrew J. Stewart, Stephen J. Paisey, and Stephen B. Dunnett. "Systematic and detailed analysis of behavioural tests in the rat middle cerebral artery occlusion model of stroke: Tests for long-term assessment." Journal of Cerebral Blood Flow & Metabolism 37, no. 4 (July 20, 2016): 1349–61. http://dx.doi.org/10.1177/0271678x16654921.
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In order to test therapeutics, functional assessments are required. In pre-clinical stroke research, there is little consensus regarding the most appropriate behavioural tasks to assess deficits, especially when testing over extended times in milder models with short occlusion times and small lesion volumes. In this study, we comprehensively assessed 16 different behavioural tests, with the aim of identifying those that show robust, reliable and stable deficits for up to two months. These tasks are regularly used in stroke research, as well as being useful for examining striatal dysfunction in models of Huntington’s and Parkinson’s disease. Two cohorts of male Wistar rats underwent the intraluminal filament model of middle cerebral artery occlusion (30 min) and were imaged 24 h later. This resulted in primarily subcortical infarcts, with a small amount of cortical damage. Animals were tested, along with sham and naïve groups at 24 h, seven days, and one and two months. Following behavioural testing, brains were processed and striatal neuronal counts were performed alongside measurements of total brain and white matter atrophy. The staircase, adjusting steps, rotarod and apomorphine-induced rotations were the most reliable for assessing long-term deficits in the 30 min transient middle cerebral artery occlusion model of stroke.
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Yi, Kyung Sik, Chi-Hoon Choi, Sang-Rae Lee, Hong Jun Lee, Youngjeon Lee, Kang-Jin Jeong, Jinwoo Hwang, Kyu-Tae Chang, and Sang-Hoon Cha. "Sustained diffusion reversal with in-bore reperfusion in monkey stroke models: Confirmed by prospective magnetic resonance imaging." Journal of Cerebral Blood Flow & Metabolism 37, no. 6 (July 20, 2016): 2002–12. http://dx.doi.org/10.1177/0271678x16659302.
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Although early diffusion lesion reversal after recanalization treatment of acute ischaemic stroke has been observed in clinical settings, the reversibility of lesions observed by diffusion-weighted imaging remains controversial. Here, we present consistent observations of sustained diffusion lesion reversal after transient middle cerebral artery occlusion in a monkey stroke model. Seven rhesus macaques were subjected to endovascular transient middle cerebral artery occlusion with in-bore reperfusion confirmed by repeated prospective diffusion-weighted imaging. Early diffusion lesion reversal was defined as lesion reversal at 3 h after reperfusion. Sustained diffusion lesion reversal was defined as the difference between the ADC-derived pre-reperfusion maximal ischemic lesion volume (ADCD-P Match) and the lesion on 4-week follow-up FLAIR magnetic resonance imaging. Diffusion lesions were spatiotemporally assessed using a 3-D voxel-based quantitative technique. The ADCD-P Match was 9.7 ± 6.0% (mean ± SD) and the final infarct was 1.2–6.0% of the volume of the ipsilateral hemisphere. Early diffusion lesion reversal and sustained diffusion lesion reversal were observed in all seven animals, and the calculated percentages compared with their ADCD-P Match ranged from 8.3 to 51.9% (mean ± SD, 26.9 ± 15.3%) and 41.7–77.8% (mean ± SD, 65.4 ± 12.2%), respectively. Substantial sustained diffusion lesion reversal and early reversal were observed in all animals in this monkey model of transient focal cerebral ischaemia.
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West, G. Alexander, Kiarash J. Golshani, Kristian P. Doyle, Nikola S. Lessov, Theodore R. Hobbs, Steven G. Kohama, Martin M. Pike, et al. "A New Model of Cortical Stroke in the Rhesus Macaque." Journal of Cerebral Blood Flow & Metabolism 29, no. 6 (April 22, 2009): 1175–86. http://dx.doi.org/10.1038/jcbfm.2009.43.
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Primate models are essential tools for translational research in stroke but are reportedly inconsistent in their ability to produce cortical infarcts of reproducible size. Here, we report a new stroke model using a transorbital, reversible, two-vessel occlusion approach in male rhesus macaques that produces consistent and reproducible cortical infarcts. The right middle cerebral artery (distal to the orbitofrontal branch) and both anterior cerebral arteries were occluded with vascular clips. Bilateral occlusion of the anterior cerebral artery was critical for reducing collateral flow to the ipsilateral cortex. Reversible ischemia was induced for 45, 60, or 90 mins ( n = 2/timepoint) and infarct volume and neurologic outcome were evaluated. The infarcts were located predominantly in the cortex and increased in size with extended duration of ischemia determined by T2-weighted magnetic resonance imaging. Infarct volume measured by 2,3,5-triphenyl tetrazolium chloride and cresyl violet staining corroborated magnetic resonance imaging results. Neurologic deficit scores worsened gradually with longer occlusion times. A subset of animals ( n = 5) underwent 60 mins of ischemia resulting in consistent infarct volumes primarily located to the cortex that correlated well with neurologic deficit scores. This approach offers promise for evaluating therapeutic interventions in stroke.
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Chaparro, Rafael E., Miwa Izutsu, Toshihiro Sasaki, Huaxin Sheng, Yi Zheng, Homa Sadeghian, Tao Qin, et al. "Sustained Functional Improvement by Hepatocyte Growth Factor-Like Small Molecule BB3 after Focal Cerebral Ischemia in Rats and Mice." Journal of Cerebral Blood Flow & Metabolism 35, no. 6 (February 25, 2015): 1044–53. http://dx.doi.org/10.1038/jcbfm.2015.23.
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Hepatocyte growth factor (HGF), efficacious in preclinical models of acute central nervous system injury, is burdened by administration of full-length proteins. A multiinstitutional consortium investigated the efficacy of BB3, a small molecule with HGF-like activity that crosses the blood-brain barrier in rodent focal ischemic stroke using Stroke Therapy Academic Industry Roundtable (STAIR) and Good Laboratory Practice guidelines. In rats, BB3, begun 6 hours after temporary middle cerebral artery occlusion (tMCAO) reperfusion, or permanent middle cerebral artery occlusion (pMCAO) onset, and continued for 14 days consistently improved long-term neurologic function independent of sex, age, or laboratory. BB3 had little effect on cerebral infarct size and no effect on blood pressure. BB3 increased HGF receptor c-Met phosphorylation and synaptophysin expression in penumbral tissue consistent with a neurorestorative mechanism from HGF-like activity. In mouse tMCAO, BB3 starting 10 minutes after reperfusion and continued for 14 days improved neurologic function that persisted for 8 weeks in some, but not all measures. Study in animals with comorbidities and those exposed to common stroke drugs are the next steps to complete preclinical assessment. These data, generated in independent, masked, and rigorously controlled settings, are the first to suggest that the HGF pathway can potentially be harnessed by BB3 for neurologic benefit after ischemic stroke.
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Henning, Erica C., Christi A. Ruetzler, Martin R. Gaudinski, Tom C.-C. Hu, Lawrence L. Latour, John M. Hallenbeck, and Steven Warach. "Feridex Preloading Permits Tracking of CNS-Resident Macrophages after Transient Middle Cerebral Artery Occlusion." Journal of Cerebral Blood Flow & Metabolism 29, no. 7 (May 6, 2009): 1229–39. http://dx.doi.org/10.1038/jcbfm.2009.48.
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At this time, the pathophysiology of macrophage involvement and their role in stroke progression are poorly understood. Recently, T2- and T2*-weighted magnetic resonance imaging (MRI), after intravenous administration of iron-oxide particles, have been used to understand the inflammatory cascade. Earlier studies report that image enhancement after stroke is from iron-laden macrophages; however, they do not account for potential blood-brain barrier disruption and nonspecific contrast enhancement. In this study, spontaneously hypertensive rats were preloaded with Feridex 7 days before stroke, permitting the labeling of bone-marrow-derived macrophages. Three-dimensional gradient-echo imaging showed average signal decreases of 13% to 23% in preloaded animals, concentrated on the lesion periphery and reaching a maximum on days 2 to 4 after stroke. Immunohistochemistry showed ED-2+, PB+, MHC-II+ and TNF-α+ perivascular macrophages (PVM), meningeal macrophages (MM), and choroid plexus macrophages (CPM). ED-1+ and IBA+ tissue macrophages and/or activated microglia were located throughout the lesion, but were PB−. These findings indicate the following: (1) Feridex preloading permits tracking of the central nervous system (CNS)-resident macrophages (PVM, MM, and CPM) and (2) CNS-resident macrophages likely play an integral role in the inflammatory cascade through antigen presentation and expression of proinflammatory cytokines. Further refinement of this method should permit noninvasive monitoring of inflammation and potential evaluation of antiinflammatory therapies in preclinical models of stroke.
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Sysoev, Yu I., V. A. Prikhodko, I. A. Titovich, V. E. Karev, and S. V. Okovityy. "Changes in somatosensory evoked potentials in rats following transient cerebral ischemia." Acta Biomedica Scientifica 7, no. 4 (September 3, 2022): 190–200. http://dx.doi.org/10.29413/abs.2022-7.4.22.
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Background. Cerebral ischemia induced by transient middle cerebral artery occlusion is one of the most popular ischemic stroke models used to evaluate drug candidates with neuroprotective properties. The possibilities of combining this model with neurophysiological techniques (e.g., electroencephalography, electrocorticography, evoked potential registration, etc.) to assess the effectiveness of novel pharmacotherapeutic strategies appear to be of great interest to current biomedical research.The aim. Identifying specific changes in somatosensory evoked potentials occurring after cerebral ischemia induced by middle cerebral artery occlusion in rats.Materials and methods. A total number of 18 white outbred male rats were randomized into 3 groups by 6 animals in each: 1) control (presumably healthy animals); 2) ischemia-30 (30-minute middle cerebral artery occlusion); 3) ischemia-45 (45-minute occlusion). At post-surgery day 7, cortical responses to sequential electrical stimulation of left and right n. ischiadicus were registered. N1, P2, N2, P3, and N3 peak latencies and amplitudes, peak-to-peak interval durations and amplitudes were calculated. Spearman’s rank correlation coefficients were used to assess the relationship between ischemia duration and evoked potential parameters, and the Chaddock scale was used to qualitatively evaluate the strength of correlations.Results. The rats subjected to cerebral ischemia demonstrated a decrease in some of the peak amplitudes of the ipsi- and contralateral somatosensory potentials evoked by n. ischiadicus stimulation. In the injured hemisphere, decreased P2 and N3 peak and P3–N3 interval amplitudes were registered ipsilaterally, and decreased P3 peak amplitudes and N2–P3 interval durations were observed contralaterally.Conclusions. The obtained data suggest that somatosensory evoked potential registration and analysis can be used to evaluate the functional state of central nerve tracts in rats subjected to cerebral ischemia.
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Sawada, Hironobu, Naoko Nishimura, Eriko Suzuki, Jie Zhuang, Keiko Hasegawa, Hiroyuki Takamatsu, Kazuo Honda, and Keiji Hasumi. "SMTP-7, a Novel Small-Molecule Thrombolytic for Ischemic Stroke: A Study in Rodents and Primates." Journal of Cerebral Blood Flow & Metabolism 34, no. 2 (November 6, 2013): 235–41. http://dx.doi.org/10.1038/jcbfm.2013.191.
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SMTP-7 ( Stachybotrys microspora triprenyl phenol-7), a small molecule that promotes plasminogen activation through the modulation of plasminogen conformation, has excellent therapeutic activity against cerebral infarction in several rodent models. Detailed evaluations of SMTP-7 in a primate stroke model are needed for effective, safe drug development. Here we evaluated SMTP-7 in a monkey photochemical-induced thrombotic middle cerebral artery (MCA) occlusion model ( n=6), in which MCA occlusion was followed by recanalization/reocclusion. SMTP-7 (10 mg/kg, intravenous infusion) significantly increased the postinfusion MCA recanalization rate (32.5-fold, P=0.043) and ameliorated the post-24-h neurologic deficit (by 29%, P=0.02), cerebral infarct (by 46%, P=0.033), and cerebral hemorrhage (by 51%, P=0.013) compared with the vehicle control animals. In normal monkeys, SMTP-7 did not affect general physiologic or hemostatic variables, including coagulation and platelet parameters. Investigations in rodent models of transient and permanent focal cerebral ischemia, as well as arterial thrombosis and bleeding tests, suggest a role for SMTP-7's regulated profibrinolytic action and neuroprotective properties in the monkey MCA occlusion model. In conclusion, SMTP-7 is effective in treating thrombotic stroke in monkeys. SMTP-7 is thus a promising candidate for the development of alternative therapy for ischemic stroke.
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Edwardson, Matthew A., Ximing Wang, Brent Liu, Li Ding, Christianne J. Lane, Caron Park, Monica A. Nelsen, et al. "Stroke Lesions in a Large Upper Limb Rehabilitation Trial Cohort Rarely Match Lesions in Common Preclinical Models." Neurorehabilitation and Neural Repair 31, no. 6 (February 22, 2017): 509–20. http://dx.doi.org/10.1177/1545968316688799.
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Background. Stroke patients with mild-moderate upper extremity motor impairments and minimal sensory and cognitive deficits provide a useful model to study recovery and improve rehabilitation. Laboratory-based investigators use lesioning techniques for similar goals. Objective. To determine whether stroke lesions in an upper extremity rehabilitation trial cohort match lesions from the preclinical stroke recovery models used to drive translational research. Methods. Clinical neuroimages from 297 participants enrolled in the Interdisciplinary Comprehensive Arm Rehabilitation Evaluation (ICARE) study were reviewed. Images were characterized based on lesion type (ischemic or hemorrhagic), volume, vascular territory, depth (cortical gray matter, cortical white matter, subcortical), old strokes, and leukoaraiosis. Lesions were compared with those of preclinical stroke models commonly used to study upper limb recovery. Results. Among the ischemic stroke participants, median infarct volume was 1.8 mL, with most lesions confined to subcortical structures (61%) including the anterior choroidal artery territory (30%) and the pons (23%). Of ICARE participants, <1% had lesions resembling proximal middle cerebral artery or surface vessel occlusion models. Preclinical models of subcortical white matter injury best resembled the ICARE population (33%). Intracranial hemorrhage participants had small (median 12.5 mL) lesions that best matched the capsular hematoma preclinical model. Conclusions. ICARE subjects are not representative of all stroke patients, but they represent a clinically and scientifically important subgroup. Compared with lesions in general stroke populations and widely studied animal models of recovery, ICARE participants had smaller, more subcortically based strokes. Improved preclinical-clinical translational efforts may require better alignment of lesions between preclinical and human stroke recovery models.
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Graham, Steven H., Jun Chen, Frank R. Sharp, and Roger P. Simon. "Limiting Ischemic Injury by Inhibition of Excitatory Amino Acid Release." Journal of Cerebral Blood Flow & Metabolism 13, no. 1 (January 1993): 88–97. http://dx.doi.org/10.1038/jcbfm.1993.11.
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Excitatory amino acids (EAAs) are important mediators of ischemic injury in stroke. N-Methyl-d-aspartate (NMDA) receptor antagonists have been shown to be very effective neuroprotective agents in animal models of stroke, but may have unacceptable toxicity for human use. An alternative approach is to inhibit the release of EAAs during stroke. BW1003C87 [5-(2,3,5-trichlorophenyl)-2,4-diaminopyrimidine], a drug that inhibits veratrine-induced release of the EAA glutamate in vitro, was tested in a rat model of proximal middle cerebral artery (MCA) occlusion. BW1003C87 significantly decreased ischemia-induced glutamate release in brain when given either 5 min before or 15 min following permanent MCA occlusion. Pretreated and posttreated rats had smaller infarct volumes and preserved glucose metabolism in the ischemic cortex at 24 h after MCA occlusion. BW1003C87 did not induce heat shock protein in the cingulate or retrosplenial cortex, suggesting that it does not injure neurons in these regions as do NMDA antagonists. These results demonstrate that drugs that inhibit glutamate release in ischemia may be nontoxic and show promise for the treatment of stroke.
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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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South, Kieron, Ohud Saleh, Eloise Lemarchand, Graham Coutts, Craig J. Smith, Ingo Schiessl, and Stuart M. Allan. "Robust thrombolytic and anti-inflammatory action of a constitutively active ADAMTS13 variant in murine stroke models." Blood 139, no. 10 (March 10, 2022): 1575–87. http://dx.doi.org/10.1182/blood.2021012787.
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Abstract Advances in our understanding of ADAMTS13 structure, and the conformation changes required for full activity, have rejuvenated the possibility of its use as a thrombolytic therapy. We have tested a novel Ala1144Val ADAMTS13 variant (constitutively active [ca] ADAMTS13) that exhibits constitutive activity, characterized using in vitro assays of ADAMTS13 activity, and greatly enhanced thrombolytic activity in 2 murine models of ischemic stroke, the distal FeCl3 middle cerebral artery occlusion (MCAo) model and transient middle cerebral artery occlusion (tMCAO) with systemic inflammation and ischemia/reperfusion injury. The primary measure of efficacy in both models was restoration of regional cerebral blood flow (rCBF) to the MCA territory, which was determined using laser speckle contrast imaging. The caADAMTS13 variant exhibited a constitutively active conformation and a fivefold enhanced activity against fluorescence resonance energy transfer substrate von Willebrand factor 73 (FRETS-VWF73) compared with wild-type (wt) ADAMTS13. Moreover, caADAMTS13 inhibited VWF-mediated platelet capture at subphysiological concentrations and enhanced t-PA/plasmin lysis of fibrin(ogen), neither of which were observed with wtADAMTS13. Significant restoration of rCBF and reduced lesion volume was observed in animals treated with caADAMTS13. When administered 1 hour after FeCl3 MCAo, the caADAMTS13 variant significantly reduced residual VWF and fibrin deposits in the MCA, platelet aggregate formation, and neutrophil recruitment. When administered 4 hours after reperfusion in the tMCAo model, the caADAMTS13 variant induced a significant dissolution of platelet aggregates and a reduction in the resulting tissue hypoperfusion. The caADAMTS13 variant represents a potentially viable therapeutic option for the treatment of acute ischemic stroke, among other thrombotic indications, due to its enhanced in vitro and in vivo activities that result from its constitutively active conformation.
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Bingham, Deborah, Stephen J. Martin, I. Mhairi Macrae, and Hilary V. O. Carswell. "Watermaze Performance after Middle Cerebral Artery Occlusion in the Rat: The Role of Sensorimotor versus Memory Impairments." Journal of Cerebral Blood Flow & Metabolism 32, no. 6 (February 29, 2012): 989–99. http://dx.doi.org/10.1038/jcbfm.2012.16.
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In rodent stroke models, investigation of deficits in spatial memory using the Morris watermaze may be confounded by coexisting sensory or motor impairments. To target memory specifically, we devised a watermaze protocol to minimize the impact of sensory and motor impairments in female Lister-hooded rats exposed to proximal electrocoagulation of the middle cerebral artery (MCAO). Rats were trained in a reference-memory task comprising 4 trials/day; trial 1 being a probe trial (platform absent for the first 60 seconds). Training ended once animals reached a strict criterion based on the probe-trial performance. Memory retention was tested 1, 7, and 28 days later. The MCAO did not affect the number of days to reach criterion during acquisition or the time spent in target quadrant during retention testing, compared with sham or unoperated rats. However, MCAO rats showed slightly poorer accuracy in crossing the platform location and increased thigmotactic swimming compared with controls. Our results show that spatial memory deficits are minimal in this rodent stroke model, and suggest that previously published watermaze impairments are attributable to sensory and motor deficits but not memory deficits. We recommend using probe trials and training to a predetermined performance criterion in future studies assessing watermaze memory deficits in rodent stroke models.
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Wu, Cheng-Tien, Ting-Hua Yang, Man-Chih Chen, Siao-Syun Guan, Chang-Mu Chen, and Shing-Hwa Liu. "Therapeutic Effect of Icaritin on Cerebral Ischemia-Reperfusion-Induced Senescence and Apoptosis in an Acute Ischemic Stroke Mouse Model." Molecules 27, no. 18 (September 7, 2022): 5783. http://dx.doi.org/10.3390/molecules27185783.
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An ischemic stroke is brain damage caused by interruption of blood supply to the brain that can cause death and long-term disability. New medical strategies or therapies are urgently needed for ischemic stroke. Icaritin (ICT) is a metabolite of icariin (ICA), which are two active flavonoid components extracted from Herba epimedii and considered neuroprotective agents in animal models of Alzheimer’s disease and ischemic stroke. The therapeutic effect of ICT on ischemic still remains to be clarified. The aim of this study was to investigate the therapeutic effect of ICT on cerebral ischemia-reperfusion-associated senescence and apoptosis in a middle cerebral artery occlusion (MCAO) mouse model (ischemia for 50 min and reperfusion for 24 h). Administration of ICT after ischemia significantly reduced MCAO-induced neurological damage, infarct volume, and histopathological changes in the brain of acute ischemic stroke mice. ICT treatment could also reduce neuronal apoptosis and senescence and reversed the expression of apoptosis- and senescence-related signaling proteins. These findings suggest that ICT may have therapeutic potential to ameliorate acute ischemic stroke.
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Bahor, Zsanett, Jing Liao, Malcolm R. Macleod, Alexandra Bannach-Brown, Sarah K. McCann, Kimberley E. Wever, James Thomas, et al. "Risk of bias reporting in the recent animal focal cerebral ischaemia literature." Clinical Science 131, no. 20 (October 13, 2017): 2525–32. http://dx.doi.org/10.1042/cs20160722.
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Background: Findings from in vivo research may be less reliable where studies do not report measures to reduce risks of bias. The experimental stroke community has been at the forefront of implementing changes to improve reporting, but it is not known whether these efforts are associated with continuous improvements. Our aims here were firstly to validate an automated tool to assess risks of bias in published works, and secondly to assess the reporting of measures taken to reduce the risk of bias within recent literature for two experimental models of stroke. Methods: We developed and used text analytic approaches to automatically ascertain reporting of measures to reduce risk of bias from full-text articles describing animal experiments inducing middle cerebral artery occlusion (MCAO) or modelling lacunar stroke. Results: Compared with previous assessments, there were improvements in the reporting of measures taken to reduce risks of bias in the MCAO literature but not in the lacunar stroke literature. Accuracy of automated annotation of risk of bias in the MCAO literature was 86% (randomization), 94% (blinding) and 100% (sample size calculation); and in the lacunar stroke literature accuracy was 67% (randomization), 91% (blinding) and 96% (sample size calculation). Discussion: There remains substantial opportunity for improvement in the reporting of animal research modelling stroke, particularly in the lacunar stroke literature. Further, automated tools perform sufficiently well to identify whether studies report blinded assessment of outcome, but improvements are required in the tools to ascertain whether randomization and a sample size calculation were reported.
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Yang, Po-Sheng, Po-Yen Lin, Chao-Chien Chang, Meng-Che Yu, Ting-Lin Yen, Chang-Chou Lan, Thanasekaran Jayakumar, and Chih-Hao Yang. "Antrodia camphorataPotentiates Neuroprotection against Cerebral Ischemia in Rats via Downregulation of iNOS/HO-1/Bax and Activated Caspase-3 and Inhibition of Hydroxyl Radical Formation." Evidence-Based Complementary and Alternative Medicine 2015 (2015): 1–8. http://dx.doi.org/10.1155/2015/232789.
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Antrodia camphorata(A. camphorata) is a fungus generally used in Chinese folk medicine for treatment of viral hepatitis and cancer. Our previous study foundA. camphoratahas neuroprotective properties and could reduce stroke injury in cerebral ischemia animal models. In this study, we sought to investigate the molecular mechanisms of neuroprotective effects ofA. camphoratain middle cerebral artery occlusion (MCAO) rats. A selective occlusion of the middle cerebral artery (MCA) with whole blood clots was used to induce ischemic stroke in rats and they were orally treated withA. camphorata(0.25 and 0.75 g/kg/day) alone or combined with aspirin (5 mg/kg/day). To provide insight into the functions ofA. camphoratamediated neuroprotection, the expression of Bax, inducible nitric oxide synthase (iNOS), haem oxygenase-1 (HO-1), and activated caspase-3 was determined by Western blot assay. Treatment of aspirin alone significantly reduced the expressions of HO-1 (P<0.001), iNOS (P<0.001), and Bax (P<0.01) in ischemic regions. The reduction of these expressions was more potentiated when rats treated by aspirin combined withA. camphorata(0.75 g/kg/day). Combination treatment also reduced apoptosis as measured by a significant reduction in active caspase-3 expression in the ischemic brain compared to MCAO group (P<0.01). Moreover, treatment ofA. camphoratasignificantly (P<0.05) reduced fenton reaction-induced hydroxyl radical (OH•) formation at a dose of 40 mg/mL. Taken together,A. camphoratahas shown neuroprotective effects in embolic rats, and the molecular mechanisms may correlate with the downregulation of Bax, iNOS, HO-1, and activated caspase-3 and the inhibition of OH•signals.
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Langhauser, Friederike, Eva Gob, Peter Kraft, Christian Geis, Joachim Schmitt, Marc Brede, Kirsten Göbel, et al. "Kininogen Deficiency Protects From Ischemic Neurodegeneration in Mice by Reducing Thrombosis, Blood-Brain-Barrier Damage and Inflammation." Blood 120, no. 21 (November 16, 2012): 104. http://dx.doi.org/10.1182/blood.v120.21.104.104.
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Abstract Abstract 104 Background and objective: High molecular weight kininogen (HK) is an abundant plasma protein that serves as an important component of the intrinsic pathway of coagulation. Recent studies have suggested an important role for the intrinsic coagulation pathway in pathologic thrombosis. We have previously described the production of kininogen deficient mice (Kng1−/−), and the prolongation of Rose-Bengal induced carotid artery occlusion in these animals with no effect on the bleeding time. Kininogen also plays a central role in enhancing vascular permeability through the release of the nonapeptide bradykinin following cleavage by plasma kallikrein, and has been implicated in mediating acute inflammatory responses. Since thrombosis and inflammation are hallmarks of ischemic stroke still unamenable to therapeutic interventions, we hypothesized that the severity of acute ischemic stroke would be ameliorated in kininogen deficient mice. Results: We investigated the consequences of kininogen deficiency in models of ischemic stroke. Kng−/− mice of either sex subjected to transient middle cerebral artery occlusion (tMCAO) developed dramatically smaller brain infarctions and less severe neurological deficits without an increase in infarct associated hemorrhage. This protective effect was preserved at later stages of infarction as well as in elderly mice, but was lost after replacement of exogenous kininogen in the deficient mice. The improved outcomes were attributable to markedly reduced thrombus formation in ischemic vessels of mKng1−/− mice, improved cerebral blood flow, and less severe blood-brain barrier damage and edema formation. Moreover, the ingress of inflammatory cells (monocytes and neutrophils), and levels of IL-1 were significantly decreased in the absence of kininogen, consistent with a reduced inflammatory response following ischemic injury. The survival of mice subjected to tMCAO was markedly improved compared to control animals. Conclusion: Mice deficient in kininogen were markedly protected from acute ischemic stroke in the transient middle cerebral artery occlusion model. Protection was mediated through decreased thrombus formation, diminished vascular permeability, and a dampened inflammatory response. The mechanisms underlying these altered responses are currently under investigation. However, since kininogen appears to be instrumental in pathologic thrombus formation and inflammation, but entirely dispensable for normal hemostasis, kininogen inhibition may offer a safe and selective strategy for combating the effects of stroke and other thromboembolic diseases. Disclosures: No relevant conflicts of interest to declare.
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Ren, Yubo, Megumi Hashimoto, William A. Pulsinelli, and Thaddeus S. Nowak. "Hypothermic Protection in Rat Focal Ischemia Models: Strain Differences and Relevance to “Reperfusion Injury”." Journal of Cerebral Blood Flow & Metabolism 24, no. 1 (January 2004): 42–53. http://dx.doi.org/10.1097/01.wcb.0000095802.98378.91.
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Hypothermic protection was compared in Long-Evans and spontaneously hypertensive rat (SHR) strains using transient focal ischemia, and in Wistar and SHR strains using permanent focal ischemia. Focal ischemia was produced by distal surgical occlusion of the middle cerebral artery and tandem occlusion of the ipsilateral common carotid artery (MCA/CCAO). Moderate hypothermia of 2 hours' duration was produced by systemic cooling to 32 °C, with further cooling of the brain achieved by reducing to 30°C the temperature of the saline drip superfusing the exposed occlusion site. Infarct volume was determined from serial hematoxylin and eosin-stained frozen sections obtained routinely at 24 hours, or in some cases after 3 days' survival. In the SHR, moderate hypothermia was only effective when initiated before recirculation after a 90-minute occlusion period. In contrast, the same intervention was strikingly effective in the Long-Evans rat even when initiated after as long as 30-minute reperfusion after a 3-hour occlusion. This magnitude and duration of cooling was not protective in permanent MCA/CCAO in the SHR, but such transient hypothermia did effectively reduce infarct volume after permanent occlusions in Wistar rats. These results show striking differences in the temporal window for hypothermic protection among rat focal ischemia models. As expected, “reperfusion injury” in the Long-Evans strain is particularly responsive to delayed cooling. The finding that the SHR can be protected by hypothermia initiated immediately before recirculation suggests a rapidly evolving component of injury occurs subsequent to reperfusion in this model as well. Hypothermic protection after permanent occlusion in Wistar rats identifies a transient, temperature-sensitive phase of infarct evolution that is not evident in the unreperfused SHR. These observations confirm that distinct mechanisms can underlie the temporal progression of injury in rat stroke models, and emphasize the critical importance of considering model and strain differences in extrapolating results of hypothermic protection studies in animals to the design of interventions in clinical stroke.
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Rewell, Sarah SJ, Amy L. Jeffreys, Steven A. Sastra, Susan F. Cox, John A. Fernandez, Elena Aleksoska, H. Bart van der Worp, Leonid Churilov, Malcolm R. Macleod, and David W. Howells. "Hypothermia revisited: Impact of ischaemic duration and between experiment variability." Journal of Cerebral Blood Flow & Metabolism 37, no. 10 (January 13, 2017): 3380–90. http://dx.doi.org/10.1177/0271678x16688704.
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To assess the true effect of novel therapies for ischaemic stroke, a positive control that can validate the experimental model and design is vital. Hypothermia may be a good candidate for such a positive control, given the convincing body of evidence from animal models of ischaemic stroke. Taking conditions under which substantial efficacy had been seen in a meta-analysis of hypothermia for focal ischaemia in animal models, we undertook three randomised and blinded studies examining the effect of hypothermia induced immediately following the onset of middle cerebral artery occlusion on infarct volume in rats (n = 15, 23, 264). Hypothermia to a depth of 33℃ and maintained for 130 min significantly reduced infarct volume compared to normothermia treatment (by 27–63%) and depended on ischaemic duration (F(3,244) = 21.242, p < 0.05). However, the protective effect varied across experiments with differences in both the size of the infarct observed in normothermic controls and the time to reach target temperature. Our results highlight the need for sample size and power calculations to take into account variations between individual experiments requiring induction of focal ischaemia.
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Bambakidis, Nicholas C., Mary Petrullis, Kui Xu, Brian Rothstein, Ioannis Karampelas, Youzhi Kuang, Warren R. Selman, Joseph C. LaManna, and Robert H. Miller. "Improvement of neurological recovery and stimulation of neural progenitor cell proliferation by intrathecal administration of Sonic hedgehog." Journal of Neurosurgery 116, no. 5 (May 2012): 1114–20. http://dx.doi.org/10.3171/2012.1.jns111285.
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Object Sonic hedgehog (Shh) is a glycoprotein molecule that has been shown to be associated with the proliferative capacity of endogenous neural precursor cells during embryonic development. It has also been shown to regulate the proliferative capacity of neural stem cells in the adult subventricular zone (SVZ), which are also upregulated in animal models of ischemic stroke. In the present study, the effects of exogenous administration of intrathecal Shh protein were examined in the setting of a rodent model of ischemic stroke, with particular attention given to endogenous neural stem cell proliferation and migration as well as inducible differences in behavioral recovery. Methods A rodent model of ischemic stroke was created using the intraluminal suture method of reversible middle cerebral artery occlusion. Animals were treated with intrathecal administration of Shh protein at 24 hours after the onset of the stroke. Behavioral testing was performed, and the animals were killed for measurements of infarct volume 7 days after stroke. Immunohistochemical staining was performed and measurements of cellular proliferation were obtained, with a focus on the proportion and distribution of neural progenitor cells in the SVZ. These values were compared across experimental groups. Results Treatment with intrathecal Shh protein resulted in significant improvement in behavioral function compared with the control group, with a significant reduction of ischemic tissue in the cerebral hemisphere. An increase of nestin immunoreactive cells was observed along the SVZ. Conclusions Intrathecal Shh agonist at doses that upregulate spinal cord GLI1 transcription increases the population of neural precursor cells after spinal cord injury in adult rats. Intrathecal administration of Shh protein appears to have a neuroprotective effect in animal models of ischemic stroke and is associated with improved behavioral recovery, which may be related to its effects on neurogenesis in the SVZ and could be associated with improved functional recovery.
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Willing, Alison E., Martina Vendrame, Jennifer Mallery, C. Jordan Cassady, Cyndy D. Davis, Juan Sanchez-Ramos, and Paul R. Sanberg. "Mobilized Peripheral Blood Cells Administered Intravenously Produce Functional Recovery in Stroke." Cell Transplantation 12, no. 4 (May 2003): 449–54. http://dx.doi.org/10.3727/000000003108746885.
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Filgratism (granulocyte colony stimulating factor, G-CSF)-mobilized peripheral blood progenitor cells (PBPCs) have replaced bone marrow (BM) as a preferred source of autologous stem cells, in light of the faster hematologic recovery and lesser supportive care requirement exhibited by PBPC transplants. Other hematopoietic stem cells, like the human umbilical cord blood-derived stem cells (hUCBs), and nonhematopoietic stem cells have been shown to improve motor function in rodent models of injury and degenerative disease. In the present study we transplanted either G-CSF-mobilized PBPCs or hUCBs in rats 24 h after permanent middle cerebral artery occlusion (MCAO), and assessed their behavioral abnormalities in spontaneous activity and spontaneous motor asymmetry. In both transplanted groups of rats we observed a significant reduction of the stroke-induced hyperactivity compared with nontransplanted, stroked animals. In addition, transplantation of G-CSF PBPC and hUCB cells prevented the development of extensive motor asymmetry. Our findings raise the possibility that PBPCs could provide a novel transplantation therapy to treat stroke.
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Wei, Lili, Haozhe Shi, Xiao Lin, Xin Zhang, Yuhui Wang, George Liu, and Xunde Xian. "Impact of Cholesterol on Ischemic Stroke in Different Human-Like Hamster Models: A New Animal Model for Ischemic Stroke Study." Cells 8, no. 9 (September 4, 2019): 1028. http://dx.doi.org/10.3390/cells8091028.
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Rationale: While high low-density lipoprotein cholesterol (LDL-C) and low high-density lipoprotein cholesterol (HDL-C) levels are positively associated with cardiovascular events, it is still unclear whether familial hypercholesterolemia (FH) and Tangier’s disease (TD), caused by mutations in LDLR and ABCA1, respectively, influence ischemic stroke (IS) in humans. Objective: We sought to establish an easier, more effective, and time-saving method to induce IS, then studied the precise effects of different types of lipoproteins on IS. Methods and Results: A new technique termed contralateral middle cerebral artery occlusion (c-MCAO) was introduced to human-like hamster models to induce IS. Compared to traditional distal MCAO (d-MCAO) induced by electrocoagulation, c-MCAO resulted in a more severe IS with larger infarct sizes and more blood–brain barrier (BBB) disruption after 24 h. It was shown that c-MCAO markedly elicited an increase in brain infarct volume and BBB leakage in both homozygous LDLR (LDLR–/–) and ABCA1 knockout (ABCA1–/–) hamsters, but not in heterozygous LDLR knockout (LDLR+/–) hamsters when compared to wild-type (WT) controls. Conclusions: Using human-like genetically engineered hamsters, our findings demonstrated that both high LDL-C level caused by homozygous LDLR deficiency and severe low HDL-C level caused by deleting ABCA1 were risk factors of IS. As such, we believe the development of this novel IS hamster model is suitable for future ischemic/reperfusion studies.
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Dillon-Carter, Ora, Rowena E. Johnston, Cesario V. Borlongan, Mary Ellen Truckenmiller, Mark Coggiano, and William J. Freed. "T155g-Immortalized Kidney Cells Produce Growth Factors and Reduce Sequelae of Cerebral Ischemia." Cell Transplantation 11, no. 3 (April 2002): 251–59. http://dx.doi.org/10.3727/096020198390012.
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Fetal rat kidney cells produce high levels of glial-derived neurotrophic factor (GDNF) and exert neuroprotective effects when transplanted into the brain in animal models of Parkinson's disease and stroke. The purpose of the present experiment was to produce kidney cell lines that secrete GDNF. Genes encoding two truncated N-terminal fragments of SV40 large T antigen, T155g and T155c, which does not code for small t antigen, were used. T155g was transduced into E17 cultured fetal Sprague-Dawley rat kidney cortex cells using a plasmid vector, and T155c was transduced with a plasmid and a retroviral vector. Sixteen clones were isolated from cultures transfected with the T155g-expressing plasmid. No cell lines were obtained with T155c. Four clones produced GDNF at physiological concentrations ranging from 55 to 93 pg/ml of medium. These four clones were transplanted into the ischemic core or penumbra of rats that had undergone middle cerebral artery occlusion (MCAO). Three of the four clones reduced the volume of infarction and the behavioral abnormalities normally resulting from MCAO. Blocking experiments with antibodies to GDNF and platelet-derived growth factor (PDGF) suggested that these growth factors contributed only minimally to the reduction in infarct volume and behavioral abnormality. These cell lines may be useful for intracerebral transplantation in animal models of brain injury, stroke, or Parkinson's disease.
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Liu, Fudong, Rongwen Yuan, Sharon E. Benashski, and Louise D. McCullough. "Changes in Experimental Stroke Outcome across the Life Span." Journal of Cerebral Blood Flow & Metabolism 29, no. 4 (February 18, 2009): 792–802. http://dx.doi.org/10.1038/jcbfm.2009.5.
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Acute ischemic stroke is a leading cause of mortality and disability in the elderly. Age is the most important nonmodifiable risk factor for stroke, yet many preclinical models continue to examine only young male animals. It remains unclear how experimental stroke outcomes change with aging and with biologic sex. If sex differences are present, it is not known whether these reflect an intrinsic differing sensitivity to stroke or are secondary to the loss of estrogen with aging. We subjected both young and aging mice of both sexes to middle cerebral artery occlusion (MCAO). Young female mice had smaller strokes compared with age-matched males, an effect that was reversed by ovariectomy. Stroke damage increased with aging in female mice, whereas male mice had decreased damage after MCAO. Blood–brain barrier (BBB) permeability changes are correlated with infarct size. However, aging mice had significantly less edema formation, an effect that was independent of sex and histologic damage. Differences in the cellular response to stroke occur across the life span in both male and female mice. These differences need to be considered when developing relevant therapies for stroke patients, the majority of whom are elderly.
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Yuan, Zhaohu, Zhiwu Yu, Yiyu Zhang, and Huikuan Yang. "Analysis of the Clinical Diagnostic Value of GMFB in Cerebral Infarction." Current Pharmaceutical Biotechnology 21, no. 10 (September 7, 2020): 955–63. http://dx.doi.org/10.2174/1389201021666200210102425.
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Background: Glial Maturation Factor Beta (GMFB) is a highly conserved brain-enriched protein implicated in immunoregulation, neuroplasticity and apoptosis, processes central to neural injury and repair following cerebral ischaemia. Therefore, we examined if changes in neurocellular GMFB expression and release can be used to assess brain injury following ischaemia. Methods and Results: Immunofluorescence staining, Western blotting, immunohistochemistry and ELISA were used to measure GMFB in cultured neurons and astrocytes, rat brain tissues and plasma samples from stroke model rats and stroke patients, while cell viability assays, TTC staining and micro- PET were used to assess neural cell death and infarct severity. Immunofluorescence and immunohistochemistry revealed GMFB expression mainly in astrocyte and neuronal nuclei but also in neuronal axons and dendrites. Free GMFB concentration increased progressively in the culture medium during hypoxia-hypoglycaemia treatment. Plasma GMFB concentration increased in rats subjected to middle cerebral artery occlusion (MCAO, a model of stroke-reperfusion) and in stroke patients. Plasma GMFB in MCAO model rats was strongly correlated with infarct size (R2=0.9582). Plasma GMFB concentration was also markedly elevated in stroke patients within 24 h of onset and remained elevated for more than one week. Conversely, plasma GMFB elevations were not significant in myocardial infarct patients and stroke patients without infarction. Conclusion: GMFB has the prerequisite stability, expression specificity and response dynamics to serve as a reliable indicator of ischaemic injury in animal models and stroke patients. Plasma GMFB may be a convenient non-invasive adjunct to neuroimaging for stroke diagnosis and prognosis.
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Maud, Pétrault, Ouk Thavarak, Lachaud Cédrick, Bastide Michèle, Bérézowski Vincent, Pétrault Olivier, and Bordet Régis. "Evidence for the Use of Isoflurane as a Replacement for Chloral Hydrate Anesthesia in Experimental Stroke: An Ethical Issue." BioMed Research International 2014 (2014): 1–7. http://dx.doi.org/10.1155/2014/802539.
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Since an ethical issue has been raised regarding the use of the well-known anesthetic agent chloral hydrate, owing to its mutagenic and carcinogenic effects in animals, attention of neuroscientists has turned to finding out an alternative agent able to meet not only potency, safety, and analgesic efficacy, but also reduced neuroprotective effect for stroke research. The aim of this study was to compare the potential of chloral hydrate and isoflurane for both modulating the action of the experimental neuroprotectant MK801 and exerting analgesia. After middle cerebral artery occlusion in rats, no difference was observed in 24 h survival rate, success of ischemia, or infarct volume reduction between both anesthetics. However, isoflurane exerted a more pronounced analgesic effect than chloral hydrate as evidenced by formalin test 3 hours after anesthesia onset, thus encouraging the use of isoflurane in experimental stroke models.
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Sasaki, Yuichi, Masanori Sasaki, Yuko Kataoka-Sasaki, Masahito Nakazaki, Hiroshi Nagahama, Junpei Suzuki, Daiki Tateyama, et al. "Synergic Effects of Rehabilitation and Intravenous Infusion of Mesenchymal Stem Cells After Stroke in Rats." Physical Therapy 96, no. 11 (November 1, 2016): 1791–98. http://dx.doi.org/10.2522/ptj.20150504.
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Abstract Background Intravenous infusion of mesenchymal stem cells (MSCs) derived from adult bone marrow improves behavioral function in rat stroke models. Rehabilitation therapy through physical exercise also provides therapeutic efficacy for cerebral ischemia. Objective The purpose of this study was to investigate whether synergic effects of daily rehabilitation and intravenous infusion of MSCs has therapeutic effects after stroke in rats. Design This was an experimental study. Methods A permanent middle cerebral artery occlusion (MCAO) was induced by intraluminal vascular occlusion with a microfilament. Four experimental groups were studied: group 1 (vehicle only, n=10), group 2 (vehicle + exercise, n=10), group 3 (MSCs only, n=10), and group 4 (MSCs + exercise, n=10). Rat MSCs were intravenously infused at 6 hours after MCAO, and the rats received daily rehabilitation with treadmill running exercise for 20 minutes. Lesion size was assessed at 1, 14, and 35 days using magnetic resonance imaging. Functional outcome was assessed using the Limb Placement Test. Results Both combined therapy and MSC infusion reduced lesion volume, induced synaptogenesis, and elicited functional improvement compared with the groups without MSC infusion, but the effect was greater in the combined therapy group. Limitations A limitation of this study is that the results were limited to an animal model and cannot be generalized to humans. Conclusions The data indicate that the combined therapy of daily rehabilitation and intravenous infusion of MSCs improved functional outcome in a rat MCAO model.
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García-Rodríguez, Paula, Feifei Ma, Carmen del Río, Marina Romero-Bernal, Ana M. Najar, María de la Luz Cádiz-Gurrea, Francisco Javier Leyva-Jimenez, et al. "Diet Supplementation with Polyphenol-Rich Salicornia ramosissima Extracts Protects against Tissue Damage in Experimental Models of Cerebral Ischemia." Nutrients 14, no. 23 (November 29, 2022): 5077. http://dx.doi.org/10.3390/nu14235077.
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Strokes are the second most common cause of death worldwide and a leading cause of disability. Regular consumption of polyphenols has been shown to reduce the risk of suffering a cardiovascular event. For this reason, we have investigated the protective effect of Salicornia ramosissima, a seasonal halophyte that synthetizes high amounts of bioactive compounds, including polyphenols, in response to environmental stress. Aqueous, hydroalcoholic, and ethanolic extracts were prepared to investigate if dietary supplementation prior to ischemic challenge can prevent subsequent damage using two animal models. First, we screened the protective effect against hypoxia–reoxygenation in Drosophila melanogaster and observed that both ethanolic and hydroalcoholic extracts protected flies from the deleterious effects of hypoxia. Second, we confirmed the protective effect of S. ramosissima ethanolic extract against brain ischemia using the transient middle cerebral artery occlusion mice model. Four weeks of oral supplementation with the ethanolic extract before artery occlusion reduced infarct volume and lowered the plasma levels of the DNA peroxidant product 8-hydroxydeoxyguanosine. Phytochemical profiling of S. ramosissima ethanolic extract revealed 50 compounds. Thus, it represents a valuable source of bioactive compounds that show promising disease-modifying activities and could be further developed as an effective food supplement for the prevention or treatment of neurovascular disorders.
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Learoyd, Annastazia E., Ryan Calmus, Chelsea N. Cunningham, Tim J. England, Tracy D. Farr, Kevin C. F. Fone, David A. Kendall, Saoirse E. O’Sullivan, and Rebecca C. Trueman. "A pilot of the feasibility and usefulness of an aged obese model for use in stroke research." Wellcome Open Research 6 (May 10, 2021): 104. http://dx.doi.org/10.12688/wellcomeopenres.16592.1.
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Background: Animal models of stroke have been criticised as having poor predictive validity, lacking risk factors prevalent in an aging population. This pilot study examined the development of comorbidities in a combined aged and high-fat diet model, and then examined the feasibility of modelling stroke in such rats. Methods: Twelve-month old male Wistar-Han rats (n=15) were fed a 60% fat diet for 8 months during which monthly serial blood samples were taken to assess the development of metabolic syndrome and pro-inflammatory markers. Following this, to pilot the suitability of these rats for undergoing surgical models of stroke, they underwent 30min of middle cerebral artery occlusion (MCAO) alongside younger controls fed a standard diet (n=10). Survival, weight and functional outcome were monitored, and blood vessels and tissues collected for analysis. Results: A high fat diet in aged rats led to substantial obesity. These rats did not develop type 2 diabetes or hypertension. There was thickening of the thoracic arterial wall and vacuole formation in the liver; but of the cytokines examined changes were not seen. MCAO surgery and behavioural assessment was possible in this model (with some caveats discussed in manuscript). Conclusions: This study shows MCAO is possible in aged, obese rats. However, this model is not ideal for recapitulating the complex comorbidities commonly seen in stroke patients.
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Beard, Daniel J., Zhaojin Li, Anna M. Schneider, Yvonne Couch, Marilyn J. Cipolla, and Alastair M. Buchan. "Rapamycin Induces an eNOS (Endothelial Nitric Oxide Synthase) Dependent Increase in Brain Collateral Perfusion in Wistar and Spontaneously Hypertensive Rats." Stroke 51, no. 9 (September 2020): 2834–43. http://dx.doi.org/10.1161/strokeaha.120.029781.
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Background and Purpose: Rapamycin is a clinically approved mammalian target of rapamycin inhibitor that has been shown to be neuroprotective in animal models of stroke. However, the mechanism of rapamycin-induced neuroprotection is still being explored. Our aims were to determine if rapamycin improved leptomeningeal collateral perfusion, to determine if this is through eNOS (endothelial nitric oxide synthase)-mediated vessel dilation and to determine if rapamycin increases immediate postreperfusion blood flow. Methods: Wistar and spontaneously hypertensive rats (≈14 weeks old, n=22 and n=15, respectively) were subjected to ischemia by middle cerebral artery occlusion (90 and 120 minutes, respectively) with or without treatment with rapamycin at 30-minute poststroke. Changes in middle cerebral artery and collateral perfusion territories were measured by dual-site laser Doppler. Reactivity to rapamycin was studied using isolated and pressurized leptomeningeal anastomoses. Brain injury was measured histologically or with triphenyltetrazolium chloride staining. Results: In Wistar rats, rapamycin increased collateral perfusion (43±17%), increased reperfusion cerebral blood flow (16±8%) and significantly reduced infarct volume (35±6 versus 63±8 mm 3 , P <0.05). Rapamycin dilated leptomeningeal anastomoses by 80±9%, which was abolished by nitric oxide synthase inhibition. In spontaneously hypertensive rats, rapamycin increased collateral perfusion by 32±25%, reperfusion cerebral blood flow by 44±16%, without reducing acute infarct volume 2 hours postreperfusion. Reperfusion cerebral blood flow was a stronger predictor of brain damage than collateral perfusion in both Wistar and spontaneously hypertensive rats. Conclusions: Rapamycin increased collateral perfusion and reperfusion cerebral blood flow in both Wistar and comorbid spontaneously hypertensive rats that appeared to be mediated by enhancing eNOS activation. These findings suggest that rapamycin may be an effective acute therapy for increasing collateral flow and as an adjunct therapy to thrombolysis or thrombectomy to improve reperfusion blood flow.
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Kim, Young R., In J. Huang, Seong-Ryong Lee, Emiri Tejima, Joseph B. Mandeville, Maurits PA van Meer, George Dai, et al. "Measurements of BOLD/CBV Ratio Show Altered fMRI Hemodynamics during Stroke Recovery in Rats." Journal of Cerebral Blood Flow & Metabolism 25, no. 7 (March 9, 2005): 820–29. http://dx.doi.org/10.1038/sj.jcbfm.9600084.
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Brain responses to external stimuli after permanent and transient ischemic insults have been documented using cerebral blood volume weighted (CBVw) functional magnetic resonance imaging (fMRI) in correlation with tissue damage and neurological recovery. Here, we extend our previous studies of stroke recovery in rat models of focal cerebral ischemia by comparing blood oxygen level-dependent (BOLD) and cerebral blood volume (CBV) changes. Responses to forepaw stimulation were measured in normal rats ( n = 5) and stroke rats subjected to 2 h of middle cerebral artery occlusion ( n = 6). Functional magnetic resonance imaging was performed 2 weeks after stroke to evaluate the recovery process. After stroke, animals showed variable degrees of fMRI activation in ipsilesional cortex, the extent of which did not correlate with structural damages as measured using apparent diffusion coefficient, fractional anisotropy, blood volume, and vessel size index. While the contralesional cortex showed good overlap between BOLD and CBV-activated regions, the ipsilesional cortex showed low covariance between significantly activated voxels by BOLD and CBVw techniques. In particular, the relative activation during contralateral stimuli in the ipsilesional somatosensory cortex was significantly higher for CBVw responses than BOLD, which might be due to stroke-related alterations in fMRI hemodynamic coupling. Aberrant subcortical activations were also observed. When unaffected forelimbs were stimulated, strong bilateral responses were observed. However, little thalamic responses accompanied stimulation of affected forelimbs despite significant activation in the ipsilesional somatosensory cortex. These results suggest that stroke affects not only local hemodynamics and coupling but also other factors including neural connectivity.
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Talhada, Daniela, Niklas Marklund, Tadeusz Wieloch, Enida Kuric, and Karsten Ruscher. "Plasticity-Enhancing Effects of Levodopa Treatment after Stroke." International Journal of Molecular Sciences 22, no. 19 (September 23, 2021): 10226. http://dx.doi.org/10.3390/ijms221910226.
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Dopaminergic treatment in combination with rehabilitative training enhances long-term recovery after stroke. However, the underlying mechanisms on structural plasticity are unknown. Here, we show an increased dopaminergic innervation of the ischemic territory during the first week after stroke induced in Wistar rats subjected to transient occlusion of the middle cerebral artery (tMCAO) for 120 min. This response was also found in rats subjected to permanent focal ischemia induced by photothrombosis (PT) and mice subjected to PT or tMCAO. Dopaminergic branches were detected in the infarct core of mice and rats in both stroke models. In addition, the Nogo A pathway was significantly downregulated in rats treated with levodopa (LD) compared to vehicle-treated animals subjected to tMCAO. Specifically, the number of Nogo A positive oligodendrocytes as well as the levels of Nogo A and the Nogo A receptor were significantly downregulated in the peri-infarct area of LD-treated animals, while the number of Oligodendrocyte transcription factor 2 positive cells increased in this region after treatment. In addition, we observed lower protein levels of Growth Associated Protein 43 in the peri-infarct area compared to sham-operated animals without treatment effect. The results provide the first evidence of the plasticity-promoting actions of dopaminergic treatment following stroke.
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Shen, Xueyan, Lu Luo, Fei Wang, Kewei Yu, Hongyu Xie, Shan Tian, Gang Liu, et al. "An Enriched Environment Enhances Angiogenesis Surrounding the Cingulum in Ischaemic Stroke Rats." Neural Plasticity 2020 (November 12, 2020): 1–12. http://dx.doi.org/10.1155/2020/8840319.
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An enriched environment (EE) has been demonstrated to improve functional recovery in animal models of ischaemic stroke through enhancing vascular endothelial growth factor- (VEGF-) mediated neuroprotection accompanied by angiogenesis in the ischaemic hemisphere. Whether EEs also promote VEGF-mediated neuroprotection and angiogenesis in the contralateral hemisphere remains unclear. Here, we explored the effect of EEs on VEGF expression and angiogenesis within the contralateral cerebral cortex in a rat middle cerebral artery occlusion/reperfusion (MCAO/r) model. We assessed the expression levels of platelet endothelial cell adhesion molecule-1 (CD31), VEGF, and endothelial nitric oxide synthase (eNOS) in the whole contralateral cerebral cortex using Western blotting assay but did not find an increase in the expression of CD31, VEGF, or eNOS in MCAO/r rats housed in EEs, which suggested that EEs did not enhance the overall expression of VEGF and eNOS or angiogenesis in the entire contralateral cortex. We further analysed the local effect of EEs by immunohistochemistry and found that in and around the bilateral cingulum in MCAO/r rats housed in EEs, haematopoietic progenitor cell antigen- (CD34-) positive endothelial progenitor cells were significantly increased compared with those of rats housed in standard cages (SCs). Further experiments showed that EEs increased neuronal VEGF expression surrounding the cingulum in MCAO/r rats and robustly upregulated eNOS expression. These results revealed that EEs enhanced angiogenesis, VEGF expression, and activation of the VEGF-eNOS pathway in and/or around the cingulum in MCAO/r rats, which were involved in the functional recovery of MCAO/r rats.
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Ifergane, Gal, Matthew Boyko, Dmitri Frank, Honore N. Shiyntum, Julia Grinshpun, Ruslan Kuts, Amir B. Geva, Zeev Kaplan, Vladimir Zeldetz, and Hagit Cohen. "Biological and Behavioral Patterns of Post-Stroke Depression in Rats." Canadian Journal of Neurological Sciences / Journal Canadien des Sciences Neurologiques 45, no. 4 (June 8, 2018): 451–61. http://dx.doi.org/10.1017/cjn.2017.302.
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AbstractBackground: Post-stroke depression (PSD) is the most frequent psychiatric complication following ischemic stroke. It affects up to 60% of all patients and is associated with increased morbidity and mortality following ischemic stroke. The pathophysiology of PSD remains elusive and appears to be multifactorial, rather than “purely” biological or psychosocial in origin. Thus, valid animal models of PSD would contribute to the study of the etiology (and treatment) of this disorder. Methods: The present study depicts a rat model for PSD, using middle cerebral artery occlusion (MCAO). The two-way shuttle avoidance task, Porsolt forced-swim test, and sucrose preference test were employed to assess any depression-like behavior. Localized brain expressions of brain-derived neurotrophic factor (BDNF) protein levels were evaluated to examine the possible involvement of the brain neuronal plasticity in the observed behavioral syndrome. The raw data were subjected to unsupervised fuzzy clustering (UFC) algorithms to assess the sensitivity of bio-behavioral measures indicative of depressive symptoms post MCAO. Results: About 56% of the rats developed significant depressive-like behavioral disruptions as a result of MCAO compared with 4% in the sham-operated control rats. A pattern of a depressive-like behavioral response was common to all affected MCAO animals, characterized by significantly more escape failures and reduced number of total avoidance shuttles, a significant elevation in immobility duration, and reduced sucrose preference. Significant downregulations of BDNF protein levels in the hippocampal sub-regions, frontal cortex, and hypothalamus were observed in all affected MCAO animals. Conclusion: The UFC analysis supports the behavioral analysis and thus, lends validity to our results.
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Beard, Daniel J., Caitlin L. Logan, Damian D. McLeod, Rebecca J. Hood, Debbie Pepperall, Lucy A. Murtha, and Neil J. Spratt. "Ischemic penumbra as a trigger for intracranial pressure rise – A potential cause for collateral failure and infarct progression?" Journal of Cerebral Blood Flow & Metabolism 36, no. 5 (January 12, 2016): 917–27. http://dx.doi.org/10.1177/0271678x15625578.
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We have recently shown that intracranial pressure (ICP) increases dramatically 24 h after minor intraluminal thread occlusion with reperfusion, independent of edema. Some of the largest ICP rises were observed in rats with the smallest final infarcts. A possible alternate mechanism for this ICP rise is an increase of cerebrospinal fluid (CSF) volume secondary to choroid plexus damage (a known complication of the intraluminal stroke model used). Alternatively, submaximal injury may be needed to induce ICP elevation. Therefore, we aimed to determine (a) if choroid plexus damage contributes to the ICP elevation, (b) if varying the patency of an important internal collateral supply to the middle cerebral artery (MCA), the anterior choroidal artery (AChA), produces different volumes of ischemic penumbra and (c) if presence of ischemic penumbra (submaximal injury) is associated with ICP elevation. We found (a) no association between choroid plexus damage and ICP elevation, (b) animals with a good internal collateral supply through the AChA during MCAo had significantly larger penumbra volumes and (c) ICP elevation at ≈24 h post-stroke only occurred in rats with submaximal injury, shown in two different stroke models. We conclude that active cellular processes within the ischemic penumbra may be required for edema-independent ICP elevation.
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Vítečková Wünschová, Andrea, Adam Novobilský, Jana Hložková, Peter Scheer, Hana Petroková, Radovan Jiřík, Pavel Kulich, et al. "Thrombus Imaging Using 3D Printed Middle Cerebral Artery Model and Preclinical Imaging Techniques: Application to Thrombus Targeting and Thrombolytic Studies." Pharmaceutics 12, no. 12 (December 12, 2020): 1207. http://dx.doi.org/10.3390/pharmaceutics12121207.
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Diseases with the highest burden for society such as stroke, myocardial infarction, pulmonary embolism, and others are due to blood clots. Preclinical and clinical techniques to study blood clots are important tools for translational research of new diagnostic and therapeutic modalities that target blood clots. In this study, we employed a three-dimensional (3D) printed middle cerebral artery model to image clots under flow conditions using preclinical imaging techniques including fluorescent whole-body imaging, magnetic resonance imaging (MRI), and computed X-ray microtomography (microCT). Both liposome-based, fibrin-targeted, and non-targeted contrast agents were proven to provide a sufficient signal for clot imaging within the model under flow conditions. The application of the model for clot targeting studies and thrombolytic studies using preclinical imaging techniques is shown here. For the first time, a novel method of thrombus labeling utilizing barium sulphate (Micropaque®) is presented here as an example of successfully employed contrast agents for in vitro experiments evaluating the time-course of thrombolysis and thus the efficacy of a thrombolytic drug, recombinant tissue plasminogen activator (rtPA). Finally, the proof-of-concept of in vivo clot imaging in a middle cerebral artery occlusion (MCAO) rat model using barium sulphate-labelled clots is presented, confirming the great potential of such an approach to make experiments comparable between in vitro and in vivo models, finally leading to a reduction in animals needed.