Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0917798 (cerebral ischemia)
 17,036 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The improvement of decreased cerebral blood flow using thrombolytic agents, anti-thrombin drugs, and antiplatelet drugs has been essential for acute ischemic stroke. Edaravone, a free radical scavenger, has been commercially available as a novel neuroprotective agent for ischemic stroke in Japan from 2001. The appearance of a neuroprotective agent implies that therapeutic strategy can be expanded through a combination with thrombolysis. In the previous development, several cases have reported that neuroprotective compounds failed in clinical trials. However, recent studies have clarified that the cerebral ischemia induced the neuronal cell death by mediating multiple mechanisms with necrosis and/or apoptosis. The cytotoxicity derived from the NO/peroxynitrite/free radical generating system, one of intracellular Ca2+ signaling, is a typical event in ischemic injury, which is protected by edaravone. Furthermore, it is suggested that suppression of excessively activated voltage-dependent Na+ and Ca2+ channels is effective as a strategy for neuroprotection, since abnormal excitatory stimuli in the neuronal network result in the cerebral infarction. The development of several compounds having different mechanisms of action for acute stroke is in progress. It is therefore prospected that the various novel neuroprotective agents will be provided for assuring the option of therapeutic strategy, since the reinforcement of medical stroke care including diagnosis contributes to the prolongation of the therapeutic time window.
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PMID:[Current state on development of neuroprotective agents for cerebral ischemia]. 1218 23

Edaravone, a novel free radical scavenger, has been reported to reduce ischemic damage in rats subjected to transient focal ischemia. The aim of this study is, therefore, to investigate the effect of a combined therapy with edaravone and mild hypothermia of 35 degrees C. Sprague-Dawley rats were subjected to MCA occluding an intraluminal suture technique for 2 hrs. The rats were reperfused for 24 h and decapitated for infarct and edema analysis. Animals were randomly devided into four groups: (I) vehicle + normothermia (control) (II) vehicle + mild hypothermia (III) Edaravone + normothermia (IV) Edaravone + mild hypothermia. Mild hypothermia alone had no reduction of the brain damage. The edaravone alone significantly reduced edema volume. The combined treatment with edaravone and mild hypothermia reduced both infarct and edema volume. In addition, this treatment provided for the best functional outcome. These results demonstrate that free radical scavenger, edaravone attenuates brain edema and that the combined therapy with edaravone and mild hypothermia significantly reduces not only edema but also infarct on transient focal cerebral ischemia in rats. The neuroprotective effects seen in this study may be due to the combined interaction of antiedema activity between edaravone and mild hypothermia, suppressing free radical production.
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PMID:The neuroprotective effect of a free radical scavenger and mild hypothermia following transient focal ischemia in rats. 1475 35

Increasing data suggest that oxygen free radical species play detrimental roles in ischemic diseases. A free radical scavenger capable of inhibiting oxidative injury is expected to become a new drug for the treatment of ischemic diseases such as cerebral ischemia. Edaravon (3-methyl-1-phenyl-2-pyrazolin-5-one), which has been developed as an neuroprotective agent for more than 15 years since its discovery, is approved for the treatment of acute cerebral infarction. In this paper, the pharmacologic characteristics and clinical effects of edaravone are reviewed. In early stage of investigation, edaravone was found to have promising activities as an antioxidative radical scavenger, quenching hydroxyl radical (.OH) and inhibiting both .OH-dependent and .OH-independent lipid peroxidation. Edaravone showed inhibitory effects on both water-soluble and lipid-soluble peroxyl radical-induced peroxidation systems, which are different from the inhibitory effects of vitamins C and E in each system, respectively. Oxidative injury to cultured endothelial cells caused by arachidonate (AA) peroxides is prevented in the existence of edaravone. To clarify the characteristics of this free radical scavenger, further investigation was carried out. Edaravone ameliorated exacerbation of cortical edema induced by a focal ischemia-reperfusion model in rats, suggesting inhibitory effects on oxidative injury to the blood-brain barrier (BBB). Additionally, edaravone also prevented rat cortical edema caused by intracortical AA infusion in which free radical production and subsequent oxidative injury to the BBB are involved. With advances in in vivo measurement technology of oxygen radicals, edaravone was shown to inhibit postischemic increases in .OH production and tissue injury in the penumbral or recirculated area in rat cerebral ischemia models. In clinical studies, edaravone improved the core neurologic deficits, activities of daily living, and functional outcome of stroke patients. Furthermore, a study using proton magnetic resonance spectroscopic techniques showed that edaravone preserved N-acetyl-aspartate in stroke patients, a promising neuronal marker in the brain. Further investigation is essential for a better understanding of free radical-mediated cerebral injury during ischemia followed by recirculation. We hope that edaravone represents a promising neuroprotectant for drug therapy in acute cerebral ischemia.
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PMID:[Research and development of the free radical scavenger edaravone as a neuroprotectant]. 1504 27

The present study was aimed to evaluate the effect of the free radical scavenger Edaravone on infarct volume due to permanent MCA occlusion in mice and, if so, to elucidate the mechanism of its neuroprotective effects. Male Balb/c mice were subjected to permanent middle cerebral artery occlusion and were treated with 3.0 mg/kg of Edaravone or vehicle 30 min before ischemia. Infarct volume was assessed by 2,3,5-triphenyltetrazolium chloride (TTC) method after 24 h. Furthermore, in situ detection of superoxide in the ipsilateral neocortex was carried out using the superoxide-sensitive dye dihydroethidium (DHE) staining technique. Pretreatment with 3.0 mg/kg of Edaravone ameliorated the tissue damage in the infarct rim and significantly reduced infarct volume to about 77% of the control (p<0.05). Semi-quantitative measurement of red fluorescence emitted from DHE revealed that the superoxide increased in the ischemic core at 1 h after the onset of ischemia and extended towards the infarct rim at 3 and 6 h, and that pretreatment with 3.0 mg/kg of Edaravone significantly inhibited the increase of superoxide in the infarct rim at 3 and 6 h (p<0.01). Double staining with DHE and monoclonal antibody against NeuN showed that the majority of the nuclei positive for DHE were also positive for NeuN. These findings suggest that Edaravone salvages the boundary zone of infarct by scavenging reactive oxygen species especially in the neurons during permanent focal cerebral ischemia.
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PMID:Neuroprotective effects of the free radical scavenger Edaravone (MCI-186) in mice permanent focal brain ischemia. 1554 75

A 60-year-old man underwent percutaneous transluminal angioplasty (PTA) stent replacement of the right common carotid artery. Preoperative angiogram revealed bilateral vertebral artery occlusion and 50% stenosis in contralateral internal carotid artery. Anesthesia was induced and maintained with fentanyl and propofol by TCI. rSO2, BIS and EEG were monitored. Moderate hypothermia (33-35 degrees C) was induced by concomitant use of milrinone. Edaravone, a novel free radical scavenger, and Sendai cocktail were administered before interruption of carotid flow. During 5 minutes of test occlusion by balloon, right rSO2 decreased from 61% to 49% and EEG showed slow waves with decreased amplitude. Therefore we decided to perform PTA and stenting separately. Right rSO2 decreased from 62% to 48% during PTA (6 min occlusion), while rSO2 decreased from 66% to 50% during stenting (7.5 min occlusion). EEG also showed the similar changes as observed during test occlusion. After the procedures, rSO2 and EEG recovered in a short time. Postoperative angiogram showed an improvement of carotid artery stenosis and intracranial vessels showed no branch occlusion. Patient was maintained hypothermic (35 degrees C) for 2 days after surgery. He recovered without additional neurological complications. We found that rSO2 was a useful, real-time and non-invasive method for evaluation of cerebral ischemia in our patient.
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PMID:[Anesthetic management of a patient undergoing PTA stent placement for right common carotid artery stenosis]. 1637 Mar 40

Edaravone, a potent antioxidant, is currently being used in the management of acute ischemic stroke in relatively high-aged populations. Mitogen activated protein kinase (MAPK) pathways have been shown to play important roles in neuronal cell death. We examined the role of MAPK pathways and the effect of treatment with edaravone in the brain after cerebral ischemia-reperfusion (I/R) injury in a bilateral carotid artery occlusion (BCAO) model with ischemia for 85 min followed by reperfusion for 45 min in aged rats. Western immunoblotting, immunostaining, enzyme-linked immunosorbent assay (ELISA), spectrophotometry, terminal deoxynucleotidyl transferase nick end labeling (TUNEL) and triphenyl tetrazolium chloride (TTC) staining were performed to evaluate various proteins in the homogenate, c-Jun NH2-terminal kinase (JNK) in the tissue sections, protein carbonyl, glutathione peroxidase (GSHPx), apoptosis and infarct size, respectively. Our results showed that I/R injury resulted in a reduction of GSHPx, but protein carbonyl content and inducible nitric oxide synthase were increased. The activation of JNK and its downstream molecule c-Jun was significantly increased after injury, whereas the activities of p38 MAPK and extracellular-regulated kinase 1/2 were slightly but not significantly increased. Edaravone (3 mg/kg, i.v.) treatment significantly reduced all of these changes. Our findings suggest that the JNK pathway differentially mediates neuronal injury in aged rats after BCAO, and edaravone treatment significantly reduces the neuronal damage after I/R injury by inhibiting oxidative stress and the JNK-c-Jun pathway with concomitant inhibition of overall MAPK activity in the brains of aged rats.
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PMID:Edaravone inhibits JNK-c-Jun pathway and restores anti-oxidative defense after ischemia-reperfusion injury in aged rats. 1659 5

Edaravone is a potent scavenger of hydroxyl radicals and is quite successful in patients with acute cerebral ischemia, and several organ-protective effects have been reported. Treatment of human microvascular endothelial cells with edaravone (1.5 microM) resulted in the enhancement of transmonolayer electrical resistance coincident with cortical actin enhancement and redistribution of focal adhesion proteins and adherens junction proteins to the cell periphery. Edaravone also induced small GTPase Rac activation and focal adhesion kinase (FAK; Tyr(576)) phosphorylation associated with sphingosine-1-phosphate receptor type 1 (S1P(1)) transactivation. S1P(1) protein depletion by the short interfering RNA technique completely abolished edaravone-induced FAK (Tyr(576)) phosphorylation and Rac activation. This is the first report of edaravone-induced endothelial barrier enhancement coincident with focal adhesion remodeling and cytoskeletal rearrangement associated with Rac activation via S1P(1) transactivation. Considering the well-established endothelial barrier-protective effect of S1P, endothelial barrier enhancement as a consequence of S1P(1) transactivation may at least partly be the potent mechanisms for the organ-protective effect of edaravone and is suggestive of edaravone as a therapeutic agent against systemic vascular barrier disorder.
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PMID:Edaravone mimics sphingosine-1-phosphate-induced endothelial barrier enhancement in human microvascular endothelial cells. 1768 98

Over the last decade, important advances have been made to support the fact that reactive oxygen species (ROS) are generated and play a harmful role during the acute and late stages of cerebral ischemia. Several drugs, such as radical scavengers and antioxidants, have been evaluated in preclinical and clinical studies. Edaravone (3-methyl-1-phenyl-2-pyrazolin-5-one; Radicut, Mitsubishi Tanabe Pharma Corporation) is a novel antioxidant that is currently used in Japan for the treatment of patients in the acute stage of cerebral infarction. Edaravone scavenges ROS and inhibits proinflammatory responses after brain ischemia in animals and humans. In particular, postischemic inflammation, leading to brain edema and infarction due to neuronal damage and endothelial cell death, can be ameliorated by edaravone. In addition to these antistroke effects, edaravone has also been shown to prevent oxidative damage to various extracerebral organs. Therefore, in addition to its usefulness in the treatment of stroke, edaravone is expected to play an integral role in the treatment of many oxidative stress-related diseases.
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PMID:The novel antioxidant edaravone: from bench to bedside. 1848 33

Edaravone is a free-radical scavenger, an agent being widely used for cerebral ischemia in Japan. To evaluate its efficacy for possible treatment of amyotrophic lateral sclerosis (ALS), we performed a randomized blind trial in ALS model mice. After identification of the clinical onset in each female G93A mutant SOD1 transgenic mouse, we intraperitoneally administered multiple doses of edaravone to the mice and observed their motor symptoms. We also counted the number of lumbar motoneurons, determined the 3-nitrotyrosine/tyrosine ratio, and evaluated the abnormal SOD1 aggregation in the spinal cord at the 10th day after the edaravone injection. Edaravone significantly slowed the motor decline of the transgenic mice. The remaining motoneurons were significantly preserved in the higher-dose edaravone-administered group, and the 3-nitrotyrosine/tyrosine ratios were reduced dose-dependently. Intriguingly, the area of abnormal SOD1 deposition in the spinal cord was significantly decreased in the higher-dose edaravone-administered group. Our results indicate that edaravone was effective to slow symptom progression and motor neuron degeneration in the ALS model mice. These favorable actions might be attributable to the yet unidentified mechanism responsible for reducing the deposition of mutant SOD1.
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PMID:Treatment with edaravone, initiated at symptom onset, slows motor decline and decreases SOD1 deposition in ALS mice. 1928 71

Edaravone is a lipophilic drug with multiple mechanisms of action. Because edaravone is a promising drug candidate for the treatment of stroke, we tested the hypothesis that edaravone would be neuroprotective following cerebral ischemia using a rabbit embolic stroke model with a well-defined behavioral endpoint. Using the rabbit small clot embolic stroke model (RSCEM), a drug or drug combination is considered beneficial if it significantly increases the amount of microclots (mg) measured in brain that produce neurologic dysfunction in 50% of a group of animals (P(50)) compared to the control group. Edaravone (100 mg/kg, s.c.), increased the P(50) value to 1.80+/-0.24 mg (p<0.05) when administered 5 min following embolization and increased P(50) values by 195% and 161% (compared to control) when administered 1 and 3 h following embolization, respectively, but was inactive when applied 6 h following embolization, compared to the cumulative control group (P(50)=0.93+/-0.16 mg). To simulate the design of current clinical trials, edaravone was also given following a standard tPA regimen, which by itself increased the P(50) value to 2.72+/-0.28 mg. When tPA was infused 1 h following embolization and edaravone was given 3 h following embolization, the P(50) was 2.68+/-0.56 mg. This study indicates that edaravone may have substantial therapeutic benefit for the treatment of AIS since it had a therapeutic widow of at least 3 h in rabbits. Edaravone can also be administered with a thrombolytic to improve behavior.
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PMID:The lipophilic multifunctional antioxidant edaravone (radicut) improves behavior following embolic strokes in rabbits: a combination therapy study with tissue plasminogen activator. 1885 64


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