Journal articles on the topic 'In vitro ischemia model'
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1
Park, Kwon Moo, Ang Chen, and Joseph V. Bonventre. "Prevention of Kidney Ischemia/Reperfusion-induced Functional Injury and JNK, p38, and MAPK Kinase Activation by Remote Ischemic Pretreatment." Journal of Biological Chemistry 276, no. 15 (January 9, 2001): 11870–76. http://dx.doi.org/10.1074/jbc.m007518200.
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MAPK activities, including JNK, p38, and ERK, are markedly enhanced after ischemiain vivoand chemical anoxiain vitro. The relative extent of JNK, p38, or ERK activation has been proposed to determine cell fate after injury. A mouse model was established in which prior exposure to ischemia protected against a second ischemic insult imposed 8 or 15 days later. In contrast to what was observed after 30 min of bilateral ischemia, when a second period of ischemia of 30- or 35-min duration was imposed 8 days later, there was no subsequent increase in plasma creatinine, decrease in glomerular filtration rate, or increase in fractional excretion of sodium. A shorter period of prior ischemia (15 min) was partially protective against subsequent ischemic injury 8 days later. Unilateral ischemia was also protective against a subsequent ischemic insult to the same kidney, revealing that systemic uremia is not necessary for protection. The ischemia-related activation of JNK and p38 and outer medullary vascular congestion were markedly mitigated by prior exposure to ischemia, whereas preconditioning had no effect on post-ischemic activation of ERK1/2. The phosphorylation of MKK7, MKK4, and MKK3/6, upstream activators of JNK and p38, was markedly reduced by ischemic preconditioning, whereas the post-ischemic phosphorylation of MEK1/2, the upstream activator of ERK1/2, was unaffected by preconditioning. Pre- and post-ischemic HSP-25 levels were much higher in the preconditioned kidney. In summary, post-ischemic JNK and p38 (but not ERK1/2) activation was markedly reduced in a model of kidney ischemic preconditioning that was established in the mouse. The reduction in JNK and p38 activation can be accounted for by reduced activation of upstream MAPK kinases. The post-ischemic activation patterns of MAPKs may explain the remarkable protection against ischemic injury observed in this model.
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Picard, Sandra, Rene Rouet, Frederic Flais, Pierre Ducouret, Gerard Babatasi, Andre Khayat, Jean-Claude Potier, Henri Bricard, and Jean-Louis Gerard. "Proarrhythmic and Antiarrhythmic Effects of Bupivacaine in an In Vitro Model of Myocardial Ischemia and Reperfusion." Anesthesiology 88, no. 5 (May 1, 1998): 1318–29. http://dx.doi.org/10.1097/00000542-199805000-00024.
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Background Bupivacaine may have toxic cardiovascular effects when accidentally administered by intravascular injection. However, its electrophysiologic effects in the presence of myocardial ischemia remain unknown. The authors evaluated the electrophysiologic and anti- and proarrhythmic effects of bupivacaine in an in vitro model of the ischemic and reperfused myocardium. Methods In a double-chamber bath, a guinea pig right ventricular muscle strip was subjected partly to normal conditions and partly to simulated ischemia followed by reperfusion. The electrophysiologic effects of bupivacaine were studied at 1, 5, and 10 microM concentrations. Results Bupivacaine (5 and 10 microM) decreased the maximal upstroke velocity of the action potential (Vmax) in normoxic conditions and further decreased (10 microM) the Vmax decrease induced by ischemic conditions. Bupivacaine reduced the mean occurrence time to the onset of myocardial conduction blocks (9 +/- 3 min; mean +/- SD; P < 0.005 with 5 and 10 microM, compared with 17 +/- 6 min during simulated ischemia with no drug or control), and it increased the number of preparations that became inexcitable to pacing (55% of preparations, with 1 microM and 100% with 5 and 10 microM, compared with 17% for the control group). The incidence of spontaneous arrhythmias was reduced by 5 and 10 microM bupivacaine during ischemia and reperfusion and was enhanced by 1 microM bupivacaine during the ischemic phase. Conclusions In guinea pig myocardium under ischemic conditions, bupivacaine induced a loss of excitability at concentrations of 5 and 10 microM. Proarrhythmic effects observed at 1 microM were considered as lower than the cardiotoxic range in normoxic conditions. The incidence of reperfusion arrhythmias was decreased at all concentrations.
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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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Lee, Won Hee, Sungkwon Kang, Pavlos P. Vlachos, and Yong Woo Lee. "A novel in vitro ischemia/reperfusion injury model." Archives of Pharmacal Research 32, no. 3 (March 2009): 421–29. http://dx.doi.org/10.1007/s12272-009-1316-9.
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Wei, Qingqing, and Zheng Dong. "Mouse model of ischemic acute kidney injury: technical notes and tricks." American Journal of Physiology-Renal Physiology 303, no. 11 (December 1, 2012): F1487—F1494. http://dx.doi.org/10.1152/ajprenal.00352.2012.
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Renal ischemia-reperfusion leads to acute kidney injury (AKI), a major kidney disease associated with an increasing prevalence and high mortality rates. A variety of experimental models, both in vitro and in vivo, have been used to study the pathogenic mechanisms of ischemic AKI and to test renoprotective strategies. Among them, the mouse model of renal clamping is popular, mainly due to the availability of transgenic models and the relatively small animal size for drug testing. However, the mouse model is generally less stable, resulting in notable variations in results. Here, we describe a detailed protocol of the mouse model of bilateral renal ischemia-reperfusion. We share the lessons and experiences gained from our laboratory in the past decade. We further discuss the technical issues that account for the variability of this model and offer relevant solutions, which may help other investigators to establish a well-controlled, reliable animal model of ischemic AKI.
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Zhou, Ya-ping, and Guo-chun Li. "Kaempferol Protects Cell Damage in In Vitro Ischemia Reperfusion Model in Rat Neuronal PC12 Cells." BioMed Research International 2020 (April 24, 2020): 1–10. http://dx.doi.org/10.1155/2020/2461079.
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Ischemic cerebral stroke is a severe neurodegenerative disease with high mortality. Ischemia and reperfusion injury plays a fundamental role in ischemic cerebral stroke. To date, the strategy for ischemic cerebral stroke treatment is limited. In the present study, we aimed to investigate the effect of kaempferol (KFL), a natural flavonol, on cell injury induced by oxygen and glucose deprivation (OGD) and reoxygenation (OGD-reoxygenation) in PC12 cells. We found that KFL inhibited OGD-induced decrease of cell viability and the increase of lactate dehydrogenase (LDH) release. OGD-induced activation of mitochondrial dysfunction, mitochondrial apoptotic pathway, and apoptosis was inhibited by KFL. KFL also reduced OGD-induced oxidative stress in PC12 cells. P66shc expression and acetylation were increased by OGD and KFL inhibited these changes. Upregulation of P66shc suppressed KFL-induced decrease of apoptosis, the decrease of LDH release, and the increase of cell viability. Furthermore, KFL inhibited OGD-induced decrease of sirtuin 1 (SIRT1) expression and downregulation of SIRT1 blocked KFL-induced decrease of apoptosis, the decrease of LDH release, and the increase of cell viability. In summary, we identified that KFL exhibited a beneficial effect against OGD-induced cytotoxicity in an ischemia/reperfusion injury cell model. The findings suggest that KFL may be a promising choice for the intervention of ischemic stroke and highlighted the SIRT1/P66shc signaling.
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Liu, Yueyang, Xiaohang Che, Haotian Zhang, Xiaoxiao Fu, Yang Yao, Jun Luo, Yu Yang, et al. "CAPN1 (Calpain1)-Mediated Impairment of Autophagic Flux Contributes to Cerebral Ischemia-Induced Neuronal Damage." Stroke 52, no. 5 (May 2021): 1809–21. http://dx.doi.org/10.1161/strokeaha.120.032749.
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Background and Purpose: CAPN1 (calpain1)—an intracellular Ca 2+ -regulated cysteine protease—can be activated under cerebral ischemia. However, the mechanisms by which CAPN1 activation promotes cerebral ischemic injury are not defined. Methods: In the present study, we used adeno-associated virus-mediated genetic knockdown and pharmacological blockade (MDL-28170) of CAPN1 to investigate the role of CAPN1 in the regulation of the autophagy-lysosomal pathway and neuronal damage in 2 models, rat permanent middle cerebral occlusion in vivo model and oxygen-glucose–deprived primary neuron in vitro model. Results: CAPN1 was activated in the cortex of permanent middle cerebral occlusion–operated rats and oxygen-glucose deprivation–exposed neurons. Genetic and pharmacological inhibition of CAPN1 significantly attenuated ischemia-induced lysosomal membrane permeabilization and subsequent accumulation of autophagic substrates in vivo and in vitro. Moreover, inhibition of CAPN1 increased autophagosome formation by decreasing the cleavage of the autophagy regulators BECN1 (Beclin1) and ATG (autophagy-related gene) 5. Importantly, the neuron-protective effect of MDL-28170 on ischemic insult was reversed by cotreatment with either class III-PI3K (phosphatidylinositol 3-kinase) inhibitor 3-methyladenine or lysosomal inhibitor chloroquine (chloroquine), suggesting that CAPN1 activation-mediated impairment of autophagic flux is crucial for cerebral ischemia-induced neuronal damage. Conclusions: The present study demonstrates for the first time that ischemia-induced CAPN1 activation impairs lysosomal function and suppresses autophagosome formation, which contribute to the accumulation of substrates and aggravate the ischemia-induced neuronal cell damage. Our work highlights the vital role of CAPN1 in the regulation of cerebral ischemia–mediated autophagy-lysosomal pathway defects and neuronal damage.
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Kelly, K. J., T. A. Sutton, N. Weathered, N. Ray, E. J. Caldwell, Z. Plotkin, and P. C. Dagher. "Minocycline inhibits apoptosis and inflammation in a rat model of ischemic renal injury." American Journal of Physiology-Renal Physiology 287, no. 4 (October 2004): F760—F766. http://dx.doi.org/10.1152/ajprenal.00050.2004.
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Tetracyclines exhibit significant anti-inflammatory properties in a variety of rheumatologic and dermatologic conditions. They have also been shown to inhibit apoptosis in certain neurodegenerative disorders. Because ischemic renal injury is characterized by both apoptosis and inflammation, we investigated the therapeutic potential of tetracyclines in a rat model of renal ischemia-reperfusion. Male Sprague-Dawley rats underwent bilateral renal artery clamp for 30 min followed by reperfusion and received either minocycline or saline for 36 h before ischemia. Minocycline reduced tubular cell apoptosis 24 h after ischemia as determined by terminal transferase-mediated dUTP nick end-labeling staining and nuclear morphology. It also decreased cytochrome c release into the cytoplasm and reduced upregulation of p53 and Bax after ischemia. The minocycline-treated group showed a significant reduction in tubular injury and cast formation. In addition, minocycline reduced the number of infiltrating leukocytes, decreased leukocyte chemotaxis both in vitro and ex vivo, and downregulated the expression of ICAM-1. Serum creatinine 24-h postischemia was significantly reduced in the minocycline-treated group. We conclude that minocycline has potent antiapoptotic and anti-inflammatory properties and protects renal function in this model of ischemia-reperfusion. Tetracyclines are among the safest and best-studied antibiotics. They are thus attractive candidates for the therapy of human ischemic acute renal failure.
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Burda, Jozef, M. Elena Martín, Miroslav Gottlieb, Mikulas Chavko, Jozef Marsala, Alberto Alcázar, Miguel Pavón, Juan L. Fando, and Matilde Salinas. "The Intraischemic and Early Reperfusion Changes of Protein Synthesis in the Rat Brain. eIF-2α Kinase Activity and Role of Initiation Factors eIF-2α and eIF-4E." Journal of Cerebral Blood Flow & Metabolism 18, no. 1 (January 1998): 59–66. http://dx.doi.org/10.1097/00004647-199801000-00006.
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Rats were subjected to the standard four-vessel occlusion model of transient cerebral ischemia (vertebral and carotid arteries). The effects of normothermic ischemia (37°C) followed or not by 30-minute reperfusion, as well as 30-minute postdecapitative ischemia, on translational rates were examined. Protein synthesis rate, as measured in a cell-free system, was significantly inhibited in ischemic rats, and the extent of inhibition strongly depended on duration and temperature, and less on the model of ischemia used. The ability of reinitiation in vitro (by using aurintricarboxylic acid) decreased after ischemia, suggesting a failure in the synthetic machinery at the initiation level. Eukaryotic initiation factor 2 (eIF-2) presented almost basal activity and levels after 30-minute normothermic ischemia, and the amount of phosphorylated eIF-2α in these samples, as well as in sham-control samples, was undetectable. The decrease in the levels of phosphorylated initiation factor 4E (eIF-4E) after 30-minute ischemia (from 32% to 16%) could explain, at least partially, the impairment of initiation during transient cerebral ischemia. After reperfusion, eIF-4E phosphorylation was almost completely restored to basal levels (29%), whereas the level of phosphorylated eIF-2α was higher (13%) than in controls and ischemic samples (both less than 2%). eIF-2α kinase activity in vitro as measured by phosphorylation of endogenous eIF-2 in the presence of ATP/Mg2+, was higher in ischemic samples (8%) than in controls (4%). It seems probable that the failure of the kinase in phosphorylating eIF-2 in vivo during ischemia is due to the depletion of ATP stores. The levels of the double-stranded activated eIF-2α kinase were slightly higher in ischemic animals than in controls. Our results suggest that the modulation of eIF-4E phosphorylation could be implicated in the regulation of translation during ischemia. On the contrary, phosphorylation of eIF-2α, by an eIF-2α kinase already activated during ischemia, represents a plausible mechanism for explaining the inhibition of translation during reperfusion
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Wang, Yang, Shao-wei Jiang, Xuan Liu, Lei Niu, Xiao-li Ge, Jin-cheng Zhang, Hai-rong Wang, Ai-hua Fei, Cheng-jin Gao, and Shu-ming Pan. "Degradation of TRPML1 in Neurons Reduces Neuron Survival in Transient Global Cerebral Ischemia." Oxidative Medicine and Cellular Longevity 2018 (December 18, 2018): 1–11. http://dx.doi.org/10.1155/2018/4612727.
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Postcardiac arrest syndrome yields poor neurological outcomes, but the mechanisms underlying this condition remain poorly understood. Autophagy plays an important role in neuronal apoptosis induced by ischemia. However, whether autophagy is involved in neuron apoptosis induced by cardiac arrest has been less studied. This study found that TRPML1 participates in cerebral ischemic reperfusion injury. Primary neurons were isolated and treated with mucolipin synthetic agonist 1 (ML-SA1), as well as infected with the recombinant lentivirus TRPML1 overexpression vector in vitro. ML-SA1 was delivered intracerebroventricularly in transient global ischemia model. Protein expression levels were determined by western blot. Neurological deficit score and the infarct volume were analyzed for the detection of neuronal damage. We found that TRPML1 was significantly downregulated in vivo and in vitro ischemic reperfusion model. We also observed that TRPML1 overexpression or treatment with the ML-SA1 attenuated neuronal death in primary neurons and ameliorated neurological dysfunction in vivo. Our findings suggested that autophagy and apoptosis were activated after transient global ischemia. Administration of ML-SA1 before transient global ischemia ameliorated neurological dysfunction possibly through the promotion of autophagy and the inhibition of apoptosis.
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Wei, Jin, Yingliang Wang, Jie Zhang, Lei Wang, Liying Fu, Byeong J. Cha, Jacentha Buggs, and Ruisheng Liu. "A mouse model of renal ischemia-reperfusion injury solely induced by cold ischemia." American Journal of Physiology-Renal Physiology 317, no. 3 (September 1, 2019): F616—F622. http://dx.doi.org/10.1152/ajprenal.00533.2018.
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Transplanted kidneys usually experience several episodes of ischemia, including cold ischemia during allograft storage in preservation solution. However, previous studies focusing on cold renal ischemia were only carried out in vitro or ex vivo. In the present study, we developed and characterized an in vivo mouse model of renal ischemia-reperfusion injury (IRI) induced exclusively by cold ischemia. C57BL/6 mice underwent right kidney nephrectomy, and the left kidney was kept cool with circulating cold saline in a kidney cup, while body temperature was maintained at 37°C. We clamped the renal pedicle and flushed out the blood inside the kidney with cold saline via an opening on the renal vein. The severity of renal IRI was examined with different ischemic durations. We found that the mice with <2 h of cold ischemia exhibited no significant changes in renal function or histopathology; animals with 3 or 4 h of cold ischemia developed into mild to moderate acute kidney injury with characteristic features, including the elevation in plasma creatinine concentration and reduction in glomerular filtration rate and tubular necrosis, followed by a subsequent recovery. However, mice with 5 h of cold ischemia died in a few days with severe acute kidney injury. In summary, we generated a mouse model of renal IRI induced exclusively by cold ischemia, which mimics graft cold storage in preservation solution, and renal function can be evaluated in vivo.
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Joshi, Dhiraj, Hemanshu Patel, Daryll M. Baker, Xu Shiwen, David J. Abraham, and Janice C. Tsui. "Development of an in vitro model of myotube ischemia." Laboratory Investigation 91, no. 8 (May 23, 2011): 1241–52. http://dx.doi.org/10.1038/labinvest.2011.79.
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Prehn, Jochen H. M., Chourouk Karkoutly, Jörg Nuglisch, Barbara Peruche, and Josef Krieglstein. "Dihydrolipoate Reduces Neuronal Injury after Cerebral Ischemia." Journal of Cerebral Blood Flow & Metabolism 12, no. 1 (January 1992): 78–87. http://dx.doi.org/10.1038/jcbfm.1992.10.
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It has been shown in vitro that dihydrolipoate (dl-6,8-dithioloctanoic acid) has antioxidant activity against microsomal lipid peroxidation. We tested dihydrolipoate for its neuroprotective activity using models of hypoxic and excitotoxic neuronal damage in vitro and rodent models of cerebral ischemia in vivo. In vitro, neuronal damage was induced in primary neuronal cultures derived form 7-day-old chick embryo telencephalon by adding either 1 m M cyanide or 1 m M glutamate to the cultures. Cyanide-exposed and dihydrolipoate-treated (10−9–10−7 M) cultures showed an increased protein and ATP content compared with controls. The glutamate-exposed cultures treated with dihydrolipoate (10−7–10−5 M) showed a decreased number of damaged neurons. In vivo, dihydrolipoate treatment (50 and 100 mg/kg) reduced brain infarction after permanent middle cerebral artery occlusion in mice and rats. Dihydrolipoate treatment (50 and 100 mg/kg) could not ameliorate neuronal damage in the rat hippocampus or cortex caused by 10 min of forebrain ischemia. A comparable neuroprotection was obtained by using dimethylthiourea, both in vitro (10−7 and 10−6 M) and at a dose of 750 mg/kg in the focal ischemia models. Lipoate, the oxidized form of dihydrolipoate, failed to reduce neuronal injury in any model tested. We conclude that dihydrolipoate, similarly to dimethylthiourea, is able to protect neurons against ischemic damage by diminishing the accumulation of reactive oxygen species within the cerebral tissue.
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Arutunyan, Ara, Luther M. Swift, and Narine Sarvazyan. "Initiation and propagation of ectopic waves: insights from an in vitro model of ischemia-reperfusion injury." American Journal of Physiology-Heart and Circulatory Physiology 283, no. 2 (August 1, 2002): H741—H749. http://dx.doi.org/10.1152/ajpheart.00096.2002.
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The objective of the present study was to directly visualize ectopic activity associated with ischemia-reperfusion and its progression to arrhythmia. To accomplish this goal, we employed a two-dimensional network of neonatal rat cardiomyocytes and a recently developed model of localized ischemia-reperfusion. Washout of the ischemia-like solution resulted in tachyarrhythmic episodes lasting 15–200 s. These episodes were preceded by the appearance of multiple ectopic sources and propagation of ectopic activity along the border of the former ischemic zone. The ectopic sources exhibited a slow rise in diastolic calcium, which disappeared upon return to the original pacing pattern. Border zone propagation of ectopic activity was followed by its escape into the surrounding control network, generating arrhythmias. Together, these observations suggest that upon reperfusion, a distinct layer, which consists of ectopically active, poorly coupled cells, is formed transiently over an injured area. Despite being neighbored by a conductive and excitable tissue, this transient functional layer is capable of sustaining autonomous waves and serving as a special conductive medium through which ectopic activity can propagate before spreading into the surrounding healthy tissue.
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Rosenzweig, Holly L., Manabu Minami, Nikola S. Lessov, Sarah C. Coste, Susan L. Stevens, David C. Henshall, Robert Meller, Roger P. Simon, and Mary P. Stenzel-Poore. "Endotoxin Preconditioning Protects against the Cytotoxic Effects of TNFα after Stroke: A Novel Role for TNFα in LPS-Ischemic Tolerance." Journal of Cerebral Blood Flow & Metabolism 27, no. 10 (February 28, 2007): 1663–74. http://dx.doi.org/10.1038/sj.jcbfm.9600464.
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Lipopolysaccharide (LPS) preconditioning provides neuroprotection against subsequent cerebral ischemic injury. Tumor necrosis factor-α (TNFα) is protective in LPS-induced preconditioning yet exacerbates neuronal injury in ischemia. Here, we define dual roles of TNFα in LPS-induced ischemic tolerance in a murine model of stroke and in primary neuronal cultures in vitro, and show that the cytotoxic effects of TNFα are attenuated by LPS preconditioning. We show that LPS preconditioning significantly increases circulating levels of TNFα before middle cerebral artery occlusion in mice and show that TNFα is required to establish subsequent neuroprotection against ischemia, as mice lacking TNFα are not protected from ischemic injury by LPS preconditioning. After stroke, LPS preconditioned mice have a significant reduction in the levels of TNFα (~ threefold) and the proximal TNFα signaling molecules, neuronal TNF-receptor 1 (TNFR1), and TNFR-associated death domain (TRADD). Soluble TNFR1 (s-TNFR1) levels were significantly increased after stroke in LPS-preconditioned mice (~ 2.5-fold), which may neutralize the effect of TNFα and reduce TNFα-mediated injury in ischemia. Importantly, LPS-preconditioned mice show marked resistance to brain injury caused by intracerebral administration of exogenous TNFα after stroke. We establish an in vitro model of LPS preconditioning in primary cortical neuronal cultures and show that LPS preconditioning causes significant protection against injurious TNFα in the setting of ischemia. Our studies suggest that TNFα is a twin-edged sword in the setting of stroke: TNFα upregulation is needed to establish LPS-induced tolerance before ischemia, whereas suppression of TNFα signaling during ischemia confers neuroprotection after LPS preconditioning.
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Pham, Phuc Van, Ngoc Bich Vu, Thuy Thi-Thanh Dao, Ha Thi-Ngan Le, Lan Thi Phi, Oanh Thuy Huynh, Mai Thi-Hoang Truong, Oanh Thi-Kieu Nguyen, and Ngoc Kim Phan. "ID: 1017 Extracellular vesicles of ETV2 transfected fibroblasts stimulate endothelial cells and improve neovascularization in a murine model of hindlimb ischemia." Biomedical Research and Therapy 4, S (September 5, 2017): 92. http://dx.doi.org/10.15419/bmrat.v4is.295.
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Ischemia are common conditions related to lack of blood supply to tissues. Depending on the ischemic sites, ischemia can cause different diseases, such as hindlimb ischemia, heart infarction and stroke. This study aims to evaluate how extracellular vesicles (EVs) derived from ETV2 transfected fibroblasts affect endothelial cell proliferation and neovascularization in a murine model of hindlimb ischemia. Human fibroblasts were isolated and cultured under standard conditions and expanded to the 3th passage before use in experiments. Human fibroblasts were transduced with a viral vector containing the ETV2 gene. Transduced cells were selected by puromycin treatment. These cells were further cultured for collection of EVs, which were isolated from culture supernatant. Following co-culture with endothelial cells, EVs were evaluated for their effect on endothelial cell proliferation and were directly injected into ischemic tissues of a murine model of hindlimb ischemia. The results showed that EVs could induce endothelial cell proliferation in vitro and improved neovascularization in a murine model of hindlimb ischemia. Our results suggest that EVs derived from ETV2-transfected fibroblasts can be promising non-cellular products for the regeneration of blood vessels.
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Martín, Abraham, Raphaël Boisgard, Benoit Thézé, Nadja Van Camp, Bertrand Kuhnast, Annelaure Damont, Michael Kassiou, Frédéric Dollé, and Bertrand Tavitian. "Evaluation of the PBR/TSPO Radioligand [18F]DPA-714 in a Rat Model of Focal Cerebral Ischemia." Journal of Cerebral Blood Flow & Metabolism 30, no. 1 (September 30, 2009): 230–41. http://dx.doi.org/10.1038/jcbfm.2009.205.
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Focal cerebral ischemia leads to an inflammatory reaction involving an overexpression of the peripheral benzodiazepine receptor (PBR)/18-kDa translocator protein (TSPO) in the cerebral monocytic lineage (microglia and monocyte) and in astrocytes. Imaging of PBR/TSPO by positron emission tomography (PET) using radiolabeled ligands can document inflammatory processes induced by cerebral ischemia. We performed in vivo PET imaging with [18F]DPA-714 to determine the time course of PBR/TSPO expression over several days after induction of cerebral ischemia in rats. In vivo PET imaging showed significant increase in DPA ( N,N-diethyl-2-(2-(4-(2-fluoroethoxy)phenyl)-5,7-dimethylpyrazolo[1,5-a]pyrimidin-3-yl)acetamide) uptake on the injured side compared with that in the contralateral area on days 7, 11, 15, and 21 after ischemia; the maximal binding value was reached 11 days after ischemia. In vitro autoradiography confirmed these in vivo results. In vivo and in vitro [18F]DPA-714 binding was displaced from the lesion by PK11195 and DPA-714. Immunohistochemistry showed increased PBR/TSPO expression, peaking at day 11 in cells expressing microglia/macrophage antigens in the ischemic area. At later times, a centripetal migration of astrocytes toward the lesion was observed, promoting the formation of an astrocytic scar. These results show that [18F]DPA-714 provides accurate quantitative information of the time course of PBR/TSPO expression in experimental stroke.
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Zhou, An, Manabu Minami, Xiaoman Zhu, Sylvia Bae, John Minthorne, Jingquan Lan, Zhi-gang Xiong, and Roger P. Simon. "Altered Biosynthesis of Neuropeptide Processing Enzyme Carboxypeptidase E after Brain Ischemia: Molecular Mechanism and Implication." Journal of Cerebral Blood Flow & Metabolism 24, no. 6 (June 2004): 612–22. http://dx.doi.org/10.1097/01.wcb.0000118959.03453.17.
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In this study, using both in vivo and in vitro ischemia models, the authors investigated the impact of brain ischemia on the biosynthesis of a key neuropeptide-processing enzyme, carboxypeptidase E (CPE). The response to brain ischemia of animals that lacked an active CPE was also examined. Combined in situ hybridization and immunocytochemical analyses for CPE showed reciprocal changes of CPE mRNA and protein, respectively, in the same cortical cells in rat brains after focal cerebral ischemia. Western blot analysis revealed an accumulation of the precursor protein of CPE in the ischemic cortex in vivo and in ischemic cortical neurons in vitro. Detailed metabolic labeling experiments on ischemic cortical neurons showed that ischemic stress caused a blockade in the proteolytic processing of CPE. When mice lacking an active CPE protease were subjected to a sublethal episode of focal cerebral ischemia, abundant TUNEL-positive cells were seen in the ischemic cortex whereas only a few were seen in the cortex of wild-type animals. These findings suggest that ischemia has an adverse impact on the neuropeptide-processing system in the brain and that the lack of an active neuropeptide-processing enzyme exacerbates ischemic brain injury.
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Mackay, Kenneth B., Sarah A. Loddick, Gregory S. Naeve, Alicia M. Vana, Gail M. Verge, and Alan C. Foster. "Neuroprotective Effects of Insulin-Like Growth Factor-Binding Protein Ligand Inhibitors in Vitro and in Vivo." Journal of Cerebral Blood Flow & Metabolism 23, no. 10 (October 2003): 1160–67. http://dx.doi.org/10.1097/01.wcb.0000087091.01171.ae.
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The role of brain insulin-like growth factors (IGFs) and IGF binding proteins (IGFBPs) in neuroprotection was further investigated using in vitro and in vivo models of cerebral ischemia by assessing the effects of IGF-I, IGF-II, and high affinity IGFBP ligand inhibitors (the peptide [Leu24, 59, 60, Ala31]hIGF-I (IGFBP-LI) and the small molecule NBI-31772 (1-(3,4-dihydroxybenzoyl)-3-hydroxycarbonyl-6, 7-dihydroxyisoquinoline), which pharmacologically displace and elevate endogenous, bioactive IGFs from IGFBPs. Treatment with IGF-I, IGF-II, or IGFBP-LI (2 μg/mL) significantly ( P < 0.05) reduced CA1 damage in organotypic hippocampal cultures resulting from 35 minutes of oxygen and glucose deprivation by 71%, 60%, and 40%, respectively. In the subtemporal middle cerebral artery occlusion (MCAO) model of focal ischemia, intracerebroventricular (icv) administration of IGF-I and IGF-II at the time of artery occlusion reduced ischemic brain damage in a dose-dependent manner, with maximum reductions in total infarct size of 37% ( P < 0.01) and 38% ( P < 0.01), respectively. In this model of MCAO, icv administration of NBI-31772 at the time of ischemia onset also dose-dependently reduced infarct size, and the highest dose (100 μg) significantly reduced both total (by 40%, P < 0.01) and cortical (by 43%, P < 0.05) infarct volume. In the intraluminal suture MCAO model, administration of NBI-31772 (50 μg icv) at the time of artery occlusion reduced both cortical infarct volume (by 40%, P < 0.01) and brain swelling (by 24%, P < 0.05), and it was still effective when treatment was delayed up to 3 hours after the induction of ischemia. These results further define the neuroprotective properties of IGFs and IGFBP ligand inhibitors in experimental models of cerebral ischemia.
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Kunimi, Hiromitsu, Yukihiro Miwa, Hiroyoshi Inoue, Kazuo Tsubota, and Toshihide Kurihara. "A Novel HIF Inhibitor Halofuginone Prevents Neurodegeneration in a Murine Model of Retinal Ischemia-Reperfusion." International Journal of Molecular Sciences 20, no. 13 (June 28, 2019): 3171. http://dx.doi.org/10.3390/ijms20133171.
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Neurodegeneration caused with retinal ischemia or high intraocular pressure is irreversible in general. We have focused on the role of hypoxia-inducible factor (HIF) in retinal homeostasis and revealed that HIF inhibition may be effective against retinal neovascular and neurodegeneration. In this study, we performed in vitro screening of natural products and found halofuginone, which is a derivative of febrifugine extracted from hydrangea, as a novel HIF inhibitor. Administration of halofuginone showed a significant neuroprotective effect by inhibiting HIF-1α expression in a murine retinal ischemia-reperfusion model histologically and functionally. These results indicate that halofuginone can be a neuroprotective agent in ischemic retinal degenerative diseases.
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Gelderblom, Mathias, Frank Leypoldt, Jan Lewerenz, Gabriel Birkenmayer, Denise Orozco, Peter Ludewig, John Thundyil, et al. "The Flavonoid Fisetin Attenuates Postischemic Immune Cell Infiltration, Activation and Infarct Size after Transient Cerebral Middle Artery Occlusion in Mice." Journal of Cerebral Blood Flow & Metabolism 32, no. 5 (January 11, 2012): 835–43. http://dx.doi.org/10.1038/jcbfm.2011.189.
Full textAbstract:
The development of the brain tissue damage in ischemic stroke is composed of an immediate component followed by an inflammatory response with secondary tissue damage after reperfusion. Fisetin, a flavonoid, has multiple biological effects, including neuroprotective and antiinflammatory properties. We analyzed the effects of fisetin on infarct size and the inflammatory response in a mouse model of stroke, temporary middle cerebral artery occlusion, and on the activation of immune cells, murine primary and N9 microglial and Raw264.7 macrophage cells and human macrophages, in an in vitro model of inflammatory immune cell activation by lipopolysaccharide (LPS). Fisetin not only protected brain tissue against ischemic reperfusion injury when given before ischemia but also when applied 3 hours after ischemia. Fisetin also prominently inhibited the infiltration of macrophages and dendritic cells into the ischemic hemisphere and suppressed the intracerebral immune cell activation as measured by intracellular tumor necrosis factor α (TNFα) production. Fisetin also inhibited LPS-induced TNFα production and neurotoxicity of macrophages and microglia in vitro by suppressing nuclear factor κB activation and JNK/Jun phosphorylation. Our findings strongly suggest that the fisetin-mediated inhibition of the inflammatory response after stroke is part of the mechanism through which fisetin is neuroprotective in cerebral ischemia.
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Packard, Amy E. B., Jason C. Hedges, Frances R. Bahjat, Susan L. Stevens, Michael J. Conlin, Andres M. Salazar, and Mary P. Stenzel-Poore. "Poly-IC Preconditioning Protects against Cerebral and Renal Ischemia-Reperfusion Injury." Journal of Cerebral Blood Flow & Metabolism 32, no. 2 (November 16, 2011): 242–47. http://dx.doi.org/10.1038/jcbfm.2011.160.
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Preconditioning induces ischemic tolerance, which confers robust protection against ischemic damage. We show marked protection with polyinosinic polycytidylic acid (poly-IC) preconditioning in three models of murine ischemia-reperfusion injury. Poly-IC preconditioning induced protection against ischemia modeled in vitro in brain cortical cells and in vivo in models of brain ischemia and renal ischemia. Further, unlike other Toll-like receptor (TLR) ligands, which generally induce significant inflammatory responses, poly-IC elicits only modest systemic inflammation. Results show that poly-IC is a new powerful prophylactic treatment that offers promise as a clinical therapeutic strategy to minimize damage in patient populations at risk of ischemic injury.
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Yang, Shao-Hua, Evelyn Perez, Jason Cutright, Ran Liu, Zhen He, Arthur L. Day, and James W. Simpkins. "Testosterone increases neurotoxicity of glutamate in vitro and ischemia-reperfusion injury in an animal model." Journal of Applied Physiology 92, no. 1 (January 1, 2002): 195–201. http://dx.doi.org/10.1152/jappl.2002.92.1.195.
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Increasing evidence has demonstrated striking sex differences in the outcome of neurological injury. Whereas estrogens contribute to these differences by attenuating neurotoxicity and ischemia-reperfusion injury, the effects of testosterone are unclear. The present study was undertaken to determine the effects of testosterone on neuronal injury in both a cell-culture model and a rodent ischemia-reperfusion model. Glutamate-induced HT-22 cell-death model was used to evaluate the effects of testosterone on cell survival. Testosterone was shown to significantly increase the toxicity of glutamate at a 10 μM concentration, whereas 17β-estradiol significantly attenuated the toxicity at the same concentration. In a rodent stroke model, ischemia-reperfusion injury was induced by temporal middle cerebral artery occlusion (MCAO) for 1 h and reperfusion for 24 h. To avoid the stress-related testosterone reduction, male rats were castrated and testosterone was replaced by testosterone pellet implantation. Testosterone pellets were removed at 1, 2, 4, or 6 h before MCAO to determine the duration of acute testosterone depletion effects on infarct volume. Ischemic lesion volume was significantly decreased from 239.6 ± 25.9 mm3 in control to 122.5 ± 28.6 mm3 when testosterone pellets were removed at 6 h before MCAO. Reduction of lesion volume was associated with amelioration of the hyperemia during reperfusion. Our in vitro and in vivo studies suggest that sex differences in response to brain injury are partly due to the consequence of damaging effects of testosterone.
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Rytter, Anna, Tobias Cronberg, Fredrik Asztély, Sailasree Nemali, and Tadeusz Wieloch. "Mouse Hippocampal Organotypic Tissue Cultures Exposed to In Vitro “Ischemia” Show Selective and Delayed CA1 Damage that is Aggravated by Glucose." Journal of Cerebral Blood Flow & Metabolism 23, no. 1 (January 2003): 23–33. http://dx.doi.org/10.1097/01.wcb.0000034361.37277.1b.
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Oxygen and glucose deprivation (OGD) in cell cultures is generally studied in a medium, such as artificial cerebrospinal fluid (CSF), with an ion composition similar to that of the extracellular fluid of the normal brain (2 to 4 mmol/L K+, 2 to 3 mmol/L Ca2+; pH 7.4). Because the distribution of ions across cell membranes dramatically shifts during ischemia, the authors exposed mouse organotypic hippocampal tissue cultures to OGD in a medium, an ischemic cerebrospinal fluid, with an ion composition similar to the extracellular fluid of the brain during ischemia in vivo (70 mmol/L K+, 0.3 mmol/L Ca2+; pH 6.8). In ischemic CSF, OGD induced a selective and delayed cell death in the CA1 region, as assessed by propidium iodide uptake. Cell death was glutamate receptor dependent since blockade of the N-methyl-D-aspartate and α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors mitigated cell damage. Hyperglycemia aggravates ischemic brain damage in vivo, whereas in vitro glucose in artificial CSF prevents oxygen deprivation-induced damage. The authors demonstrate that glucose in ischemic CSF significantly exacerbates cell damage after oxygen deprivation. This new model of in vitro “ischemia” can be useful in future studies of the mechanisms and treatment of ischemic cell death, including studies using genetically modified mice.
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Jamarkattel-Pandit, Nirmala, and Hocheol Kim. "Neuroprotective Effect of Metaplexis japonica against in vitro Ischemia Model." Journal of Health and Allied Sciences 3, no. 1 (November 24, 2019): 51–55. http://dx.doi.org/10.37107/jhas.55.
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Metaplexis japonica (Apocynaceae) is a perennial herb, extensively used in traditional medicinal system for various diseases. The purpose of the study was to evaluate the protective effect of M. japonica against in vitro ischemia. In the present study, 70% ethanol extract of M. japonica was fractionated with different polarity solvents. For in vitro ischemia, oxygen-glucose deprivation followed by reoxygenation (OGD-R) in cells was used to investigate the effects of M. japonica and its fractions. For oxidative stress model, Hydrogen peroxide (H2 O2 ) induced cell death was studied in HT22 cell line. M. japonica and its fractions significantly reduced the HT22 cell damage, which was induced by 4 hrs of OGD followed by 24 hrs of reoxygenation and 24 hrs of H2 O2, respectively. The effectiveness of ethyl acetate fraction was higher than other fractions/crude extract. Our results suggest that M. japonica could be a neuroprotective agent for the treatment of stroke.
Key words: Metaplexis japonica, Stroke, Oxygen-glucose deprivation, Neuroprotection
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Inauen, W., D. N. Granger, C. J. Meininger, M. E. Schelling, H. J. Granger, and P. R. Kvietys. "An in vitro model of ischemia/reperfusion-induced microvascular injury." American Journal of Physiology-Gastrointestinal and Liver Physiology 259, no. 1 (July 1, 1990): G134—G139. http://dx.doi.org/10.1152/ajpgi.1990.259.1.g134.
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The major objective of this study was to develop an in vitro model of ischemia/reperfusion (I/R)-induced microvascular injury. Cultured venular endothelial cells were grown to confluency, labeled with 51Cr, and exposed to different durations of anoxia (0.5, 1, 2, 3, and 4 h). 51Cr release and cell detachment (indexes of cell injury) were determined at different times after reoxygenation (1, 2, 4, 6, 8, and 18 h). Because in vivo studies have implicated neutrophils in I/R injury, in some experiments human neutrophils were added to the endothelial cells upon reoxygenation. Periods of anoxia greater than or equal to 2 h resulted in 70-80% 51Cr release and 80-95% cell detachment upon reoxygenation. Under these conditions (near maximal injury), the addition of neutrophils produced negligible effects. Periods of anoxia less than or equal to 1 h resulted in 30-40% 51Cr release and 50-60% cell detachment. Under these conditions (moderate cell injury), addition of neutrophils enhanced endothelial cell injury. Using a 30-min period of anoxia, we also assessed the effects of superoxide dismutase (SOD; 300 U/ml) and allopurinol (20 microM) on anoxia/reoxygenation (A/R)-induced injury in the presence or absence of neutrophils. In the absence of neutrophils, SOD or allopurinol did not protect against A/R-induced injury. However, in the presence of neutrophils, both SOD and allopurinol attenuated the increases in 51Cr release. The results derived using this in vitro model of I/R injury are largely consistent with published in vivo studies. Thus this in vitro model may provide further insights regarding the mechanisms involved in I/R injury.
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Sullivan, Breandan L., David Leu, Donald M. Taylor, Christian S. Fahlman, and Philip E. Bickler. "Isoflurane Prevents Delayed Cell Death in an Organotypic Slice Culture Model of Cerebral Ischemia." Anesthesiology 96, no. 1 (January 1, 2002): 189–95. http://dx.doi.org/10.1097/00000542-200201000-00033.
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Background General anesthetics reduce neuronal death caused by focal cerebral ischemia in rodents and by in vitro ischemia in cultured neurons and brain slices. However, in intact animals, the protective effect may enhance neuronal survival for only several days after an ischemic injury, possibly because anesthetics prevent acute but not delayed cell death. To further understand the mechanisms and limitations of volatile anesthetic neuroprotection, the authors developed a rat hippocampal slice culture model of cerebral ischemia that permits assessment of death and survival of neurons for at least 2 weeks after simulated ischemia. Methods Survival of CA1, CA3, and dentate gyrus neurons in cultured hippocampal slices (organotypic slice culture) was examined 2-14 days after 45 min of combined oxygen-glucose deprivation at 37 degrees C (OGD). Delayed cell death was serially measured in each slice by quantifying the binding of propidium iodide to DNA with fluorescence microscopy. Results Neuronal death was greatest in the CA1 region, with maximal death occurring 3-5 days after OGD. In CA1, cell death was 80 +/- 18% (mean +/- SD) 3 days after OGD and was 80-100% after 1 week. Death of 70 +/- 16% of CA3 neurons and 48 +/- 28% of dentate gyrus neurons occurred by the third day after OGD. Both isoflurane (1%) and the N-methyl-D-aspartate antagonist MK-801 (10 microm) reduced cell death to levels similar to controls (no OGD) for 14 days after the injury. Isoflurane also reduced cell death in CA1 and CA3 caused by application of 100 but not 500 microm glutamate. Cellular viability (calcein fluorescence) and morphology were preserved in isoflurane-protected neurons. Conclusions In an in vitro model of simulated ischemia, 1% isoflurane is of similar potency to 10 microm MK-801 in preventing delayed cell death. Modulation of glutamate excitotoxicity may contribute to the protective mechanism.
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Chen, Miao, Feng Wang, Limin Fan, Hairong Wang, and Shuo Gu. "Long Noncoding RNA TUG1 Aggravates Cerebral Ischemia/Reperfusion Injury by Acting as a ceRNA for miR-3072-3p to Target St8sia2." Oxidative Medicine and Cellular Longevity 2022 (April 19, 2022): 1–20. http://dx.doi.org/10.1155/2022/9381203.
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Long noncoding RNA taurine-upregulated gene 1 (TUG1) is considered to be involved in postischemic cerebral inflammation, whereas polysialic acid (polySia, PSA), the product of St8sia2, constitutes polysialylated neural adhesion cell molecule (PSA-NCAM) in both mice and humans and that cerebral PSA-NCAM level is elevated in neuronal progenitor cells in response to transient focal ischemia. Herein, we aim to identify novel miRNAs that bridge the functions of St8sia2 and TUG1 in ischemia-associated injuries. In both in vivo (C57BL/6J mouse ischemia/reperfusion, I/R model) and in vitro (mouse neuroblastoma N2A cell oxygen glucose deprivation/reoxygenation, OGD model) settings, we observed upregulated TUG1 and St8sia2 after the induction of ischemic injury, accompanied by reduced miR-3072-3p expression. We performed siRNA-induced TUG1 knockdown combined with the induction of ischemic injury; the results showed that inhibiting TUG1 expression led to the reduced infarct area and improved neurological deficit. Through bioinformatics analysis, miR-3072-3p was found to target both St8sia2 and TUG1, which was subsequently verified by the luciferase reporter system and RNA binding protein immunoprecipitation assay. Also, the addition of miR-3072-3p mimic/inhibitor resulted in reduced/elevated St8sia2 expression at the protein level. Further studies revealed that in both in vivo and in vitro settings, TUG1 bound competitively to miR-3072-3p to regulate St8sia2 expression and promote apoptosis. In summary, targeting the TUG1/miR-3072-3p/St8sia2 regulatory cascade, a novel cascade we identified in cerebral ischemia injury, may render feasible therapeutic possibilities for overcoming cerebral ischemic insults.
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Kakkar, Rakesh, Dallas P. Seitz, Rani Kanthan, Raju VS Rajala, Jasim M. Radhi, Xinto Wang, Mohammed K. Pasha, Rui Wang, and Rajendra K. Sharma. "Calmodulin-dependent cyclic nucleotide phosphodiesterase in an experimental rat model of cardiac ischemiareperfusion." Canadian Journal of Physiology and Pharmacology 80, no. 1 (January 1, 2002): 59–66. http://dx.doi.org/10.1139/y02-001.
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In the present study, we investigated the activity and expression of calmodulin-dependent cyclic nucleotide phosphodiesterase (CaMPDE) and the effects of calpains in rat heart after ischemia and reperfusion. Immunohistochemical studies indicated that CaMPDE in normal heart is localized in myocardial cells. Rat ischemic heart showed a decrease in CaMPDE activity in the presence of Ca2+ and calmodulin; however, in ischemicreperfusion tissue a progressive increase in Ca2+ and calmodulin-independent cyclic nucleotide phosphodiesterase (CaM-independent PDE) activity was observed. Perfusion of hearts with cell-permeable calpain inhibitor suppressed the increase of Ca2+ and CaM-independent PDE activity. Protein expression of CaMPDE was uneffected by hypoxic injury to rat myocardium. The purified heart CaMPDE was proteolyzed by calpains into a 45 kDa immunoreactive fragment in vitro. Based on these results, we propose that hypoxic injury to rat myocardium results in the generation of CaM-independent PDE by calpain mediated proteolysis, allowing the maintenance of cAMP concentrations within the physiological range.Key words: phosphodiesterase, calmodulin, calpains, heart, ischemia, reperfusion.
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Deng, Ziteng, Jiao Li, Xiaoquan Tang, Dan Li, Yazhou Wang, Shengxi Wu, Kai Fan, and Yunfei Ma. "Leonurine Reduces Oxidative Stress and Provides Neuroprotection against Ischemic Injury via Modulating Oxidative and NO/NOS Pathway." International Journal of Molecular Sciences 23, no. 17 (September 5, 2022): 10188. http://dx.doi.org/10.3390/ijms231710188.
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Leonurine (Leo) has been found to have neuroprotective effects against cerebral ischemic injury. However, the exact molecular mechanism underlying its neuroprotective ability remains unclear. The aim of the present study was to investigate whether Leo could provide protection through the nitric oxide (NO)/nitric oxide synthase (NOS) pathway. We firstly explored the effects of NO/NOS signaling on oxidative stress and apoptosis in in vivo and in vitro models of cerebral ischemia. Further, we evaluated the protective effects of Leo against oxygen and glucose deprivation (OGD)-induced oxidative stress and apoptosis in PC12 cells. We found that the rats showed anxiety-like behavior, and the morphology and number of neurons were changed in a model of photochemically induced cerebral ischemia. Both in vivo and in vitro results show that the activity of superoxide dismutase (SOD) and glutathione (GSH) contents were decreased after ischemia, and reactive oxygen species (ROS) and malondialdehyde (MDA) levels were increased, indicating that cerebral ischemia induced oxidative stress and neuronal damage. Moreover, the contents of NO, total NOS, constitutive NOS (cNOS) and inducible NOS (iNOS) were increased after ischemia in rat and PC12 cells. Treatment with L-nitroarginine methyl ester (L-NAME), a nonselective NOS inhibitor, could reverse the change in NO/NOS expression and abolish these detrimental effects of ischemia. Leo treatment decreased ROS and MDA levels and increased the activity of SOD and GSH contents in PC12 cells exposed to OGD. Furthermore, Leo reduced NO/NOS production and cell apoptosis, decreased Bax expression and increased Bcl-2 levels in OGD-treated PC12 cells. All the data suggest that Leo protected against oxidative stress and neuronal apoptosis in cerebral ischemia by inhibiting the NO/NOS system. Our findings indicate that Leo could be a potential agent for the intervention of ischemic stroke and highlighted the NO/NOS-mediated oxidative stress signaling.
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Luo, Yumin, Guodong Cao, Wei Pei, Cristine O'Horo, Steven H. Graham, and Jun Chen. "Induction of Caspase-Activated Deoxyribonuclease Activity after Focal Cerebral Ischemia and Reperfusion." Journal of Cerebral Blood Flow & Metabolism 22, no. 1 (January 2002): 15–20. http://dx.doi.org/10.1097/00004647-200201000-00002.
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Deoxyribonucleic acid fragmentation at nucleosomal junctions is a hallmark of neuronal apoptosis in ischemic brain injury, for which the mechanism is not fully understood. Using the in vitro cell-free apoptosis assay, the authors found that caspase-3–dependent deoxyribonuclease activity caused internucleosomal DNA fragmentation in brain-cell extracts in a rat model of transient focal ischemia. This in vitro deoxyribonuclease activity was completely inhibited by purified inhibitor of caspase-activated deoxyribonuclease protein, the specific endogenous inhibitor of caspase-activated deoxyribonuclease, or by caspase-activated deoxyribonuclease immunodepletion. The induction of the deoxyribonuclease activity was correlated with caspase-3 activation and caspase-3–mediated degradation of inhibitor of caspase-activated deoxyribonuclease. Furthermore, inhibiting caspase-3–like protease activity prevented the endogenous induction of internucleosomal DNA fragmentation in the ischemic brain. These results suggest that caspase-3–dependent caspase-activated deoxyribonuclease activity plays an important role in mediating DNA fragmentation after focal ischemia.
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Zhu, Qingwei, Qing Li, Xin Niu, Guowei Zhang, Xiaozheng Ling, Jieyuan Zhang, Yang Wang, and Zhifeng Deng. "Extracellular Vesicles Secreted by Human Urine-Derived Stem Cells Promote Ischemia Repair in a Mouse Model of Hind-Limb Ischemia." Cellular Physiology and Biochemistry 47, no. 3 (2018): 1181–92. http://dx.doi.org/10.1159/000490214.
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Background/Aims: Our previous studies have shown that human urine-derived stem cells (USCs) have great potential as a cell source for cytotherapy and tissue engineering and that extracellular vesicles (EVs) secreted by USCs (USCs-EVs) can prevent diabetes-induced kidney injury in an animal model. The present study was designed to evaluate the effects of USCs-EVs on ischemia repair. Methods: USCs-EVs were isolated and purified by a battery of centrifugation and filtration steps. The USCs-EVs were then characterized by transmission electron microscopy, western blot and tunable resistive pulse sensing techniques. After intramuscularly transplanting USCs-EVs into an ischemic mouse hind-limb, we observed the therapeutic effects of USCs-EVs on perfusion by laser doppler perfusion imaging, angiogenesis and muscle regeneration by histology and immunohistochemistry techniques over 21 days. We subsequently tested whether USCs-EVs can induce the proliferation of a human microvascular endothelial cell line HMEC-1 and a mouse myoblast cell line C2C12 by cell counting kit 8 assay in vitro. Meanwhile, the potential growth factors in the USCs-EVs and supernatants of the USCs cultures were detected by enzyme-linked immunosorbent assay. Results: The USCs-EVs were spherical vesicles with a diameter of 30–150 nm and expressed exosomal markers, such as CD9, CD63 and Tsg101. Ischemic limb perfusion and function were markedly increased in the hind-limb ischemia (HLI) model after USCs-EVs administration. Moreover, angiogenesis and muscle regeneration levels were significantly higher in the USCs-EVs treatment group than in the PBS group. The in vitro experiments showed that USCs-EVs facilitated HMEC-1 and C2C12 cell proliferation in a dose-dependent manner. Conclusions: These results revealed for the first time that USCs-EVs efficiently attenuate severe hind-limb ischemic injury and represent a novel therapy for HLI.
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Siegel, Andre, and R. Roy Baker. "Activities of enzymes in platelet activating factor biosynthetic pathways in the gerbil model of cerebral ischemia." Biochemistry and Cell Biology 74, no. 3 (May 1, 1996): 347–54. http://dx.doi.org/10.1139/o96-037.
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The activities of enzymes in platelet activating factor (PAF) biosynthetic pathways were analyzed in hippocampal and cerebral cortical regions of normal and ischemic gerbil brain to assess changes in enzyme activities and potential modulators that could explain the accentuated production of PAF seen in ischemia. Global forebrain ischemia was produced by bilateral carotid artery ligation, and the effectiveness of the ligation was shown by free fatty acid release and ATP depletion. Specific activities of 1-alkyl-2-acetyl-sn-glycerol (AAG) choline phosphotransferase, 1-alkyl-sn-glycero-3-phosphate (AGP) acetyl transferase, and 1-alkyl-sn-glycero-3-phosphocholine (lyso PAF) acetyl transferase in tissue homogenates were in the ratio 4:1:0.1, respectively. Sham-operated and ischemic or ischemic–reperfused tissues showed similar activities for individual enzymes, indicating that enzyme levels or activation states did not change in ischemic or reperfused tissues. However, small metabolites (relevant to ischemia) added to the in vitro assays did modify enzyme activities. Physiological concentrations of MgATP severely inhibited AGP acetyl transferase activity, and this resulted in the ratio of AGP acyl transferase to AGP acetyl transferase activities changing from 48:1 in the presence of 2.5 mM MgATP to 6:1 in the absence of MgATP. This suggests that falling ATP levels in cerebral ischemia may promote the de novo pathway of PAF biosynthesis by releasing inhibition of AGP acetyl transferase. Lyso PAF acetyl transferase was much less active than AGP acetyl transferase and was also inhibited by MgATP. AAG choline phosphotransferase was not inhibited by MgATP but was inhibited by calcium. However the superior specific activity of the choline phosphotransferase in comparison with the AGP acetyl transferase suggested that the lowered choline phosphotransferase activity in the presence of rising intracellular calcium would not seriously compromise the synthesis of PAF by the de novo route. Both acetyl transferase enzymes were also inhibited by oleoyl CoA.Key words: gerbil, cerebral ischemia, platelet activating factor, enzymes.
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Trumbeckaite, Sonata, Neringa Pauziene, Darius Trumbeckas, Mindaugas Jievaltas, and Rasa Baniene. "Caffeic Acid Phenethyl Ester Reduces Ischemia-Induced Kidney Mitochondrial Injury in Rats." Oxidative Medicine and Cellular Longevity 2017 (2017): 1–11. http://dx.doi.org/10.1155/2017/1697018.
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During partial nephrectomy, the avoidance of ischemic renal damage is extremely important as duration of renal artery clamping (i.e., ischemia) influences postoperative kidney function. Mitochondria (main producer of ATP in the cell) are very sensitive to ischemia and undergo damage during oxidative stress. Finding of a compound which diminishes ischemic injury to kidney is of great importance. Caffeic acid phenethyl ester (CAPE), biologically active compound of propolis, might be one of the promising therapeutic agents against ischemia-caused damage. Despite wide range of biological activities of CAPE, detailed biochemical mechanisms of its action at the level of mitochondria during ischemia are poorly described and need to be investigated. We investigated if CAPE (22 mg/kg and 34 mg/kg, injected intraperitoneally) has protective effects against short (20 min) and longer time (40 min) rat kidney ischemia in an in vitro ischemia model. CAPE ameliorates in part ischemia-induced renal mitochondrial injury, improves oxidative phosphorylation with complex I-dependent substrate glutamate/malate, increases Ca2+ uptake by mitochondria, blocks ischemia-induced caspase-3 activation, and protects kidney cells from ischemia-induced necrosis. The protective effects on mitochondrial respiration rates were seen after shorter (20 min) time of ischemia whereas reduction of apotosis and necrosis and increase in Ca2+ uptake were revealed after both, shorter and longer time of ischemia.
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NAPPER, GENEVIEVE A., and MICHAEL KALLONIATIS. "Neurochemical changes following postmortem ischemia in the rat retina." Visual Neuroscience 16, no. 6 (November 1999): 1169–80. http://dx.doi.org/10.1017/s0952523899166161.
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Glutamate and γ-aminobutyric acid (GABA) are the dominant amino acids in the retina and brain. The manufacturing and degradation pathways of both of these amino acids are intricately linked with the tricarboxylic acid cycle leading to rapid redistribution of these amino acids after metabolic insult. Postmortem ischemia in mammalian retina predominantly results in a loss of glutamate and GABA from neurons and accumulation of these amino acids within Müller cells. This accumulation of glutamate and GABA in Müller cells may occur as a result of increased release of these neurotransmitters from neurons, and decreased degradation. Quantification of the semisaturation value (half-maximal response) for glutamate and GABA Müller cell loading during postmortem ischemia indicated a shorter semisaturation value for GABA than glutamate. Such changes are consistent with a single aerobically dependent GABA-degradation pathway, and the existence of multiple glutamate-degradation pathways. Comparison with the in vitro ischemic model showed similar qualitative characteristics, but a markedly increased semisaturation time for glutamate and GABA Müller cell loading (a factor of 5–10) in the postmortem ischemia model. We interpret these differences to indicate that the in vitro condition provides a more immediate and/or severe ischemic insult. In the postmortem ischemia model, the delayed glial cell loading implies the availability of internal stores of both glucose and/or oxygen. Increased glial and neuronal immunoreactivity for the amino acids involved in transamination reactions, aspartate, alanine, leucine, and ornithine was observed, indicating a potential shift in the equilibrium of transamination reactions associated with glutamate production. These findings provide evidence that, in the rat retina, there are multiple pathways subserving glutamate production/degradation that include a multitude of transamination reactions. Further evidence is therefore provided to support a role for all four amino acids in glutamate metabolism within a variety of retinal neurons and glia.
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Shao, Jun, Chen Miao, Zhi Geng, Maohong Gu, Yanhu Wu, and Qingguo Li. "Effect of eNOS on Ischemic Postconditioning-Induced Autophagy against Ischemia/Reperfusion Injury in Mice." BioMed Research International 2019 (February 10, 2019): 1–11. http://dx.doi.org/10.1155/2019/5201014.
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Autophagy is involved in the development of numerous illnesses, including ischemia/reperfusion (I/R). Endothelial nitric oxide synthase (eNOS) participates in the protective effects of ischemic postconditioning (IPostC). However, it remains unclear whether eNOS-mediated autophagy serves as a critical role in IPostC in the hearts of mice, in protecting against I/R injury. In the present study, the hearts of mice with left anterior descending coronary artery ligation were studied as I/R models. H9c2 cells underwent exposure to hypoxia/reoxygenation (H/R) and were examined as in vitro model. IPostC reduced mice myocardial infarct size and improved the structure of the heart. IPostC increased the formation of autophagosomes and increased the phosphorylation of eNOS and adenosine monophosphate-activated protein kinase (AMPK). Autophagy and eNOS inhibition suppressed the cardioprotective effects of IPostC. AMPK or eNOS inhibition abolished the improvement effect of IPostC on autophagy. AMPK inhibition decreased eNOS phosphorylation in the heart. Additionally, H9c2 cells suffering hypoxia were used as in vitro model. Autophagy or eNOS inhibition abolished the protective effects of hypoxic postconditioning (HPostC) against H/R injury. AMPK and eNOS inhibition/knockout decreased autophagic activity in the HPostC group. These results indicated that IPostC protects the heart against I/R injury, partially via promoting AMPK/eNOS-mediated autophagy.
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Lin, Gen, Ruichun Long, Xiaoqing Yang, Songsong Mao, and Hongying Li. "Etomidate Alleviates Ischemia-Anoxia Reperfusion Injury in Intestinal Epithelial Cells by Inhibiting the Activation of traf6-Regulated NF-KB Signaling." Journal of Biomaterials and Tissue Engineering 12, no. 5 (May 1, 2022): 1015–21. http://dx.doi.org/10.1166/jbt.2022.2990.
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Objective: The present study aimed to investigate the role of etomidate in intestinal cell ischemia and hypoxia-reperfusion injury and potential mechanisms. Method: In this study, we establish the intestinal epithelial cells ischemia-reperfusion model in vitro. CCK8 was used to detect cell viability and flow cytometry assay was used to detect apoptosis levels of treated OGD/R model cells. ELISA measured the expression level of oxidative stress factors and inflammatory factors. Furthermore, western blot assay was used to detect the expression the apoptosis-related factors and TNFR-associated factors in treated OGD/R model cells. Result: Etomidate does not affect the activity of intestinal epithelial cells, and can protect intestinal epithelial cells to reduce ischemiareperfusion injury, and the expression of inflammatory factors and oxidative stress in cells with mild intestinal epithelial ischemia-reperfusion injury. Etomidate alleviates apoptosis of intestinal epithelial ischemia-reperfusion injury cells. Etomidate inhibits the activation of traf6-mediated NF-κB signal during ischemia-anoxia reperfusion of intestinal epithelial cells. Conclusion: Taken together, our study demonstrated that etomidate attenuates inflammatory response and apoptosis in intestinal epithelial cells during ischemic hypoxia-reperfusion injury and inhibits activation of NF-κB signaling regulated by TRAF6.
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Castillo, Ximena, Katia Rosafio, Matthias T. Wyss, Konstantin Drandarov, Alfred Buck, Luc Pellerin, Bruno Weber, and Lorenz Hirt. "A Probable Dual Mode of Action for Both L- and D-Lactate Neuroprotection in Cerebral Ischemia." Journal of Cerebral Blood Flow & Metabolism 35, no. 10 (June 3, 2015): 1561–69. http://dx.doi.org/10.1038/jcbfm.2015.115.
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Lactate has been shown to offer neuroprotection in several pathologic conditions. This beneficial effect has been attributed to its use as an alternative energy substrate. However, recent description of the expression of the HCA1 receptor for lactate in the central nervous system calls for reassessment of the mechanism by which lactate exerts its neuroprotective effects. Here, we show that HCA1 receptor expression is enhanced 24 hours after reperfusion in an middle cerebral artery occlusion stroke model, in the ischemic cortex. Interestingly, intravenous injection of L-lactate at reperfusion led to further enhancement of HCA1 receptor expression in the cortex and striatum. Using an in vitro oxygen-glucose deprivation model, we show that the HCA1 receptor agonist 3,5-dihydroxybenzoic acid reduces cell death. We also observed that D-lactate, a reputedly non-metabolizable substrate but partial HCA1 receptor agonist, also provided neuroprotection in both in vitro and in vivo ischemia models. Quite unexpectedly, we show D-lactate to be partly extracted and oxidized by the rodent brain. Finally, pyruvate offered neuroprotection in vitro whereas acetate was ineffective. Our data suggest that L- and D-lactate offer neuroprotection in ischemia most likely by acting as both an HCA1 receptor agonist for non-astrocytic (most likely neuronal) cells as well as an energy substrate.
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Zhu, Jiaying, Zhu Zhu, Yipin Ren, Yukang Dong, Yaqi Li, and Xiulin Yang. "LINGO-1 shRNA protects the brain against ischemia/reperfusion injury by inhibiting the activation of NF-κB and JAK2/STAT3." Human Cell 34, no. 4 (April 8, 2021): 1114–22. http://dx.doi.org/10.1007/s13577-021-00527-x.
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AbstractLINGO-1 may be involved in the pathogenesis of cerebral ischemia. However, its biological function and underlying molecular mechanism in cerebral ischemia remain to be further defined. In our study, middle cerebral artery occlusion/reperfusion (MACO/R) mice model and HT22 cell oxygen–glucose deprivation/reperfusion (OGD/R) were established to simulate the pathological process of cerebral ischemia in vivo and in vitro and to detect the relevant mechanism. We found that LINGO-1 mRNA and protein were upregulated in mice and cell models. Down-regulation LINGO-1 improved the neurological symptoms and reduced pathological changes and the infarct size of the mice after MACO/R. In addition, LINGO-1 interference alleviated apoptosis and promoted cell proliferation in HT22 of OGD/R. Moreover, down-regulation of LINGO-1 proved to inhibit nuclear translocation of p-NF-κB and reduce the expression level of p-JAK2 and p-STAT3. In conclusion, our data suggest that shLINGO-1 attenuated ischemic injury by negatively regulating NF-KB and JAK2/STAT3 pathways, highlighting a novel therapeutic target for ischemic stroke.
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Moreira, Tiago JTP, Karin Pierre, Fumihiko Maekawa, Cendrine Repond, Aleta Cebere, Sture Liljequist, and Luc Pellerin. "Enhanced Cerebral Expression of MCT1 and MCT2 in a Rat Ischemia Model Occurs in Activated Microglial Cells." Journal of Cerebral Blood Flow & Metabolism 29, no. 7 (April 29, 2009): 1273–83. http://dx.doi.org/10.1038/jcbfm.2009.50.
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Monocarboxylate transporters (MCTs) are essential for the use of lactate, an energy substrate known to be overproduced in brain during an ischemic episode. The expression of MCT1 and MCT2 was investigated at 48 h of reperfusion from focal ischemia induced by unilateral extradural compression in Wistar rats. Increased MCT1 mRNA expression was detected in the injured cortex and hippocampus of compressed animals compared to sham controls. In the contralateral, uncompressed hemisphere, increases in MCT1 mRNA level in the cortex and MCT2 mRNA level in the hippocampus were noted. Interestingly, strong MCT1 and MCT2 protein expression was found in peri-lesional macrophages/microglia and in an isolectin B4+/S100β+ cell population in the corpus callosum. In vitro, MCT1 and MCT2 protein expression was observed in the N11 microglial cell line, whereas an enhancement of MCT1 expression by tumor necrosis factor-α (TNF-α) was shown in these cells. Modulation of MCT expression in microglia suggests that these transporters may help sustain microglial functions during recovery from focal brain ischemia. Overall, our study indicates that changes in MCT expression around and also away from the ischemic area, both at the mRNA and protein levels, are a part of the metabolic adaptations taking place in the brain after ischemia.
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Alechinsky, Louise, Frederic Favreau, Petra Cechova, Sofiane Inal, Pierre-Antoine Faye, Cecile Ory, Raphaël Thuillier, et al. "Tannic Acid Improves Renal Function Recovery after Renal Warm Ischemia–Reperfusion in a Rat Model." Biomolecules 10, no. 3 (March 12, 2020): 439. http://dx.doi.org/10.3390/biom10030439.
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Background and purpose: Ischemia–reperfusion injury is encountered in numerous processes such as cardiovascular diseases or kidney transplantation; however, the latter involves cold ischemia, different from the warm ischemia found in vascular surgery by arterial clamping. The nature and the intensity of the processes induced by ischemia types are different, hence the therapeutic strategy should be adapted. Herein, we investigated the protective role of tannic acid, a natural polyphenol in a rat model reproducing both renal warm ischemia and kidney allotransplantation. The follow-up was done after 1 week. Experimental approach: To characterize the effect of tannic acid, an in vitro model of endothelial cells subjected to hypoxia–reoxygenation was used. Key results: Tannic acid statistically improved recovery after warm ischemia but not after cold ischemia. In kidneys biopsies, 3 h after warm ischemia–reperfusion, oxidative stress development was limited by tannic acid and the production of reactive oxygen species was inhibited, potentially through Nuclear Factor erythroid-2-Related factor 2 (NRF2) activation. In vitro, tannic acid and its derivatives limited cytotoxicity and the generation of reactive oxygen species. Molecular dynamics simulations showed that tannic acid efficiently interacts with biological membranes, allowing efficient lipid oxidation inhibition. Tannic acid also promoted endothelial cell migration and proliferation during hypoxia. Conclusions: Tannic acid was able to improve renal recovery after renal warm ischemia with an antioxidant effect putatively extended by the production of its derivatives in the body and promoted cell regeneration during hypoxia. This suggests that the mechanisms induced by warm and cold ischemia are different and require specific therapeutic strategies.
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Gu, Yu-Huan, Masato Kanazawa, Stephanie Y. Hung, Xiaoyun Wang, Shunichi Fukuda, James A. Koziol, and Gregory J. del Zoppo. "Cathepsin L Acutely Alters Microvessel Integrity within the Neurovascular Unit during Focal Cerebral Ischemia." Journal of Cerebral Blood Flow & Metabolism 35, no. 11 (July 22, 2015): 1888–900. http://dx.doi.org/10.1038/jcbfm.2015.170.
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During focal cerebral ischemia, the degradation of microvessel basal lamina matrix occurs acutely and is associated with edema formation and microhemorrhage. These events have been attributed to matrix metalloproteinases (MMPs). However, both known protease generation and ligand specificities suggest other participants. Using cerebral tissues from a non-human primate focal ischemia model and primary murine brain endothelial cells, astrocytes, and microglia in culture, the effects of active cathepsin L have been defined. Within 2 hours of ischemia onset cathepsin L, but not cathepsin B, activity appears in the ischemic core, around microvessels, within regions of neuron injury and cathepsin L expression. In in vitro studies, cathepsin L activity is generated during experimental ischemia in microglia, but not astrocytes or endothelial cells. In the acidic ischemic core, cathepsin L release is significantly increased with time. A novel ex vivo assay showed that cathepsin L released from microglia during ischemia degrades microvessel matrix, and interacts with MMP activity. Hence, the loss of microvessel matrix during ischemia is explained by microglial cathepsin L release in the acidic core during injury evolution. The roles of cathepsin L and its interactions with specific MMP activities during ischemia are relevant to strategies to reduce microvessel injury and hemorrhage.
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Towfigh, Shirin, Tracy Heisler, David A. Rigberg, O. Joe Hines, Jason Chu, David W. McFadden, and Charles Chandler. "Intestinal Ischemia and the Gut–Liver Axis: An in Vitro Model." Journal of Surgical Research 88, no. 2 (February 2000): 160–64. http://dx.doi.org/10.1006/jsre.1999.5767.
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Li, Yang, Yue Guan, Ying Wang, Chun-Lei Yu, Feng-Guo Zhai, and Li-Xin Guan. "Neuroprotective Effect of the Ginsenoside Rg1 on Cerebral Ischemic Injury In Vivo and In Vitro Is Mediated by PPARγ-Regulated Antioxidative and Anti-Inflammatory Pathways." Evidence-Based Complementary and Alternative Medicine 2017 (2017): 1–9. http://dx.doi.org/10.1155/2017/7842082.
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The ginsenoside Rg1 exerts a neuroprotective effect during cerebral ischemia/reperfusion injury. Rg1 has been previously reported to improve PPARγexpression and signaling, consequently enhancing its regulatory processes. Due to PPARγ’s role in the suppression of oxidative stress and inflammation, Rg1’s PPARγ-normalizing capacity may play a role in the observed neuroprotective action of Rg1 during ischemic brain injury. We utilized a middle cerebral artery ischemia/reperfusion injury model in rats in addition to an oxygen glucose deprivation model in cortical neurons to elucidate the mechanisms underlying the neuroprotective effects of Rg1. We found that Rg1 significantly increased PPARγexpression and reduced multiple indicators of oxidative stress and inflammation. Ultimately, Rg1 treatment improved neurological function and diminished brain edema, indicating that Rg1 may exert its neuroprotective action on cerebral ischemia/reperfusion injury through the activation of PPARγsignaling. In addition, the present findings suggested that Rg1 was a potent PPARγagonist in that it upregulated PPARγexpression and was inhibited by GW9662, a selective PPARγantagonist. These findings expand our previous understanding of the molecular basis of the therapeutic action of Rg1 in cerebral ischemic injury, laying the ground work for expanded study and clinical optimization of the compound.
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Ma, YinZhong, Li Li, LingLei Kong, ZhiMei Zhu, Wen Zhang, JunKe Song, Junlei Chang, and GuanHua Du. "Pinocembrin Protects Blood-Brain Barrier Function and Expands the Therapeutic Time Window for Tissue-Type Plasminogen Activator Treatment in a Rat Thromboembolic Stroke Model." BioMed Research International 2018 (2018): 1–13. http://dx.doi.org/10.1155/2018/8943210.
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Tissue-type plasminogen activator (t-PA) remains the only approved therapy for acute ischemic stroke but has a restrictive treatment time window of 4.5 hr. Prolonged ischemia causes blood-brain barrier (BBB) damage and increases the incidence of hemorrhagic transformation (HT) secondary to reperfusion. In this study, we sought to determine the effect of pinocembrin (PCB; a pleiotropic neuroprotective agent) on t-PA administration-induced BBB damage in a novel rat thromboembolic stroke model. By assessing the leakage of Evans blue into the ischemic hemisphere, we demonstrated that PCB pretreatment 5 min before t-PA administration significantly reduced BBB damage following 2 hr, 4 hr, 6 hr, and even 8 hr ischemia. Consistently, PCB pretreatment significantly decreased t-PA infusion-resulting brain edema and infarction volume and improved the behavioral outcomes following 6 hr ischemia. Mechanistically, PCB pretreatment inhibited the activation of MMP-2 and MMP-9 and degradation of tight junction proteins (TJPs) occludin and claudin-5 in the ischemic hemisphere. Moreover, PCB pretreatment significantly reduced phosphorylation of platelet-derived growth factor receptor α (PDGFRα) as compared with t-PA alone. In an in vitro BBB model, PCB decreased transendothelial permeability upon hypoxia/aglycemia through inhibiting PDGF-CC secretion. In conclusion, we demonstrated that PCB pretreatment shortly before t-PA infusion significantly protects BBB function and improves neurological outcomes following prolonged ischemia beyond the regular 4.5 hr t-PA time window. PCB pretreatment may represent a novel means of increasing the safety and the therapeutic time window of t-PA following ischemic stroke.
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Wang, Chen-xi, Jun-jun Guo, An-jie Di, Yu Zhu, Wei-min Han, An-ran Cheng, Cheng Li, et al. "The Protective Effect of Cx43 Protein-Mediated Phosphocreatine on Myocardial Ischemia/Reperfusion Injury." Cardiology Research and Practice 2021 (January 22, 2021): 1–9. http://dx.doi.org/10.1155/2021/8838151.
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Objectives. To verify the protective effect of phosphocreatine on myocardium in an ischemic model and the possible mechanism of action. Methods. The model of myocardial ischemia/reperfusion (I/R) was established by the ligation balloon method. 30 SD rats were randomly divided into three groups, n = 10 in each group. Sham operation group: the coronary artery was not blocked and observed for 120 minutes. The ischemia/reperfusion (I/R) group was given ischemia for 30 minutes and ischemia reperfusion for 90 minutes. Phosphocreatine (PCr) group: after 30 minutes of ischemia, the rats were intraperitoneally injected with PCr (200 mg/kg) for 90 minutes. The animal groups of myocardial ischemia/reperfusion model in vitro were the same as those in vivo. The heart was removed by thoracotomy and washed immediately in H-K buffer solution. Then, the heart was installed on the Langendorff instrument. The concentration of PCr perfusion fluid in the PCr group was 10 mmol/L. The changes in coronary blood flow in isolated myocardium were recorded. The heart rate and electrocardiogram were recorded by RM6240BT. At the end of the experiment, myocardial pathological sections and Cx43 immunofluorescence staining were made, and the contents of malondialdehyde (MDA) in myocardial tissue were detected. Results. Phosphocreatinine treatment improved the myocardial ischemia model, performance in electrocardiogram (ECG) changes (ST segment apparent), and histological changes (decrease in necrotic myocardial cells, inflammatory cell infiltration, and a reduction in myocardial edema). At the same time, MDA decreased, while coronary blood flow and Cx43 expression significantly improved. Conclusions. Phosphocreatine can improve the electrocardiogram and restore histologic changes in ischemic myocardium and coronary blood flow. The postulated mechanism is by inhibiting the generation of free oxygen radicals and restoring the expression of Cx43 protein.
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Rybachuk, O., V. Кyryk, P. Poberezhny, G. Butenko, G. Skibo, and T. Pivneva. "Effect of the bone marrow multipotent mesenchimal stromal cells to the neural tissue after ischemic injury in vitro." Cell and Organ Transplantology 2, no. 1 (May 31, 2014): 74–78. http://dx.doi.org/10.22494/cot.v2i1.38.
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Stem cells application in neural system injuries is an actual and prospective scientific field of modern regenerative medicine. In recent years much attention has been paid for study of regenerative effects of multipotent mesenchymal stromal cells (MMSCs) from different sources on injured tissues.The aim of our study was to determine the level of tissue damage in hippocampus after in vitro model of ischemia and to investigate the effect of bone marrow MMSСs in non-contact co-culture with ischemic neural tissue. The ischemic injury of neural tissue in vitro was modeling in organotypic hippocampal slice culture (OHCs) by oxygen-glucose deprivation (OGD).Immunohistochemical analysis after 24 hours of BM-MMSCs co-cultivation with OHCs after ischemia showed a significant reduction of caspase-3-positive dead neural cells, as compared to those in ischemic damage without BM-MMSCs co-cultivation, and reducing of glial cells activation. After co-cultivation of OHCs after OGD with BM-MMSCs there remained cytoarchitectonics of the neural tissue.Analyzing of our data, the neuroprotective effects of BM-MMSCs in non-contact co-cultivation with ischemic hippocampal organotypic slice culture is shown.
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Peng, Hui, Tong-Chun Wen, Junya Tanaka, Nobuji Maeda, Seiji Matsuda, Junzo Desaki, Satoko Sudo, Bo Zhang, and Masahiro Sakanaka. "Epidermal Growth Factor Protects Neuronal Cells In Vivo and In Vitro against Transient Forebrain Ischemia- and Free Radical-Induced Injuries." Journal of Cerebral Blood Flow & Metabolism 18, no. 4 (April 1998): 349–60. http://dx.doi.org/10.1097/00004647-199804000-00002.
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Epidermal growth factor (EGF) has been considered to be a candidate for neurotrophic factors on the basis of the results of several in vitro studies. However, the in vivo effect of EGF on ischemic neurons as well as its mechanism of action have not been fully understood. In the present in vivo study using a gerbil ischemia model, we examined the effects of EGF on ischemia-induced learning disability and hippocampal CA1 neuron damage. Cerebroventricular infusion of EGF (24 or 120 ng/d) for 7 days to gerbils starting 2 hours before or immediately after transient forebrain ischemia caused a significant prolongation of response latency time in a passive avoidance task in comparison with the response latency of vehicle-treated ischemic animals. Subsequent histologic examinations showed that EGF effectively prevented delayed neuronal death of CA1 neurons in the stratum pyramidale and preserved synapses intact within the strata moleculare, radiatum, and oriens of the hippocampal CA1 region. In situ detection of DNA fragmentation (TUNEL staining) revealed that ischemic animals infused with EGF contained fewer TUNEL-positive neurons in the hippocampal CA1 field than those infused with vehicle alone at the seventh day after ischemia. In primary hippocampal cultures, EGF (0.048 to 6.0 ng/mL) extended the survival of cultured neurons, facilitated neurite outgrowth, and prevented neuronal damage caused by the hydroxyl radical-producing agent FeSO4 and by the peroxynitrite-producing agent 3-morpholinosydnonimine in a dose-dependent manner. Moreover, EGF significantly attenuated FeSO4-induced lipid peroxidation of cultured neurons. These findings suggest that EGF has a neuroprotective effect on ischemic hippocampal neurons in vivo possibly through inhibition of free radical neurotoxicity and lipid peroxidation.
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Chen, Timothy, and Gordana Vunjak-Novakovic. "In Vitro Models of Ischemia-Reperfusion Injury." Regenerative Engineering and Translational Medicine 4, no. 3 (May 11, 2018): 142–53. http://dx.doi.org/10.1007/s40883-018-0056-0.
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Cao, Jinyi, Kai Wang, Lu Lei, Lu Bai, Ruimin Liang, Yi Qiao, Jialin Duan, et al. "Astragaloside and/or Hydroxysafflor Yellow A Attenuates Oxygen-Glucose Deprivation-Induced Cultured Brain Microvessel Endothelial Cell Death through Downregulation of PHLPP-1." Evidence-Based Complementary and Alternative Medicine 2020 (December 15, 2020): 1–12. http://dx.doi.org/10.1155/2020/3597527.
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The incidence of ischemic stroke, a life-threatening condition in humans, amongst Asians is high and the prognosis is poor. In the absence of effective therapeutics, traditional Chinese medicines have been used that have shown promising results. It is crucial to identify traditional Chinese medicine formulas that protect the blood-brain barrier, which is damaged by an ischemic stroke. In this study, we aimed to elucidate such formulas. Brain microvascular endothelial cells (BMECs) were used to establish an in vitro ischemia-reperfusion model for oxygen-glucose deprivation (OGD) experiments to evaluate the function of two traditional Chinese medicines, namely, astragaloside (AS-IV) and hydroxysafflor yellow A (HSYA), in protecting against BMEC. Our results revealed that AS-IV and HSYA attenuated the cell loss caused by OGD by increasing cell proliferation and inhibiting cell apoptosis. In addition, these compounds promoted the migration and invasion of BMECs in vitro. Furthermore, we found that BMECs rescued by AS-IV and HSYA could be functionally activated in vitro, with AS-IV and HSYA showing synergetic effects in rescuing BMECs survival in vitro by reducing the expression of PHLPP-1 and activating Akt signaling. Our results elucidated the potential of AS-IV and HSYA in the prevention and treatment of stroke by protecting against cerebral ischemia-reperfusion injury.