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Journal articles on the topic 'Experimental ischemic stroke'
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Meadows, Kristy L. "Experimental models of focal and multifocal cerebral ischemia: a review." Reviews in the Neurosciences 29, no. 6 (August 28, 2018): 661–74. http://dx.doi.org/10.1515/revneuro-2017-0076.
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AbstractRodent and rabbit stroke models have been instrumental in our current understanding of stroke pathophysiology; however, translational failure is a significant problem in preclinical ischemic stroke research today. There are a number of different focal cerebral ischemia models that vary in their utility, pathophysiology of causing disease, and their response to treatments. Unfortunately, despite active preclinical research using these models, treatment options for ischemic stroke have not significantly advanced since the food and drug administration approval of tissue plasminogen activator in 1996. This review aims to summarize current stroke therapies, the preclinical experimental models used to help develop stroke therapies, as well as their advantages and limitations. In addition, this review discusses the potential for naturally occurring canine ischemic stroke models to compliment current preclinical models and to help bridge the translational gap between small mammal models and human clinical trials.
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Yang, Fan, Ziying Wang, Xinbing Wei, Huirong Han, Xianfang Meng, Yan Zhang, Weichen Shi, et al. "NLRP3 Deficiency Ameliorates Neurovascular Damage in Experimental Ischemic Stroke." Journal of Cerebral Blood Flow & Metabolism 34, no. 4 (January 15, 2014): 660–67. http://dx.doi.org/10.1038/jcbfm.2013.242.
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Although the innate immune response to induce postischemic inflammation is considered as an essential step in the progression of cerebral ischemia injury, the role of innate immunity mediator NLRP3 in the pathogenesis of ischemic stroke is unknown. In this study, focal ischemia was induced by middle cerebral artery occlusion in NLRP3−/−, NOX2−/−, or wild-type (WT) mice. By magnetic resonance imaging (MRI), Evans blue permeability, and electron microscopic analyses, we found that NLRP3 deficiency ameliorated cerebral injury in mice after ischemic stroke by reducing infarcts and blood–brain barrier (BBB) damage. We further showed that the contribution of NLRP3 to neurovascular damage was associated with an autocrine/paracrine pattern of NLRP3-mediated interleukin-1 β (IL-1 β) release as evidenced by increased brain microvessel endothelial cell permeability and microglia-mediated neurotoxicity. Finally, we found that NOX2 deficiency improved outcomes after ischemic stroke by mediating NLRP3 signaling. This study for the first time shows the contribution of NLRP3 to neurovascular damage and provides direct evidence that NLRP3 as an important target molecule links NOX2-mediated oxidative stress to neurovascular damage in ischemic stroke. Pharmacological targeting of NLRP3-mediated inflammatory response at multiple levels may help design a new approach to develop therapeutic strategies for prevention of deterioration of cerebral function and for the treatment of stroke.
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Vannucci, Susan J., Lisa B. Willing, Shozo Goto, Nabil J. Alkayed, Robert M. Brucklacher, Teresa L. Wood, Javad Towfighi, Patricia D. Hurn, and Ian A. Simpson. "Experimental Stroke in the Female Diabetic, db/db, Mouse." Journal of Cerebral Blood Flow & Metabolism 21, no. 1 (January 2001): 52–60. http://dx.doi.org/10.1097/00004647-200101000-00007.
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Diabetic hyperglycemia increases brain damage after cerebral ischemia in animals and humans, although the underlying mechanisms remain unclear. Gender-linked differences in ischemic tolerance have been described but have not been studied in the context of diabetes. In the current study, we used a model of unilateral common carotid artery ligation, combined with systemic hypoxia, to study the effects of diabetes and gender on hypoxic–ischemic (HI) brain damage in the genetic model of Type II diabetes, the db/db, mouse. Male and female, control and db/db, mice were subjected to right common carotid artery ligation followed by varying periods of hypoxia (8% oxygen/92% nitrogen) to assess mortality, infarct volume, and tissue damage by light microscopic techniques. End-ischemic regional cerebral blood flow (CBF) was determined using [14C] iodoantipyrine autoradiography. Glycolytic and high energy phosphate compounds were measured in blood and brain by enzymatic and fluorometric techniques. Gender and diabetes had significant effects on mortality from HI and extent of brain damage in the survivors. Female mice were more resistant than their male counterparts, such that the severity (mortality and infarction size) in the male diabetics > female diabetics ~ male controls > female controls. End-ischemic CBF and depletion of cerebral high energy reserves were comparable among all groups. Surprisingly, female diabetic mice were more hyperglycemic and demonstrated a greater prolonged lactacidosis than the males; however, they were more resistant to damage. The results suggest a unique pathophysiology of hypoxia–ischemia in the female diabetic brain.
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Sommer, Clemens J. "Ischemic stroke: experimental models and reality." Acta Neuropathologica 133, no. 2 (January 7, 2017): 245–61. http://dx.doi.org/10.1007/s00401-017-1667-0.
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Li, Xiao-Qiu, Lin Tao, Zhong-He Zhou, Yu Cui, and Hui-Sheng Chen. "Remote ischemic conditioning for acute moderate ischemic stroke (RICAMIS): Rationale and design." International Journal of Stroke 15, no. 4 (October 3, 2019): 454–60. http://dx.doi.org/10.1177/1747493019879651.
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Rationale A large number of basic and clinical studies have proved that remote ischemic conditioning has neuroprotective effect. For example, remote ischemic conditioning showed a neuroprotective role in cerebral ischemia-reperfusion injury model. Recent clinical studies suggested that remote ischemic conditioning may improve neurological function and reduce the risk of recurrence in ischemic stroke patients. However, there is a lack of convincing evidence for the neuroprotective effect of remote ischemic conditioning on ischemic stroke, which deserves further study. Aim To explore the efficacy and safety of remote ischemic conditioning for acute moderate ischemic stroke. Sample size estimates A maximum of 1800 subjects are required to test the superiority hypothesis with 80% power according to a one-sided 0.025 level of significance, stratified by gender, age, time from onset to treatment, National Institutes of Health Stroke Scale (6–10 vs. 11–16), degree of responsible vessel stenosis, location of stenosis, and stroke etiology. Methods and design Remote Ischemic Conditioning for Acute Moderate Ischemic Stroke is a prospective, random, open label, blinded endpoint and multi-center study. The subjects are divided into experimental group and control group randomly. The experimental group was treated with remote ischemic conditioning twice daily with 200 mmHg pressure for 10–14 days besides guideline-based therapy. The control group was treated according to the guidelines. Study outcome The primary efficacy endpoint is favorable functional outcome, defined as modified Rankin Scale 0–1 at 90 days post-randomization.
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Zhou, Yuan, Shanshan Zhang, and Xiang Fan. "Role of Polyphenols as Antioxidant Supplementation in Ischemic Stroke." Oxidative Medicine and Cellular Longevity 2021 (June 25, 2021): 1–19. http://dx.doi.org/10.1155/2021/5471347.
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Stroke is the second most common cause of death globally and the leading cause of death in China. The pathogenesis of cerebral ischemia injury is complex, and oxidative stress plays an important role in the fundamental pathologic progression of cerebral damage in ischemic stroke. Previous studies have preliminarily confirmed that oxidative stress should be a potential therapeutic target and antioxidant as a treatment strategy for ischemic stroke. Emerging experimental studies have demonstrated that polyphenols exert the antioxidant potential to play the neuroprotection role after ischemic stroke. This comprehensive review summarizes antioxidant effects of some polyphenols, which have the most inhibition effects on reactive oxygen species generation and oxidative stress after ischemic stroke.
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Safari, Anahid, Rasool Safari, and Afshin Borhani-Haghighi. "Immunology of stroke." Galen Medical Journal 5 (May 24, 2016): 10–17. http://dx.doi.org/10.31661/gmj.v5is1.592.
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Stroke, a multifactorial disease, has distinct pathophysiologic mechanisms, among which inflammation plays a pivotal role. Various types of inflammatory cells, substances, and molecules emerge in the ischemic stroke. Neutrophils, Tcell subtypes, macrophages, microglial cells, dendritic cell, mast cells, asrocytes, as influential cell, tumor necrosis factor_α, interleukin-17, interleukin-10, as released substances, and vascular cell adhesion molecule-1 (VCAM-1), leukocyte very late antigen-4 (VLA-4), and glial fibrillary acidic protein (GFAP), as cellular adhesion molecules. Lymphocytes' invasion to the ischemic brain tissue occurs as the result of VLA-4 ̶ VCAM-1 interaction. Regarding Tcell subtypes, CD4+ cells have known detrimental effects in the ischemic area, while natural killer T cells (NKT cells) and γδ T cells have minor importance in the early stage of ischemia. While some studies proved the cerebroprotective impact of T regulatory cells, others refuted this by presenting a prominent harmful role of them. Bcells have important protective function by releasing IL-10. Neutrophils along with microglial cell, appearing as the first inflammatory cell in the ischemic tissue, and also macrophages deteriorate ischemia. Mast cells and dendritic cells are of great value in stroke progression. The resting astrocytes are neuroprotective, whereas the activated ones present detrimental function in the ischemic region by expression of GFAP. Hence, stroke consequences occur as the result of systemic inflammatory response. The more activation of this system, the poorer neurological outcomes would be observed. As expected, anti-inflammatory interventions in the experimental stroke in animals, have revealed successful results as less infarct size and attenuated neurological damages.
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Gafarova, M. E., G. M. Naumova, M. V. Gulyaev, V. B. Koshelev, I. A. Sokolova, and M. A. Domashenko. "Erythrocyte (dis)aggregation in stroke model in rats." Regional blood circulation and microcirculation 14, no. 2 (June 30, 2015): 63–69. http://dx.doi.org/10.24884/1682-6655-2015-14-2-63-69.
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Introduction and aim of the study. Ischemic stroke develops in conjunction with interruption of blood flow in microvessels that depends on rheological blood properties. There is a lack of knowledge in hemorheological features of experimental stroke making more difficult to value the relevance of stroke models. The study aims investigation of microhemorheological parameters in two experimental stroke models - thromboembolic model and middle cerebral artery (MCA) ligation model. Methods. Male Wistar rats were subjected to focal brain ischemia in MCA ligation stroke model or thromboembolic stroke model. The neurological deficit, the size of ischemic brain lesion and hemorheological parameters (hematocrit, kinetics of red blood cells (RBC) (dis)aggregation and RBC deformability) were evaluated. Results. The neurological deficit was correlated with the size of brain ischemic lesion. The increased rate of RBC aggregate formation was detected in both stroke models. At the same time, the strength of RBC aggregates changed in a model-dependent manner, namely, it raised sharply in the MCA ligation stroke model, but was somewhat decreased in thromboembolic stroke model. Conclusion. The focal stroke models produce repeatable and neurologically significant lesions of brain followed with fundamental changes in the hemorheological parameters. The way of ischemia producing can be crucial for the direction of hemorheological changes.
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Sheng, Siyuan P., Beilei Lei, Michael L. James, Christopher D. Lascola, Talaignair N. Venkatraman, Jin Yong Jung, Mervyn Maze, et al. "Xenon Neuroprotection in Experimental Stroke." Anesthesiology 117, no. 6 (December 1, 2012): 1262–75. http://dx.doi.org/10.1097/aln.0b013e3182746b81.
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Background Xenon has been proven to be neuroprotective in experimental brain injury. The authors hypothesized that xenon would improve outcome from focal cerebral ischemia with a delayed treatment onset and prolonged recovery interval. Methods Rats were subjected to 70 min temporary focal ischemia. Ninety minutes later, rats were treated with 0, 15, 30, or 45% Xe for 20 h or 0 or 30% Xe for 8, 20, or 44 h. Outcome was measured after 7 days. In another experiment, after ischemia, rats were maintained at 37.5° or 36.0°C for 20 h with or without 30% Xe. Outcome was assessed 28 days later. Finally, mice were subjected to intracerebral hemorrhage with or without 30% Xe for 20 h. Brain water content, hematoma volume, rotarod function, and microglial activation were measured. Results Cerebral infarct sizes (mean±SD) for 0, 15, 30, and 45% Xe were 212±27, 176±55, 160±32, and 198±54 mm, respectively (P=0.023). Neurologic scores (median±interquartile range) followed a similar pattern (P=0.002). Infarct size did not vary with treatment duration, but neurologic score improved (P=0.002) at all xenon exposure durations (8, 20, and 44 h). Postischemic treatment with either 30% Xe or subtherapeutic hypothermia (36°C) had no effect on 28-day outcome. Combination of these interventions provided long-term benefit. Xenon improved intracerebral hemorrhage outcome measures. Conclusion Xenon improved focal ischemic outcome at 7, but not 28 days postischemia. Xenon combined with subtherapeutic hypothermia produced sustained recovery benefit. Xenon improved intracerebral hemorrhage outcome. Xenon may have potential for clinical stroke therapy under carefully defined conditions.
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Xie, Luokun, Wenjun Li, Jessica Hersh, Ran Liu, and Shao-Hua Yang. "Experimental ischemic stroke induces long-term T cell activation in the brain." Journal of Cerebral Blood Flow & Metabolism 39, no. 11 (August 10, 2018): 2268–76. http://dx.doi.org/10.1177/0271678x18792372.
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Mounting evidence has demonstrated that both innate and adaptive immune cells infiltrate into the brain after ischemic stroke. T cell invasion has been found in the ischemic region up to one month post experimental ischemic stroke and has been shown to persist for years in stroke patients. However, the function and phenotypic characteristics of the brain invading T cells after ischemic stroke have not been investigated. In the current study, we determined the function of brain invading T cells in the acute and chronic phase following experimental ischemic stroke induced by transient middle cerebral artery occlusion. We observed a significant increase of CD4+ and CD8+ T cells presented in the peri-infarct area at up to one month after experimental ischemic stroke. The brain invading T cells after ischemic stroke demonstrated close interaction with active astrocytes and a progressive proinflammatory phenotype as evidenced by the increased expression of T cell activation markers CD44 and CD25, proinflammatory cytokines INF-γ, IL-17, IL-10, TNF-α, and perforin, with corresponding transcriptional factors T-bet and RORc. Our results indicated a prolonged activation of brain invading CD4+ and CD8+ T cells after ischemic stroke which may play a role in the neural repair process after stroke.
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Patrizz, Anthony N., Jose F. Moruno-Manchon, Lena M. O’Keefe, Sarah J. Doran, Anita R. Patel, Venugopal R. Venna, Andrey S. Tsvetkov, Jun Li, and Louise D. McCullough. "Sex-Specific Differences in Autophagic Responses to Experimental Ischemic Stroke." Cells 10, no. 7 (July 20, 2021): 1825. http://dx.doi.org/10.3390/cells10071825.
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Ischemic stroke triggers a series of complex pathophysiological processes including autophagy. Differential activation of autophagy occurs in neurons derived from males versus females after stressors such as nutrient deprivation. Whether autophagy displays sexual dimorphism after ischemic stroke is unknown. We used a cerebral ischemia mouse model (middle cerebral artery occlusion, MCAO) to evaluate the effects of inhibiting autophagy in ischemic brain pathology. We observed that inhibiting autophagy reduced infarct volume in males and ovariectomized females. However, autophagy inhibition enhanced infarct size in females and in ovariectomized females supplemented with estrogen compared to control mice. We also observed that males had increased levels of Beclin1 and LC3 and decreased levels of pULK1 and p62 at 24 h, while females had decreased levels of Beclin1 and increased levels of ATG7. Furthermore, the levels of autophagy markers were increased under basal conditions and after oxygen and glucose deprivation in male neurons compared with female neurons in vitro. E2 supplementation significantly inhibited autophagy only in male neurons, and was beneficial for cell survival only in female neurons. This study shows that autophagy in the ischemic brain differs between the sexes, and that autophagy regulators have different effects in a sex-dependent manner in neurons.
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Khan, Mohd Muazzam, Badruddeen, Mohd Mujahid, Juber Akhtar, Mohammad Irfan Khan, and Usama Ahmad. "An Overview of Stroke: Mechanism, In vivo Experimental Models Thereof, and Neuroprotective Agents." Current Protein & Peptide Science 21, no. 9 (December 11, 2020): 860–77. http://dx.doi.org/10.2174/1389203721666200617133903.
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Background: Stroke is one of the causes of death and disability globally. Brain attack is because of the acute presentation of stroke, which highlights the requirement for decisive action to treat it. Objective: The mechanism and in-vivo experimental models of stroke with various neuroprotective agents are highlighted in this review. Method: The damaging mechanisms may proceed by rapid, nonspecific cell lysis (necrosis) or by the active form of cell death (apoptosis or necroptosis), depending upon the duration and severity and of the ischemic insult. Results: Identification of injury mediators and pathways in a variety of experimental animal models of global cerebral ischemia has directed to explore the target-specific cytoprotective strategies, which are critical to clinical brain injury outcomes. Conclusion: The injury mechanism, available encouraging medicaments thereof, and outcomes of natural and modern medicines for ischemia have been summarized. In spite of available therapeutic agents (thrombolytics, calcium channel blockers, NMDA receptor antagonists and antioxidants), there is a need for an ideal drug for strokes.
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Campos, Francisco, Tomás Sobrino, Pedro Ramos-Cabrer, Bárbara Argibay, Jesús Agulla, María Pérez-Mato, Raquel Rodríguez-González, David Brea, and José Castillo. "Neuroprotection by glutamate oxaloacetate transaminase in ischemic stroke: An experimental study." Journal of Cerebral Blood Flow & Metabolism 31, no. 6 (January 26, 2011): 1378–86. http://dx.doi.org/10.1038/jcbfm.2011.3.
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As ischemic stroke is associated with an excessive release of glutamate into the neuronal extracellular space, a decrease in blood glutamate levels could provide a mechanism to remove it from the brain tissue, by increasing the brain-blood gradient. In this regard, the ability of glutamate oxaloacetate transaminase (GOT) to metabolize glutamate in blood could represent a potential neuroprotective tool for ischemic stroke. This study aimed to determine the neuroprotective effects of GOT in an animal model of cerebral ischemia by means of a middle cerebral arterial occlusion (MCAO) following the Stroke Therapy Academic Industry Roundtable (STAIR) group guidelines. In this animal model, oxaloacetate-mediated GOT activation inhibited the increase of blood and cerebral glutamate after MCAO. This effect is reflected in a reduction of infarct size, smaller edema volume, and lower sensorimotor deficits with respect to controls. Magnetic resonance spectroscopy confirmed that the increase of glutamate levels in the brain parenchyma after MCAO is inhibited after oxaloacetate-mediated GOT activation. These findings show the capacity of the GOT to remove glutamate from the brain by means of blood glutamate degradation, and suggest the applicability of this enzyme as an efficient and novel neuroprotective tool against ischemic stroke.
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COŞAR, Aymer. "Ischemic stroke models in adult experimental animals." Journal of Cellular Neuroscience and Oxidative Stress 11, no. 2 (June 27, 2019): 14. http://dx.doi.org/10.37212/jcnos.584699.
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Belayev, Ludmila, Larissa Khoutorova, Kristal D. Atkins, Tiffany N. Eady, Song Hong, Yan Lu, Andre Obenaus, and Nicolas G. Bazan. "Docosahexaenoic Acid Therapy of Experimental Ischemic Stroke." Translational Stroke Research 2, no. 1 (November 4, 2010): 33–41. http://dx.doi.org/10.1007/s12975-010-0046-0.
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Simon, Roger P., Masaki Niiro, and Ryder Gwinn. "Prior ischemic stress protects against experimental stroke." Neuroscience Letters 163, no. 2 (December 1993): 135–37. http://dx.doi.org/10.1016/0304-3940(93)90364-q.
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Krey, Lea, Fred Lühder, Kathrin Kusch, Bozena Czech-Zechmeister, Birte Könnecke, Tiago Fleming Outeiro, and George Trendelenburg. "Knockout of Silent Information Regulator 2 (SIRT2) Preserves Neurological Function after Experimental Stroke in Mice." Journal of Cerebral Blood Flow & Metabolism 35, no. 12 (July 29, 2015): 2080–88. http://dx.doi.org/10.1038/jcbfm.2015.178.
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Sirtuin-2 (Sirt2) is a member of the NAD+-dependent protein deacetylase family. Various members of the sirtuin class have been found to be involved in processes related to longevity, regulation of inflammation, and neuroprotection. Induction of Sirt2 mRNA was found in the whole hemisphere after experimental stroke in a recent screening approach. Moreover, Sirt2 protein is highly expressed in myelin-rich brain regions after stroke. To examine the effects of Sirt2 on ischemic stroke, we induced transient focal cerebral ischemia in adult male Sirt2-knockout and wild-type mice. Two stroke models with different occlusion times were applied: a severe ischemia (45 minutes of middle cerebral artery occlusion (MCAO)) and a mild one (15 minutes of MCAO), which was used to focus on subcortical infarcts. Neurological deficit was determined at 48 hours after 45 minutes of MCAO, and up to 7 days after induction of 15 minutes of cerebral ischemia. In contrast to recent data on Sirt1, Sirt2−/− mice showed less neurological deficits in both models of experimental stroke, with the strongest manifestation after 48 hours of reperfusion. However, we did not observe a significant difference of stroke volumes or inflammatory cell count between Sirt2-deficient and wild-type mice. Thus we postulate that Sirt2 mediates myelin-dependent neuronal dysfunction during the early phase after ischemic stroke.
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Guo, Chao, Wen-Jun Wang, Yu-Cheng Liao, Chao Zhao, Ying Yin, Min-Na Yao, Yi Ding, and Jing-Wen Wang. "Effect and Mechanisms of Quercetin for Experimental Focal Cerebral Ischemia: A Systematic Review and Meta-Analysis." Oxidative Medicine and Cellular Longevity 2022 (February 25, 2022): 1–13. http://dx.doi.org/10.1155/2022/9749461.
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Quercetin, a naturally occurring flavonoid, is mainly extracted from tea, onions, and apples. It has the underlying neuroprotective effect on experimental ischemic stroke. A systematic review and meta-analysis were used to assess quercetin’s efficacy and possible mechanisms in treating focal cerebral ischemia. Compared with the control group, twelve studies reported a remarkable function of quercetin in improving the neurological function score (NFS) ( P < 0.05 ), and twelve studies reported a significant effect on reducing infarct volume ( P < 0.05 ). Moreover, two and three studies showed that quercetin could alleviate blood-brain barrier (BBB) permeability and brain water content, respectively. The mechanisms of quercetin against focal cerebral ischemia are diverse, involving antioxidation, antiapoptotic, anti-inflammation, and calcium overload reduction. On the whole, the present study suggested that quercetin can exert a protective effect on experimental ischemic stroke. Although the effect size may be overestimated because of the quality of studies and possible publication bias, these results indicated that quercetin might be a promising neuroprotective agent for human ischemic stroke. This study is registered with PROSPERO, number CRD 42021275656.
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Taha, Aladdin, Joaquim Bobi, Ruben Dammers, Rick M. Dijkhuizen, Antje Y. Dreyer, Adriaan C. G. M. van Es, Fabienne Ferrara, et al. "Comparison of Large Animal Models for Acute Ischemic Stroke: Which Model to Use?" Stroke 53, no. 4 (April 2022): 1411–22. http://dx.doi.org/10.1161/strokeaha.121.036050.
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Translation of acute ischemic stroke research to the clinical setting remains limited over the last few decades with only one drug, recombinant tissue-type plasminogen activator, successfully completing the path from experimental study to clinical practice. To improve the selection of experimental treatments before testing in clinical studies, the use of large gyrencephalic animal models of acute ischemic stroke has been recommended. Currently, these models include, among others, dogs, swine, sheep, and nonhuman primates that closely emulate aspects of the human setting of brain ischemia and reperfusion. Species-specific characteristics, such as the cerebrovascular architecture or pathophysiology of thrombotic/ischemic processes, significantly influence the suitability of a model to address specific research questions. In this article, we review key characteristics of the main large animal models used in translational studies of acute ischemic stroke, regarding (1) anatomy and physiology of the cerebral vasculature, including brain morphology, coagulation characteristics, and immune function; (2) ischemic stroke modeling, including vessel occlusion approaches, reproducibility of infarct size, procedural complications, and functional outcome assessment; and (3) implementation aspects, including ethics, logistics, and costs. This review specifically aims to facilitate the selection of the appropriate large animal model for studies on acute ischemic stroke, based on specific research questions and large animal model characteristics.
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Xu, Hongbei, Mingyao You, Xiang Xiang, Jun Zhao, Ping Yuan, Lan Chu, and Chenchen Xie. "Molecular Mechanism of Epimedium Extract against Ischemic Stroke Based on Network Pharmacology and Experimental Validation." Oxidative Medicine and Cellular Longevity 2022 (October 27, 2022): 1–31. http://dx.doi.org/10.1155/2022/3858314.
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Ischemic stroke exhibits high morbidity, disability, and mortality, and treatments for ischemic stroke are limited despite intensive research. The potent neuroprotective benefits of Epimedium against ischemic stroke have gained lots of interest. Nevertheless, systematic research on the direct role and mechanisms of Epimedium in ischemic stroke is still lacking. Network pharmacology analysis coupled with experimental verification was utilized to systematically evaluate the potential pharmacological mechanism of Epimedium against ischemic stroke. The TCMSP database was used to mine the bioactive ingredients and Epimedium’s targets. The DrugBank, OMIM, and GeneCards databases were employed to identify potential targets of ischemic stroke. GO and KEGG pathway analyses were also carried out. The interaction between active components and hub targets was confirmed via molecular docking. An experimental ischemic stroke model was used to evaluate the possible therapeutic mechanism of Epimedium. As a result, 23 bioactive compounds of Epimedium were selected, and 30 hub targets of Epimedium in its function against ischemic stroke were identified, and molecular docking results demonstrated good binding. The IL-17 signaling pathway was revealed as a potentially significant pathway, with the NF-κB and MAPK/ERK signaling pathways being involved. Furthermore, in vivo experiments demonstrated that Epimedium treatment could improve neurological function and reduce infarct volume. Additionally, Epimedium reduced the activation of microglia and astrocytes in both the ischemic penumbra of the hippocampus and cerebral cortex following ischemic stroke. Western blot and RT–qPCR analyses demonstrated that Epimedium not only depressed the expression of IL-1β, TNF-α, IL-6, and IL-4 but also inhibited the NF-κB and MAPK/ERK signaling pathways. This study applied network pharmacology and in vivo experiment to explore possible mechanism of Epimedium’s role against ischemic stroke, which provides insight into the treatment of ischemic stroke.
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Siracusa, Chiara, Jolanda Sabatino, Isabella Leo, Ceren Eyileten, Marek Postuła, and Salvatore De De Rosa. "Circular RNAs in Ischemic Stroke: Biological Role and Experimental Models." Biomolecules 13, no. 2 (January 22, 2023): 214. http://dx.doi.org/10.3390/biom13020214.
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Ischemic stroke is among the leading causes of morbidity, disability, and mortality worldwide. Despite the recent progress in the management of acute ischemic stroke, timely intervention still represents a challenge. Hence, strategies to counteract ischemic brain injury during and around the acute event are still lacking, also due to the limited knowledge of the underlying mechanisms. Despite the increasing understanding of the complex pathophysiology underlying ischemic brain injury, some relevant pieces of information are still required, particularly regarding the fine modulation of biological processes. In this context, there is emerging evidence that the modulation of circular RNAs, a class of highly conserved non-coding RNA with a closed-loop structure, are involved in pathophysiological processes behind ischemic stroke, unveiling a number of potential therapeutic targets and possible clinical biomarkers. This paper aims to provide a comprehensive overview of experimental studies on the role of circular RNAs in ischemic stroke.
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Roberts, Jill, Leon de Hoog, and Gregory J. Bix. "Mice deficient in endothelial α5 integrin are profoundly resistant to experimental ischemic stroke." Journal of Cerebral Blood Flow & Metabolism 37, no. 1 (July 22, 2016): 85–96. http://dx.doi.org/10.1177/0271678x15616979.
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Stroke is a disease in dire need of better therapies. We have previously shown that a fragment of the extracellular matrix proteoglycan, perlecan, has beneficial effects following cerebral ischemia via the α5β1 integrin receptor. We now report that endothelial cell selective α5 integrin deficient mice (α5 KO) are profoundly resistant to ischemic infarct after transient middle cerebral artery occlusion. Specifically, α5 KOs had little to no infarct 2–3 days post-stroke, whereas controls had an increase in mean infarct volume over the same time period as expected. Functional outcome is also improved in the α5 KOs compared with controls. Importantly, no differences in cerebrovascular anatomy or collateral blood flow were noted that could account for this difference in ischemic injury. Rather, we demonstrate that α5 KOs have increased blood-brain barrier integrity (increased expression of claudin-5, and absent brain parenchymal IgG extravasation) after stroke compared with controls, which could explain their resistance to ischemic injury. Additionally, inhibition of α5 integrin in vitro leads to decreased permeability of brain endothelial cells following oxygen-glucose deprivation. Together, these findings indicate endothelial cell α5 integrin plays an important role in stroke outcome and blood-brain barrier integrity, suggesting that α5 integrin could be a novel therapeutic target for stroke.
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Kanazawa, Masato, Tetsuya Takahashi, Masanori Ishikawa, Osamu Onodera, Takayoshi Shimohata, and Gregory J. del Zoppo. "Angiogenesis in the ischemic core: A potential treatment target?" Journal of Cerebral Blood Flow & Metabolism 39, no. 5 (March 6, 2019): 753–69. http://dx.doi.org/10.1177/0271678x19834158.
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The ischemic penumbra is both a concept in understanding the evolution of cerebral tissue injury outcome of focal ischemia and a potential therapeutic target for ischemic stroke. In this review, we examine the evidence that angiogenesis can contribute to beneficial outcomes following focal ischemia in model systems. Several studies have shown that, following cerebral ischemia, endothelial proliferation and subsequent angiogenesis can be detected beginning four days after cerebral ischemia in the border of the ischemic core, or in the ischemic periphery, in rodent and non-human primate models, although initial signals appear within hours of ischemia onset. Components of the neurovascular unit, its participation in new vessel formation, and the nature of the core and penumbra responses to experimental focal cerebral ischemia, are considered here. The potential co-localization of vascular remodeling and axonal outgrowth following focal cerebral ischemia based on the definition of tissue remodeling and the processes that follow ischemic stroke are also considered. The region of angiogenesis in the ischemic core and its surrounding tissue (ischemic periphery) may be a novel target for treatment. We summarize issues that are relevant to model studies of focal cerebral ischemia looking ahead to potential treatments.
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Omae, Tsuyoshi, Matthew D. Silva, Orna Mayzel-Org, Mark Kazemi, Fihai Li, Christopher H. Sotak, and Marc Fisher. "Temporal evolution of Diffusion / Perfusion Mismatch in a Rat Stroke Model." Stroke 32, suppl_1 (January 2001): 351. http://dx.doi.org/10.1161/str.32.suppl_1.351-c.
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P69 Background and Purpose: Diffusion-weighted imaging (DWI) and perfusion-weighted imaging (PWI) can rapidly detect lesions in acute ischemic stroke. Studies show that lesions by PWI are sometimes larger than those of DWI in patients with acute ischemic stroke, suggests that the mismatch between DWI and PWI is potentially predictive of tissue at high risk for evolving into infarction. The aims of this study were to detect the evolution of the DWI/PWI mismatch in permanent focal experimental ischemia and transient focal experimental ischemia. Methods: Rats were subjected to permanent (n=8) and 60 minutes of temporary ischemia (n=8) using the intraluminal middle cerebral artery occlusion method and then underwent DWI and PWI after occlusion. Rats in the transient ischemic experiments were reperfused 60 minutes after occlusion. An apparent diffusion coefficient map and a cerebral blood flow index map were used to calculate the percent hemispheric lesion volume (%HLV) for each MRI parameter. Results: In permanent ischemia, %HLVs by DWI were 21%, 45%, 60%, 87%, and 101% of %HLV by PWI at 15, 30, 60, 90 and 120 minutes after ischemia, respectively. The ratio did not change after 120 minutes. With 60 minutes of temporary ischemia, the changes were almost the same as those in permanent ischemia before reperfusion. After reperfusion the lesions on PWI were smaller than those on DWI. The DWI lesion did not increase after reperfusion, and was the almost the same size as just before reperfusion. Conclusions: The DWI/PWI mismatch disappears at 2 hours after permanent ischemia, and the region of DWI/PWI mismatch can be saved from ischemic damage if reperfused early, but ischemic lesions seen on DWI can not be reduced by reperfusion after 60 minutes of temporary ischemia in this rat stroke model.
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Cheon, So Yeong, Eun Jung Kim, Jeong Min Kim, and Bon-Nyeo Koo. "Cell Type-Specific Mechanisms in the Pathogenesis of Ischemic Stroke: The Role of Apoptosis Signal-Regulating Kinase 1." Oxidative Medicine and Cellular Longevity 2018 (2018): 1–9. http://dx.doi.org/10.1155/2018/2596043.
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Stroke has become a more common disease worldwide. Despite great efforts to develop treatment, little is known about ischemic stroke. Cerebral ischemia activates multiple cascades of cell type-specific pathomechanisms. Ischemic brain injury consists of a complex series of cellular reactions in various cell types within the central nervous system (CNS) including platelets, endothelial cells, astrocytes, neutrophils, microglia/macrophages, and neurons. Diverse cellular changes after ischemic injury are likely to induce cell death and tissue damage in the brain. Since cells in the brain exhibit different functional roles at distinct time points after injury (acute/subacute/chronic phases), it is difficult to pinpoint genuine roles of cell types after brain injury. Many experimental studies have shown the association of apoptosis signal-regulating kinase 1 (ASK1) with cellular pathomechanisms after cerebral ischemia. Blockade of ASK1, by either pharmacological or genetic manipulation, leads to reduced ischemic brain injury and subsequent neuroprotective effects. In this review, we present the cell type-specific pathophysiology of the early phase of ischemic stroke, the role of ASK1 suggested by preclinical studies, and the potential use of ASK suppression, either by pharmacologic or genetic suppression, as a promising therapeutic option for ischemic stroke recovery.
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Hoehn, Benjamin, Thomas M. Ringer, Lijun Xu, Rona G. Giffard, Robert M. Sapolsky, Gary K. Steinberg, and Midori A. Yenari. "Overexpression of HSP72 after Induction of Experimental Stroke Protects Neurons from Ischemic Damage." Journal of Cerebral Blood Flow & Metabolism 21, no. 11 (November 2001): 1303–9. http://dx.doi.org/10.1097/00004647-200111000-00006.
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The 72-kD inducible heat shock protein (HSP72) can attenuate cerebral ischemic injury when overexpressed before ischemia onset. Whether HSP72 overexpression is protective when applied after ischemia onset is not known, but would have important clinical implications. Fifty-seven rats underwent middle cerebral artery occlusion for 1 hour. Defective herpes simplex viral (HSV) vectors expressing hsp72 with lacZ as a reporter were delivered 0.5, 2, and 5 hours after ischemia onset into each striatum. Control animals received an identical vector containing only lacZ. Striatal neuron survival at 2 days was improved by 23% and 15% when HSP72 vectors were delayed 0.5 and 2 hours after ischemic onset, respectively ( P < 0.05). However, when delayed by 5 hours, HSP72 overexpression was no longer protective. This is the first demonstration that HSP72 gene transfer even after ischemia onset is neuroprotective. Because expression from these HSV vectors begins 4 to 6 hours after injection, this suggests that the temporal therapeutic window for HSP72 is at least 6 hours after ischemia onset. Future strategies aimed at enhancing HSP72 expression after clinical stroke may be worth pursuing. The authors suggest that in the future HSP72 may be an effective treatment for stroke.
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Archer, David P., Andrew M. Walker, Sarah K. McCann, Joanna J. Moser, and Ramana M. Appireddy. "Anesthetic Neuroprotection in Experimental Stroke in Rodents." Anesthesiology 126, no. 4 (April 1, 2017): 653–65. http://dx.doi.org/10.1097/aln.0000000000001534.
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Abstract Background Patients undergoing endovascular therapy for acute ischemic stroke may require general anesthesia to undergo the procedure. At present, there is little clinical evidence to guide the choice of anesthetic in this acute setting. The clinical implications of experimental studies demonstrating anesthetic neuroprotection are poorly understood. Here, the authors evaluated the impact of anesthetic treatment on neurologic outcome in experimental stroke. Methods Controlled studies of anesthetics in stroke using the filament occlusion model were identified in electronic databases up to December 15, 2015. The primary outcome measures, infarct volume, and neurologic deficit score were used to calculate the normalized mean difference for each comparison. Meta-analysis of normalized mean difference values provided estimates of neuroprotection and contributions of predefined factors: study quality, the timing of treatment, and the duration of ischemia. Results In 80 retrieved publications anesthetic treatment reduced neurologic injury by 28% (95% CI, 24 to 32%; P < 0.0001). Internal validity was high: publication bias enhanced the effect size by 4% or less, effect size increased with study quality (P = 0.0004), and approximately 70% of studies were adequately powered. Apart from study quality, no predefined factor influenced neuroprotection. Neuroprotection failed in animals with comorbidities. Neuroprotection by anesthetics was associated with prosurvival mechanisms. Conclusions Anesthetic neuroprotection is a robust finding in studies using the filament occlusion model of ischemic stroke and should be assumed to influence outcomes in studies using this model. Neuroprotection failed in female animals and animals with comorbidities, suggesting that the results in young male animals may not reflect human stroke.
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Cheng, Jian, Weidong Hu, Thomas J. Toung, Zhizheng Zhang, Susan M. Parker, Charles E. Roselli, and Patricia D. Hurn. "Age-Dependent Effects of Testosterone in Experimental Stroke." Journal of Cerebral Blood Flow & Metabolism 29, no. 3 (November 12, 2008): 486–94. http://dx.doi.org/10.1038/jcbfm.2008.138.
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Although male sex is a well-recognized risk factor for stroke, the role of androgens in cerebral ischemia remains unclear. Therefore, we evaluated effects of testosterone on infarct size in both young adult and middle-aged rats (Wistar, 3-month versus 14-month old) and mice (C57/BL6, 3-month versus 12-month old) subjected to middle cerebral artery occlusion. In young adult groups, castrates displayed less ischemic damage as compared with intact males and castrates with testosterone replacement (Cortex: 24% in castrates versus 42% in intact versus 40% with testosterone; Striatum: 45% versus 73% versus 70%) at 22 h reperfusion. Surprisingly, supplementing testosterone in middle-aged rats to the physiologic levels ordinarily seen in young males reduced infarction (Cortex: 2% with testosterone versus 31%; Striatum: 38% with testosterone versus 68%). Testosterone effects on infarct size were blocked by the androgen receptor (AR) antagonist flutamide and further confirmed in young versus middle-aged mice. Baseline cerebral aromatase mRNA levels and activity were not different between young and middle-aged rats. Aromatase activity increased in ischemic tissue, but only in young males. Lastly, stroke damage was not different in aging aromatase knockout mice versus wild-type controls. Our findings indicate that testosterone's effects in experimental stroke are age dependent, mediated via AR, but not cerebral aromatase.
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Wang, Hui-Lin, Qi-Hui Zhou, Meng-Bei Xu, Xiao-Li Zhou, and Guo-Qing Zheng. "Astragaloside IV for Experimental Focal Cerebral Ischemia: Preclinical Evidence and Possible Mechanisms." Oxidative Medicine and Cellular Longevity 2017 (2017): 1–13. http://dx.doi.org/10.1155/2017/8424326.
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Astragaloside IV (AST-IV) is a principal component of Radix Astragali seu Hedysari (Huangqi) and exerts potential neuroprotection in experimental ischemic stroke. Here, we systematically assessed the effectiveness and possible mechanisms of AST-IV for experimental acute ischemic stroke. An electronic search in eight databases was conducted from inception to March 2016. The study quality score was evaluated using the CAMARADES. Rev Man 5.0 software was used for data analyses. Thirteen studies with 244 animals were identified. The study quality score of included studies ranged from 3/10 to 8/10. Eleven studies showed significant effects of AST-IV for ameliorating the neurological function score (P<0.05); seven studies for reducing the infarct volume (P<0.05); and three or two studies for reducing the brain water content and Evans blue leakage (P<0.05), respectively, compared with the control. The mechanisms of AST-IV for ischemic stroke are multiple such as antioxidative/nitration stress reaction, anti-inflammatory, and antiapoptosis. In conclusion, the findings of present study indicated that AST-IV could improve neurological deficits and infarct volume and reduce the blood-brain barrier permeability in experimental cerebral ischemia despite some methodological flaws. Thus, AST-IV exerted a possible neuroprotective effect during the cerebral ischemia/reperfusion injury largely through its antioxidant, anti-inflammatory, and antiapoptosis properties.
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Sokolov, M. E., F. V. Bashirov, and Z. Z. Safiullov. "Experimental validation of gene therapy for ischemic stroke." Kazan medical journal 98, no. 5 (October 15, 2017): 763–69. http://dx.doi.org/10.17750/kmj2017-763.
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Aim. To develop a protocol of direct and cell-mediated gene therapy for ischemic stroke.
Methods. Viral vector carrying green fluorescent protein (GFP) reporter gene was created on the basis of human adenovirus serotype 5 (Ad5). The umbilical blood supply was preserved according to instructions of Kazan State Medical Uuniversity Stem cell bank. Umbilical cord blood mononuclear cells were isolated in a ficoll density gradient by standard procedure and transduced with Ad5-GFP. Ischemic cerebral stroke in rats was caused by distal occlusion of the middle cerebral artery through trephination hole in a temporal bone under surgical microscope. Within four hours after modeling stroke in the anesthetized animals laminectomy was performed at the L4-L5 level, and (1) 0.9% sodium chloride solution, (2) Ad5-GFP and (3) umbilical cord blood mononuclear cells + Ad5-GFP were inserted intrathecally. Survival, targeted migration to the focus of neurodegeneration, the ability to synthesize recombinant protein and the effect of umbilical cord blood mononuclear cells on the infarction area were assessed using luminescent microscopy and morphometric analysis.
Results. GFP expression in the area of the stroke was established 3 weeks after stroke modeling, both after intrathecal insertion of Ad5-GFP and after xenotransplantation of umbilical cord blood mononuclear cells Ad5-GFP transduced ex vivo. When comparing the areas of cerebral infarction 3 weeks after modeling the stroke, in animals from umbilical cord blood mononuclear cells + Ad5-GFP group the median of the infarction area was 47.4% less than in animals receiving isotonic saline solution.
Conclusion. Umbilical cord blood mononuclear cells + Ad5-GFP after intrathecal insertion to animals with ischemic stroke, are capable of targeted migration to the neurodegeneration site as well as of recombinant protein synthesis; the results suggest the expediency of delivering therapeutic genes to ischemic zone via umbilical cord blood mononuclear cells overexpressing neurotrophic factors.
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Yang, Fan, Rachita K. Sumbria, Dong Xue, Chuanhui Yu, Dan He, Shuo Liu, Annlia Paganini-Hill, and Mark Fisher. "Effects of PDE4 Pathway Inhibition in Rat Experimental Stroke." Journal of Pharmacy & Pharmaceutical Sciences 17, no. 3 (August 8, 2014): 362. http://dx.doi.org/10.18433/j3s02v.
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PURPOSE: The first genomewide association study indicated that variations in the phosphodiesterase 4D (PDE4D) gene confer risk for ischemic stroke. However, inconsistencies among the studies designed to replicate the findings indicated the need for further investigation to elucidate the role of the PDE4 pathway in stroke pathogenesis. Hence, we studied the effect of global inhibition of the PDE4 pathway in two rat experimental stroke models, using the PDE4 inhibitor rolipram. Further, the specific role of the PDE4D isoform in ischemic stroke pathogenesis was studied using PDE4D knockout rats in experimental stroke. METHODS: Rats were subjected to either the ligation or embolic stroke model and treated with rolipram (3mg/kg; i.p.) prior to the ischemic insult. Similarly, the PDE4D knockout rats were subjected to experimental stroke using the embolic model. RESULTS: Global inhibition of the PDE4 pathway using rolipram produced infarcts that were 225% (p<0.01) and 138% (p<0.05) of control in the ligation and embolic models, respectively. PDE4D knockout rats subjected to embolic stroke showed no change in infarct size compared to wild-type control. CONCLUSIONS: Despite increase in infarct size after global inhibition of the PDE4 pathway with rolipram, specific inhibition of the PDE4D isoform had no effect on experimental stroke. These findings support a role for the PDE4 pathway, independent of the PDE4D isoform, in ischemic stroke pathogenesis. This article is open to POST-PUBLICATION REVIEW. Registered readers (see “For Readers”) may comment by clicking on ABSTRACT on the issue’s contents page.
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Vivien, Denis, Maxime Gauberti, Axel Montagne, Gilles Defer, and Emmanuel Touzé. "Impact of Tissue Plasminogen Activator on the Neurovascular Unit: From Clinical Data to Experimental Evidence." Journal of Cerebral Blood Flow & Metabolism 31, no. 11 (August 31, 2011): 2119–34. http://dx.doi.org/10.1038/jcbfm.2011.127.
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About 15 million strokes occur each year worldwide. As the number one cause of morbidity and acquired disability, stroke is a major drain on public health-care funding, due to long hospital stays followed by ongoing support in the community or nursing-home care. Although during the last 10 years we have witnessed a remarkable progress in the understanding of the pathophysiology of ischemic stroke, reperfusion induced by recombinant tissue-type plasminogen activator (tPA—Actilyse) remains the only approved acute treatment by the health authorities. The objective of the present review is to provide an overview of our present knowledge about the impact of tPA on the neurovascular unit during acute ischemic stroke.
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Rajah, Gary B., and Yuchuan Ding. "Experimental neuroprotection in ischemic stroke: a concise review." Neurosurgical Focus 42, no. 4 (April 2017): E2. http://dx.doi.org/10.3171/2017.1.focus16497.
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Acute ischemic stroke (AIS) is a leading cause of disability and death worldwide. To date, intravenous tissue plasminogen activator and mechanical thrombectomy have been standards of care for AIS. There have been many advances in diagnostic imaging and endovascular devices for AIS; however, most neuroprotective therapies seem to remain largely in the preclinical phase. While many neuroprotective therapies have been identified in experimental models, none are currently used routinely to treat stroke patients. This review seeks to summarize clinical studies pertaining to neuroprotection, as well as the different preclinical neuroprotective therapies, their presumed mechanisms of action, and their future applications in stroke patients.
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Lin, Jun-Bin, Chan-Juan Zheng, Xuan Zhang, Juan Chen, Wei-Jing Liao, and Qi Wan. "Effects of Tetramethylpyrazine on Functional Recovery and Neuronal Dendritic Plasticity after Experimental Stroke." Evidence-Based Complementary and Alternative Medicine 2015 (2015): 1–10. http://dx.doi.org/10.1155/2015/394926.
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The 2,3,5,6-tetramethylpyrazine (TMP) has been widely used in the treatment of ischemic stroke by Chinese doctors. Here, we report the effects of TMP on functional recovery and dendritic plasticity after ischemic stroke. A classical model of middle cerebral artery occlusion (MCAO) was established in this study. The rats were assigned into 3 groups: sham group (sham operated rats treated with saline), model group (MCAO rats treated with saline) and TMP group (MCAO rats treated with 20 mg/kg/d TMP). The neurological function test of animals was evaluated using the modified neurological severity score (mNSS) at 3 d, 7 d, and 14 d after MCAO. Animals were euthanized for immunohistochemical labeling to measure MAP-2 levels in the peri-infarct area. Golgi-Cox staining was performed to test effect of TMP on dendritic plasticity at 14 d after MCAO. TMP significantly improved neurological function at 7 d and 14 d after ischemia, increased MAP-2 level at 14 d after ischemia, and enhanced spine density of basilar dendrites. TMP failed to affect the spine density of apical dendrites and the total dendritic length. Data analyses indicate that there was significant negative correlation between mNSS and plasticity measured at 14 d after MCAO. Thus, enhanced dendritic plasticity contributes to TMP-elicited functional recovery after ischemic stroke.
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Burrows, Fiona E., Natasha Bray, Adam Denes, Stuart M. Allan, and Ingo Schiessl. "Delayed Reperfusion Deficits after Experimental Stroke Account for Increased Pathophysiology." Journal of Cerebral Blood Flow & Metabolism 35, no. 2 (November 19, 2014): 277–84. http://dx.doi.org/10.1038/jcbfm.2014.197.
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Cerebral blood flow and oxygenation in the first few hours after reperfusion following ischemic stroke are critical for therapeutic interventions but are not well understood. We investigate changes in oxyhemoglobin (HbO2) concentration in the cortex during and after ischemic stroke, using multispectral optical imaging in anesthetized mice, a remote filament to induce either 30 minute middle cerebral artery occlusion (MCAo), sham surgery or anesthesia alone. Immunohistochemistry establishes cortical injury and correlates the severity of damage with the change of oxygen perfusion. All groups were imaged for 6 hours after MCAo or sham surgery. Oxygenation maps were calculated using a pathlength scaling algorithm. The MCAo group shows a significant drop in HbO2 during occlusion and an initial increase after reperfusion. Over the subsequent 6 hours HbO2 concentrations decline to levels below those observed during stroke. Platelets, activated microglia, interleukin-1α, evidence of BBB breakdown and neuronal stress increase within the stroked hemisphere and correlate with the severity of the delayed reperfusion deficit but not with the ΔHbO2 during stroke. Despite initial restoration of HbO2 after 30 min MCAo there is a delayed compromise that coincides with inflammation and could be a target for improved stroke outcome after thrombolysis.
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Lestro Henriques, Isabel, María Gutiérrez-Fernández, Berta Rodríguez-Frutos, Jaime Ramos-Cejudo, Laura Otero-Ortega, Teresa Navarro Hernanz, Sebastián Cerdán, José M. Ferro, and Exuperio Díez-Tejedor. "Intralesional Patterns of MRI ADC Maps Predict Outcome in Experimental Stroke." Cerebrovascular Diseases 39, no. 5-6 (2015): 293–301. http://dx.doi.org/10.1159/000381727.
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Background: After acute ischemia, the tissue that is at risk of infarction can be detected by perfusion-weighted imaging/diffusion-weighted imaging (PWI/DWI) mismatch but the time that is needed to process PWI limits its use. As DWI is highly sensitive to acute ischemic tissue damage, we hypothesized that different ADC patterns represent areas with a different potential for recovery. Methods: In a model of permanent middle cerebral artery occlusion (pMCAO), Sprague-Dawley rats were randomly distributed to sham surgery and pMCAO. We further separated the pMCAO group according to intralesional ADC pattern (homogeneous or heterogeneous). At 24 h after ischemia induction, we analyzed lesion size, functional outcome, cell death expression, and brain protection markers including ROS enzyme NOX-4. MRI included DWI (ADC maps), DTI (tractography), and PWI (CBF, CBV and MTT). Results: The lesion size was similar in pMCAO rats. Animals with a heterogeneous pattern in ADC maps showed better functional outcome in Rotarod test (p = 0.032), less expression of cell death (p = 0.014) and NOX-4 (p = 0.0063), higher intralesional CBF (p = 0.0026) and larger PWI/DWI mismatch (p = 0.007). Conclusions: In a rodent model for ischemic stroke, intralesional heterogeneity in ADC maps was related to better functional outcome in lesions of similar size and interval after pMCAO. DWI ADC maps may assist in the early identification of ischemic tissue with an increased potential for recovery as higher expression of acute protection markers, lower expression of cell death, increased PWI/DWI mismatch, and higher intralesional CBF were present in animals with a heterogeneous ADC pattern.
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Hung, Ming-Ya, Chun-Kai Yang, Jiong-Hong Chen, Li-Han Lin, and Hao-Ming Hsiao. "Novel Blood Clot Retriever for Ischemic Stroke." Micromachines 12, no. 8 (August 3, 2021): 928. http://dx.doi.org/10.3390/mi12080928.
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Stroke is the second leading cause of death in the world. Ischemic stroke, caused by the blockage of intracranial arteries, accounts for approximately 80% of strokes. Among this proportion, acute ischemic stroke, usually caused by the sudden formation of blood clots, can cause fatal blockages in arteries. We proposed a unique blood clot retriever for the treatment of acute ischemic stroke, and conducted a series of tasks, including design, computer simulation, prototyping, and bench testing, for the proof of concept. Unlike most blood clot retrievers used today, our novel design deviates from traditional stent-like blood clot retrievers and uses large closed cells, irregular spikes, and strut protrusions to achieve maximum entanglement for better retrieval performance. Experimental results showed that the retrieval rate of our blood clot retriever was 79%, which demonstrated the feasibility of our new design concept.
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Stegner, David, Sebastian Hofmann, Michael K. Schuhmann, Peter Kraft, Alexander M. Herrmann, Sandy Popp, Marlen Höhn, et al. "Loss of Orai2-Mediated Capacitative Ca 2+ Entry Is Neuroprotective in Acute Ischemic Stroke." Stroke 50, no. 11 (November 2019): 3238–45. http://dx.doi.org/10.1161/strokeaha.119.025357.
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Background and Purpose— Ischemic stroke is one of the leading causes of disability and death. The principal goal of acute stroke treatment is the recanalization of the occluded cerebral arteries, which is, however, only effective in a very narrow time window. Therefore, neuroprotective treatments that can be combined with recanalization strategies are needed. Calcium overload is one of the major triggers of neuronal cell death. We have previously shown that capacitative Ca 2+ entry, which is triggered by the depletion of intracellular calcium stores, contributes to ischemia-induced calcium influx in neurons, but the responsible Ca 2+ channel is not known. Methods— Here, we have generated mice lacking the calcium channel subunit Orai2 and analyzed them in experimental stroke. Results— Orai2-deficient mice were protected from ischemic neuronal death both during acute ischemia under vessel occlusion and during ischemia/reperfusion upon successful recanalization. Calcium signals induced by calcium store depletion or oxygen/glucose deprivation were significantly diminished in Orai2-deficient neurons demonstrating that Orai2 is a central mediator of neuronal capacitative Ca 2+ entry and is involved in calcium overload during ischemia. Conclusions— Our experimental data identify Orai2 as an attractive target for pharmaceutical intervention in acute stroke.
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Liu, Xiaoqin, Wenri Zhang, Nabil J. Alkayed, Stanley C. Froehner, Marvin E. Adams, Mahmood Amiry-Moghaddam, Ole Petter Ottersen, Patricia D. Hurn, and Anish Bhardwaj. "Lack of Sex-Linked Differences in Cerebral Edema and Aquaporin-4 Expression after Experimental Stroke." Journal of Cerebral Blood Flow & Metabolism 28, no. 12 (July 23, 2008): 1898–906. http://dx.doi.org/10.1038/jcbfm.2008.83.
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Aquaporin-4 (AQP4) has been shown to be important in the evolution of stroke-associated cerebral edema. However, the role of AQP4 in stroke-associated cerebral edema as it pertains to sex has not been previously studied. The perivascular pool of AQP4 is important in the influx and efflux of water during focal cerebral ischemia. We used mice with targeted disruption of the gene encoding α-syntrophin (α-Syn−/−) that lack the perivascular AQP4 pool but retain the endothelial pool of this protein. Infarct volume at 72 h after transient focal ischemia (90 mins) in isoflurane-anesthetized mice was attenuated in both sexes with α-Syn deletion as compared with their wild-type (WT) counterparts. There were no sex differences in hemispheric water content in WT and α-Syn−/− mice or regional AQP4 expression in WT mice. In neither sex did α-Syn deletion lead to alterations in end-ischemic regional cerebral blood flow (rCBF). These data suggest that after experimental stroke: (1) there is no difference in stroke-associated cerebral edema based on sex, (2) AQP4 does not involve in sex-based differences in stroke volume, and (3) perivascular pool of AQP4 has no significant role in end-ischemic rCBF.
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Roy-O’Reilly, Meaghan, and Louise D. McCullough. "Age and Sex Are Critical Factors in Ischemic Stroke Pathology." Endocrinology 159, no. 8 (July 11, 2018): 3120–31. http://dx.doi.org/10.1210/en.2018-00465.
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Abstract Ischemic stroke is a devastating brain injury resulting in high mortality and substantial loss of function. Understanding the pathophysiology of ischemic stroke risk, mortality, and functional loss is critical to the development of new therapies. Age and sex have a complex and interactive effect on ischemic stroke risk and pathophysiology. Aging is the strongest nonmodifiable risk factor for ischemic stroke, and aged stroke patients have higher mortality and morbidity and poorer functional recovery than their young counterparts. Importantly, patient age modifies the influence of patient sex in ischemic stroke. Early in life, the burden of ischemic stroke is higher in men, but stroke becomes more common and debilitating for women in elderly populations. The profound effects of sex and age on clinical ischemic stroke are mirrored in the results of experimental in vivo and in vitro studies. Here, we review current knowledge on the influence of age and sex in the incidence, mortality, and functional outcome of ischemic stroke in clinical populations. We also discuss the experimental evidence for sex and age differences in stroke pathophysiology and how a better understanding of these biological variables can improve clinical care and enhance development of novel therapies.
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Liu, Xiao-li, Jian-zong Du, Yu-miao Zhou, Qin-fen Shu, and Ya-guo Li. "Interleukin-16Polymorphism Is Associated with an Increased Risk of Ischemic Stroke." Mediators of Inflammation 2013 (2013): 1–5. http://dx.doi.org/10.1155/2013/564750.
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Clinical and experimental data have demonstrated that inflammation plays fundamental roles in the pathogenesis of ischemic stroke. Interleukin-16 (IL-16) is identified as a proinflammatory cytokine that is a key element in the ischemic cascade after cerebral ischemia. We aimed to examine the relationship between theIL-16polymorphisms and the risk of ischemic stroke in a Chinese population. A total of 198 patients with ischemic stroke and 236 controls were genotyped using polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) and DNA sequencing method. We found that the rs11556218TG genotype and G allele ofIL-16were associated with significantly increased risks of ischemic stroke (TG versus TT, adjusted OR = 1.88; 95% CI, 1.15–3.07; G versus T, adjusted OR = 1.54; 95% CI, 1.05–2.27, resp.). However, there were no significant differences in the genotype and allele frequencies ofIL-16rs4778889 T/C and rs4072111 C/T polymorphisms between the two groups, even after stratification analyses by age, gender, and the presence or absence of hypertension, diabetes mellitus, hypercholesterolemia, and hypertriglyceridemia. These findings indicate that theIL-16polymorphism may be related to the etiology of ischemic stroke in the Chinese population.
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Michalski, Dominik, Willi Reimann, Emma Spielvogel, Bianca Mages, Bernd Biedermann, Henryk Barthel, Björn Nitzsche, Stefan Schob, and Wolfgang Härtig. "Regionally Altered Immunosignals of Surfactant Protein-G, Vascular and Non-Vascular Elements of the Neurovascular Unit after Experimental Focal Cerebral Ischemia in Mice, Rats, and Sheep." International Journal of Molecular Sciences 23, no. 11 (May 24, 2022): 5875. http://dx.doi.org/10.3390/ijms23115875.
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The surfactant protein-G (SP-G) has recently been discovered in the brain and linked to fluid balance regulations. Stroke is characterized by impaired vessel integrity, promoting water influx and edema formation. The neurovascular unit concept (NVU) has been generated to cover not only ischemic affections of neurons or vessels but also other regionally associated cells. This study provides the first spatio-temporal characterization of SP-G and NVU elements after experimental stroke. Immunofluorescence labeling was applied to explore SP-G, vascular and cellular markers in mice (4, 24, and 72 h of ischemia), rats (24 h of ischemia), and sheep (two weeks of ischemia). Extravasated albumin indicated vascular damage within ischemic areas. Quantifications revealed decreasing SP-G signals in the ischemia-affected neocortex and subcortex. Inverse immunosignals of SP-G and vascular elements existed throughout all models. Despite local associations between SP-G and the vasculature, a definite co-localization was not seen. Along with a decreased SP-G-immunoreactivity in ischemic areas, signals originating from neurons, glial elements, and the extracellular matrix exhibited morphological alterations or changed intensities. Collectively, this study revealed regional alterations of SP-G, vascular, and non-vascular NVU elements after ischemia, and may thus stimulate the discussion about the role of SP-G during stroke.
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Shin, Tae Hwan, Da Yeon Lee, Shaherin Basith, Balachandran Manavalan, Man Jeong Paik, Igor Rybinnik, M. Maral Mouradian, Jung Hwan Ahn, and Gwang Lee. "Metabolome Changes in Cerebral Ischemia." Cells 9, no. 7 (July 7, 2020): 1630. http://dx.doi.org/10.3390/cells9071630.
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Cerebral ischemia is caused by perturbations in blood flow to the brain that trigger sequential and complex metabolic and cellular pathologies. This leads to brain tissue damage, including neuronal cell death and cerebral infarction, manifesting clinically as ischemic stroke, which is the cause of considerable morbidity and mortality worldwide. To analyze the underlying biological mechanisms and identify potential biomarkers of ischemic stroke, various in vitro and in vivo experimental models have been established investigating different molecular aspects, such as genes, microRNAs, and proteins. Yet, the metabolic and cellular pathologies of ischemic brain injury remain not fully elucidated, and the relationships among various pathological mechanisms are difficult to establish due to the heterogeneity and complexity of the disease. Metabolome-based techniques can provide clues about the cellular pathologic status of a condition as metabolic disturbances can represent an endpoint in biological phenomena. A number of investigations have analyzed metabolic changes in samples from cerebral ischemia patients and from various in vivo and in vitro models. We previously analyzed levels of amino acids and organic acids, as well as polyamine distribution in an in vivo rat model, and identified relationships between metabolic changes and cellular functions through bioinformatics tools. This review focuses on the metabolic and cellular changes in cerebral ischemia that offer a deeper understanding of the pathology underlying ischemic strokes and contribute to the development of new diagnostic and therapeutic approaches.
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Daffertshofer, Michael, and Marc Fatar. "Therapeutic ultrasound in ischemic stroke treatment: experimental evidence." European Journal of Ultrasound 16, no. 1-2 (November 2002): 121–30. http://dx.doi.org/10.1016/s0929-8266(02)00049-6.
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Lebedynets, V., L. Ostankova, D. Lebedynets, N. Bondarovich, M. Ostankov, and A. Goltsev. "Experimental ischemic stroke treatment with cryopreserved cord blood." Journal of the Neurological Sciences 381 (October 2017): 857. http://dx.doi.org/10.1016/j.jns.2017.08.2416.
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Gibson, Claire L., Laura J. Gray, Sean P. Murphy, and Philip MW Bath. "Estrogens and Experimental Ischemic Stroke: A Systematic Review." Journal of Cerebral Blood Flow & Metabolism 26, no. 9 (January 25, 2006): 1103–13. http://dx.doi.org/10.1038/sj.jcbfm.9600270.
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Zhao, Heng, Midori A. Yenari, Matthew S. Lawrence, Danye Chen, Dora Y. Ho, Robert M. Sapolsky, and Gary K. Steinberg. "Bcl-2 Overexpression Protects Against Neuron Loss in Peri-infarct Regions Following Experimental Stroke." Stroke 32, suppl_1 (January 2001): 326–27. http://dx.doi.org/10.1161/str.32.suppl_1.326-e.
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59 Purpose: Bcl-2 protects against both apoptotic and necrotic death induced by various insults, including cerebral ischemia. Ischemic injury with and without reperfusion may occur by different mechanisms, and protective strategies may be effective against one, but not the other. Here, we determine whether Bcl-2 protects against 2 different forms of focal cerebral ischemic injury within cortical penumbra in a model of experimental stroke. Methods: Bipromoter defective herpes simplex viral (HSV) vectors expressing Bcl-2 plus β-galactosidase (β-gal) as the reporter or β-gal only (control vector)were stereotaxically injected into left and right cortices using coordinates corresponding to the infarct border. 12 h later, focal ischemia was induced by occluding the middle cerebral artery (MCA) and both common carotid arteries (CCA). For the permanent occlusion model, the MCA was left occluded, but the CCAs were reopened after 2 h. For the reperfusion model, all 3 vessels were reopened after 2 h. 2 days later, brains were harvested and sections were reacted with X-gal followed by cresyl violet. X-gal positive neurons were counted in each hemisphere and expressed as the ratio of positive neurons in the ischemic side compared to the non-ischemic side. Results: Bcl-2 overexpression resulted in significantly improved cortical neuron survival within penumbral regions compared to control vector in both cases. Following reperfusion, Bcl-2 injected animals had 74±14%(n=5) survival compared to control 26±3% (n=6)(P<0.05). Following permanent MCA occlusion, Bcl-2 injected animals had 92±9%(n=5)survival vs.control, 45±5%(n=7)(P<0.05). The extent of survival from the 2 different paradigms suggest that Bcl-2 mediated protection was greater in the ischemia with permanent occlusion compared to reperfusion group. Conclusion: Bcl-2 overexpression protects against experimental stroke with and without reperfusion. The extent of protection appears to be greater for ischemia with permanent MCA occlusion. Furthermore, we show that gene transfer to penumbral zones is possible, suggesting a potential therapeutic strategy for clinical application.
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Yang, Wei, and Wulf Paschen. "Is age a key factor contributing to the disparity between success of neuroprotective strategies in young animals and limited success in elderly stroke patients? Focus on protein homeostasis." Journal of Cerebral Blood Flow & Metabolism 37, no. 10 (July 28, 2017): 3318–24. http://dx.doi.org/10.1177/0271678x17723783.
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Neuroprotection strategies to improve stroke outcome have been successful in the laboratory but not in clinical stroke trials, and thus have come under scrutiny by the medical community. Experimental stroke investigators are therefore under increased pressure to resolve this problem. Acute ischemic stroke represents a severe form of metabolic stress that activates many pathological processes and thereby impairs cellular functions. Traditionally, neuroprotection strategies were designed to improve stroke outcome by interfering with pathological processes triggered by ischemia. However, stroke outcome is also dependent on the brain’s capacity to restore cellular functions impaired by ischemia, and this capacity declines with age. It is, therefore, conceivable that this age-dependent decline in the brain’s self-healing capacity contributes to the disparity between the success of neuroprotective strategies in young animals, and limited success in elderly stroke patients. Here, prosurvival pathways that restore protein homeostasis impaired by ischemic stress should be considered, because their capacity decreases with increasing age, and maintenance of proteome fidelity is pivotal for cell survival. Boosting such prosurvival pathways pharmacologically to restore protein homeostasis and, thereby, cellular functions impaired by ischemic stress is expected to counterbalance the compromised self-healing capacity of aged brains and thereby help to improve stroke outcome.
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Zhang, Jiaming, Kai Wang, Jia Qi, Xiaodong Cao, and Feng Wang. "The Hsp90 Inhibitor 17-DMAG Attenuates Hyperglycemia-Enhanced Hemorrhagic Transformation in Experimental Stroke." BioMed Research International 2021 (February 2, 2021): 1–7. http://dx.doi.org/10.1155/2021/6668442.
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Introduction. Hemorrhagic transformation (HT) is one of the most common complications of ischemic stroke which is exacerbated by hyperglycemia. Oxidative stress, inflammatory response, and matrix metalloproteinases (MMPs) have been evidenced to play a vital role in the pathophysiology of HT. Our previous study has reported that 17-DMAG, an Hsp90 inhibitor, protects the brain against ischemic injury via inhibiting inflammation and reducing MMP-9 after ischemia. However, whether 17-DMAG would attenuate HT in hyperglycemic middle cerebral artery occlusion (MCAO) rats is still unknown. Methods. Acute hyperglycemia was induced by an injection of 50% dextrose. Rats were pretreated with 17-DMAG before MCAO. Infarction volume, hemorrhagic volume neurological scores, expressions of inflammatory molecules and tight junction proteins, and activity of MMP-2 and MMP-9 were assessed 24 h after MCAO. Results. 17-DMAG was found to reduce HT, improve neurological function, and inhibit expressions of inflammatory molecules and the activation of MMPs at 24 h after MCAO. Conclusion. These results implicated that Hsp90 could be a novel therapeutic target in HT following ischemic stroke.
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Ferrarese, Carlo, Paolo Mascarucci, Chiara Zoia, Rosella Cavarretta, Maura Frigo, Barbara Begni, Federica Sarinella, Lodovico Frattola, and Maria Grazia De Simoni. "Increased Cytokine Release from Peripheral Blood Cells after Acute Stroke." Journal of Cerebral Blood Flow & Metabolism 19, no. 9 (September 1999): 1004–9. http://dx.doi.org/10.1097/00004647-199909000-00008.
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Cytokines interleukin (IL)-6 and tumor necrosis factor (TNF)-α can play pathogenetic or protective roles in stroke. They are increased in the brain after experimental ischemia and in the CSF of patients with stroke. However, their presence in the periphery is still controversial. To determine the source and time-course of cytokines in blood of stroke patients, IL-6 and TNF-α release from blood cells and serum levels were determined in 40 patients on days 1 through 2, 4, 10, 30, and 90 after stroke. Twenty healthy age-matched volunteers were used as controls. IL-6 and TNF-α release from stimulated blood cells was increased in stroke patients, compared to controls. A peak response (+224%) was observed at day 4 for IL-6, while TNF-α release was largely and significantly increased (about three-fold compared to controls) from day 1 to 2 until day 90 after stroke. The increase in IL-6 release was significantly higher in ischemic, compared to hemorragic strokes, at days 1 and 4. Circulating IL-6 was increased at each time point. The ischemic processes in the CNS induces a long-lasting activation of IL-6 and TNF-α production in peripheral blood cells, which are a major source of serum cytokines after stroke.