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PubMed2004

Edaravone, a novel radical scavenger, inhibits oxidative modification of low-density lipoprotein (LDL) and reverses oxidized LDL-mediated reduction in the expression of endothelial nitric oxide synthase.

Edaravone, a newly synthesized synthetic radical scavenger, has been identified and adopted as an anti-stroke agent. However, its mechanism and the effect of edaravone on lipoprotein oxidation are not fully understood. Therefore, whether edaravone could suppress oxidation of low-density lipoprotein (LDL) and be involved in the expression of endothelial nitric oxide synthase (eNOS) in relation to anti-atherogenesis by improving and conserving vascular circulation was investigated. We investigated the in vitro effects of edaravone on copper- and endothelial cell-mediated LDL oxidation, and the expression of eNOS in human umbilical vein endothelial cells (HUVEC) modulated by oxidized LDL. The in vivo effect of edaravone on antioxidative effect was also studied in male rats intravenously administered with edaravone. Edaravone apparently inhibited copper- and HUVEC-mediated LDL oxidation at the concentration equivalent to serum concentrations in clinical use. The intravenous administration of edaravone also enhanced serum radical-scavenging property in rats. We tested the effect of edaravone on protein and mRNA expression of eNOS in HUVEC. Edaravone enhanced eNOS expression in HUVEC, presumably because of increased stability of eNOS mRNA, and reversed eNOS expression reduced by oxidized LDL nearly to the control levels. The present study demonstrates for the first time that edaravone increases eNOS expression with the inhibition of LDL oxidation, and that edaravone can reverse oxidized LDL-mediated reduction in eNOS expression in endothelial cells. The preventive action of edaravone from ischemic disease consequence may be attributed to these eNOS up-regulation with decreased oxidation.

Animals↗

PubMed2006

Protective effect of edaravone against the ototoxicity of Pseudomonas aeruginosa exotoxin A.

CONCLUSION: Our findings suggest that edaravone can protect against cochlear damage caused by Pseudomonas aeruginosa exotoxin A (PaExoA). OBJECTIVE: To analyze the protective effect of a free radical scavenger, edaravone, against the ototoxicity resulting from exposure of the middle ear to PaExoA. MATERIAL AND METHODS: In nine groups of albino rats the following solutions were instilled either via the tympanic membrane into the round window niche [intratympanically (i.t.)] or intravenously (i.v.): edaravone (i.v.); edaravone (i.t.); PaExoA (i.t.) + edaravone (i.t.; simultaneously); PaExoA (i.t.) + edaravone (i.t.; 1 h after); PaExoA (i.t.) + edaravone (i.t.; 24 h after); PaExoA (i.t.) + edaravone (i.v.; simultaneously); PaExoA (i.t.) + edaravone (i.v.; 1 h after); PaExoA (i.t.) + edaravone (i.v.; 24 h after); PaExoA (i.t.) + saline (i.v.). Frequency-specific (2-20 kHz) auditory brainstem responses were measured to determine hearing thresholds before and 2, 5 and 10 days after instillation. RESULTS: PaExoA had penetrated from the middle ear into the cochlea and caused hearing loss. This impairment was blocked by intratympanic injection of edaravone when given simultaneously or 1 h after the first instillation of PaExoA, or by intravenous injection of edaravone when given simultaneously. There were significant differences in protective effect between the intratympanic and intravenous routes.

ADP Ribose Transferases↗

PubMed2004

Free radical scavenger, edaravone, in stroke with internal carotid artery occlusion.

BACKGROUND: Edaravone has potent free radical quenching and antioxidant actions. The agent has been recently in commercial use for acute ischemic stroke patients. In this study, we investigated the therapeutic effect of edaravone on severe carotid-territorial stroke. METHODS: Stroke patients with internal carotid artery occlusion and baseline NIH Stroke Scale Score > or =15 were treated for 14 days with drip intravenous infusion of edaravone (n=30) and were compared with a historical control cohort of similar patients (n=31). Glycerol was also administered to all patients in both groups. RESULTS: Infarct volume (P<0.02) and midline shift (P<0.02) on CT performed on day 2 of the patients treated with edaravone were smaller than those without edaravone. For patients with edaravone, infarct volume (P<0.0001) and midline shift (P<0.0001) on days 5-7 were greater than those on day 2. Hemorrhagic transformation of infarcts on day 2 was less severe in patients with than without edaravone (P<0.03). Within 14 days after the onset of stroke, 6 patients with edaravone (20%) and 14 without edaravone (45%) died directly of stroke (P<0.03). Among all patients, only two treated with edaravone were independent without any assistance 8 weeks after the onset. CONCLUSIONS: Edaravone was associated with delayed evolution of infarcts and edema in patients with severe carotid-territorial stroke and decreased mortality during the acute stage. The agent, however, failed to prevent evolution of infarcts and edema on later days, and did not significantly improve functional outcome among the surviving patients.

Aged↗

PubMed2006

Edaravone reduces myocardial infarct size and improves cardiac function and remodelling in rabbits.

1. In the present study, we investigated the effect of 3-methyl-1-phenyl-2-pyrazolin-5-one (edaravone), a free radical scavenger, on myocardial infarct (MI) size and cardiac function in an in vivo model of MI in rabbits. We further investigated the contribution of hydroxyl radicals, superoxide and nitric oxide (NO) to its effects. 2. Anaesthetized open-chest Japanese white male rabbits were subjected to 30 min coronary occlusion and 48 h reperfusion. The control group (n = 10) was injected with saline 10 min before reperfusion. The edaravone group (n = 10) was injected with a bolus of 3 mg/kg edaravone 10 min before reperfusion. The edaravone + N(G)-nitro-L-arginine methyl ester (L-NAME) group (n = 5) was given 10 mg/kg, i.v., L-NAME 10 min before the administration of 3 mg/kg edaravone. The L-NAME group (n = 5) was given 10 mg/kg, i.v., L-NAME 20 min before reperfusion. Infarct size was measured using the triphenyl tetrazolium chloride method and is expressed as a percentage of area at risk. Cardiac function was assessed by echocardiography 14 days after infarction. 3. In another series of experiments, rabbits were subjected to 30 min coronary occlusion and 30 min reperfusion and myocardial interstitial 2,3-dihydroxybenzoic acid (DHBA) and 2,5-DHBA levels, indicators of hydroxyl radical, were measured using a microdialysis technique. 4. Infarct size in the edaravone group was significantly reduced compared with that in the control group (27.4 +/- 6.8 vs 43.4 +/- 6.8%, respectively; P < 0.05). The edaravone-induced reduction of infarct size was abolished by pretreatment with L-NAME. Myocardial interstitial levels of 2,3-DHBA and 2,5-DHBA increased 20 and 30 min after ischaemia and peaked at 10 min reperfusion in the control group. Edaravone significantly inhibited the increase in 2,3-DHBA and 2,5-DHBA levels seen during reperfusion. Dihydroethidium staining showing in situ detection of superoxide was less intense in ischaemic myocardium in the edaravone-treated group compared with the control group. Edaravone improved cardiac function and left ventricular remodelling 14 days after infarction. 5. In conclusion, edaravone significantly reduces MI size and improves cardiac function and LV remodelling by decreasing hydroxyl radicals and superoxide in the myocardium and increasing the production of NO during reperfusion in rabbits.

Animals↗

PubMed2004

[Research and development of the free radical scavenger edaravone as a neuroprotectant].

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.

Animals↗

PubMed2005

Neuroprotection and enhanced recovery with edaravone after acute spinal cord injury in rats.

STUDY DESIGN: The effect of edaravone, a novel free radical scavenger, was assessed functionally and histologically using a rat spinal cord contusion model. OBJECTIVE: To investigate the effect of edaravone on neuroprotection after spinal cord injury in rats. SUMMARY OF BACKGROUND DATA: The spinal cord injury results in immediate physical damage (primary injury), followed by a prolonged neural tissue disorder (secondary injury). This secondary injury process has been suggested to be induced by lipid peroxidation. Edaravone has been reported to inhibit lipid peroxidation in cerebral ischemia models. METHODS: Spinal cord injury at the T10 level was induced with a weight drop device (10 g weight, 25 mm height). Edaravone was administered intravenously as a bolus dose of 5 mg/kg at 5 minutes, 24 hours, and 48 hours after injury (edaravone-treated rats). In control rats, nothing was administered. Functional assessment was conducted weekly using the Basso-Beattie-Bresnahan locomotor rating scores. Histologically, a percentage of spared white matter area was calculated. The effects of intravenous administration of edaravone on lipid peroxide formation in rat spinal cord homogenate were examined using the thiobarbituric acid test for malonyldialdehyde production. RESULTS: Six weeks after injury, edaravone-treated rats showed significantly higher motor score and larger spared white matter area than control rats. The administration of edaravone attenuated malonyldialdehyde production in spinal cord homogenate by >45%. CONCLUSION: Edaravone enhanced functional recovery and preserved more spinal cord tissue after spinal cord injury in rats. The attenuation of posttraumatic lipid peroxide formation by edaravone partially contributed to this enhancement.

Acute Disease↗

PubMed2004

Radical scavenger edaravone developed for clinical use ameliorates ischemia/reperfusion injury in rat kidney.

BACKGROUND: Edaravone (3-methyl-1-phenyl-2-pyrazolin-5-one) is a potent scavenger of free radicals and has the antioxidant ability to inhibit lipid peroxidation. Its protective effect on brain ischemia has been shown. This study aimed to elucidate its possible therapeutic effects on renal oxidative stress in a rat ischemia/reperfusion model. METHODS: Ischemic acute renal failure was induced by 45-minute clamp of the left renal artery followed by administration of edaravone. Renal function and pathologic findings were examined. The generation of free radicals was observed by the fluorogenic probe, dichlorodihydrofluorescein (CM-H(2)DCFDA), and lipid peroxidation was observed by immunochemical staining and Western analysis of 4-hydroxy-2-hexenal (HHE). The ability of edaravone to reduce in vitro oxidative stress was investigated using cultured human renal tubular cells (HKC-8) and the cell viability assay with Alamar blue. RESULTS: Edaravone attenuated renal function and pathologic findings significantly. The protective effect of edaravone showed the dose-response was at the same level as that of dimethylthiourea. In addition, edaravone significantly reduced the generation of free radicals in the tubular cells indicated by CM-H(2)DCFDA. Immunochemical staining and Western analysis of HHE showed significant suppression of lipid peroxidation in edaravone-treated kidney. In HKC-8 cells loaded with CM-H(2)DCFDA, a marked elevation of fluorescence was observed after exposure to hydrogen peroxide (0.5 mmol/L, for 1 hour), which was reduced by edaravone. The cell viability assay with Alamar blue also showed the protective effect of edaravone. CONCLUSION: Edaravone ameliorates renal ischemia/reperfusion injury by scavenging free radicals produced in renal tubular cells and inhibiting lipid peroxidation.

Animals↗

PubMed2005

Free radical scavenger (edaravone) prevents endotoxin-induced liver injury after partial hepatectomy in rats.

BACKGROUND/AIMS: Infection after major surgery, such as massive hepatectomy, induces liver dysfunction, occasionally leading to multiple organ failure and death. We demonstrated the anti-inflammatory effects and functional mechanisms of 3-methyl-1-phenyl-2-pyrazolin-5-one (edaravone), a newly synthesized free radical scavenger, on an experimental model of endotoxemia after partial hepatectomy in rats. METHODS: Rats were treated with lipopolysaccharide (LPS) 48h after 70% hepatectomy. Edaravone was administered intravenously before LPS-treatment. RESULTS: Edaravone markedly improved the survival rate of LPS-treated rats after hepatectomy and inhibited increases in serum levels of AST and LDH. Histopathological analysis demonstrated that edaravone prevented inflammatory changes in the liver, kidney and spleen. Edaravone inhibited the formation of one of the markers of oxidative damage, malondialdehyde. Increases in inflammatory cytokines and cytokine-induced neutrophil chemoattractant (CINC) in serum and liver tissue were inhibited in the edaravone-treated group. An electrophoretic mobility shift assay revealed that edaravone inhibited the activation of the transcription factor, nuclear factor-kappa B (NF-kappaB). Edaravone also reduced the induction of inducible nitric oxide synthase (iNOS). CONCLUSIONS: Edaravone prevents endotoxin-induced liver injury after partial hepatectomy not only by attenuating oxidative damage, but also by reducing the production of inflammatory cytokines, CINC and iNOS, in part through the inhibition of NF-kappaB activation.

Alanine Transaminase↗

PubMed2004

Protective effect of edaravone against hypoxia-reoxygenation injury in rabbit cardiomyocytes.

1 We examined whether edaravone (Eda), a clinically available radical scavenger, directly protects cardiomyocytes from ischemia/reperfusion (I/R) injury, and whether the timing of its application is critical for protection. 2 Cardioprotective effects of edaravone were tested in the modified cell-pelleting model of ischemia and under exogenous oxidative stress (hydrogen peroxide: H2O2) in isolated adult rabbit ventricular cells. Cell death and reactive oxygen species (ROS) generation were detected using propidium iodide (PI) and DCFH-DA, respectively. These parameters were evaluated objectively using flow cytometory. 3 Hypoxia and reoxygenation aggravated the proportion of dead cells from 32.2+/-1.8% (Baseline) to 51.3+/-2.7% (Control). When 15 microm edaravone was applied either throughout the entire experiment (Through) or only at reoxygenation (Reox), cell death was significantly reduced to 39.9+/-1.8% (P<0.01 vs Control) and 43.3+/-2.5% (P<0.05 vs Control), respectively. In contrast, when edaravone was applied 10 min after reoxygenation, its protective effect disappeared. Cardioprotection by edaravone was more remarkable than that afforded by other free radical scavengers, such as ascorbate and superoxide dismutase (SOD). There is a positive correlation between the cardioprotective effect of edaravone and the extent of ROS reduction. 4 Edaravone blunted the H2O2-induced changes in electrical properties, and significantly prolonged the time to contracture induced by H2O2 in single ventricular myocytes. 5 Taken together, edaravone directly protects cardiomyocytes from I/R injury by attenuating ROS production, even when applied at the time of reoxygenation, suggesting that edaravone could be a potent cardioprotective therapeutic agent against hypoxia-reoxygenation injury.

Action Potentials↗

PubMed2005

Edaravone prevented deteriorated cardiac function after myocardial ischemia-reperfusion via inhibiting lipid peroxidation in rat.

Edaravone (3-methyl-1-phenyl-2-pyrazolin-5-one) has potent effects in the brain as a free radical scavenger in ischemia-reperfusion as well as in ischemic injuries. However, whether this free radical scavenger prevents deterioration of cardiac function and lethal ventricular arrhythmias after ischemia-reperfusion in rat heart is not clear. We aimed to assess whether free radical scavenging by edaravone maintains cardiac function and suppresses life-threatening ventricular tachyarrhythmia after myocardial ischemia-reperfusion. Twenty-nine 7-week-old male Sprague-Dawley rats had acute myocardial ischemia induced by ligation of the left coronary artery for 5 minutes followed by reperfusion. Eleven were treated by intravenous injection of edaravone at 3 mg/kg 2 minutes after coronary ligation, and 18 were left untreated. The index of systolic function (contractility; end-systolic elastance, Ees) and hemodynamics were measured by pressure-volume relationships every 5 minutes before ligation to 25 minutes after reperfusion. Blood levels of malondialdehyde (MDA) and the ischemic areas were also measured 25 minutes after reperfusion. There were no differences in the ischemic areas between the groups. Lethal reperfusion tachyarrhythmia was observed in 5 untreated rats but not in those having edaravone treatment. Ees was significantly greater in the edaravone-treated than in untreated rats from 5 to 25 minutes after reperfusion (1789 +/- 866 in untreated versus 2809 +/- 273 mm Hg/mL in edaravone-treated rats at 25 minutes, P < 0.001). MDA level was significantly lower in edaravone-treated than in untreated rats (1.44 +/- 0.29 nmol/L in edaravone-treated versus 1.90 +/- 0.28 nmol/L in untreated group, P < 0.05). The results suggest that edaravone treatment before reperfusion prevented lethal reperfusion ventricular tachyarrhythmias and deteriorated cardiac function with ischemia and ischemia-reperfusion injuries through inhibiting lipid peroxidation in terms of scavenging for free radicals.

Animals↗

PubMed2004

Extension of ischemic therapeutic time window by a free radical scavenger, Edaravone, reperfused with tPA in rat brain.

3-methyl-1-phenyl-2-pyrazolin-5-one (Edaravone) is a free radical scavenger. We tested the hypothesis that combination treatment of Edaravone and recombinant tissue plasminogen activator (tPA) extends the therapeutic time window. Male Wistar rats were subjected to 1.5-, 3.0- or 4.5-hour middle cerebral artery (MCA) occlusion (MCAO) by a nylon thread. Animals were randomly divided into four groups. The Sham group rats were operated without MCAO and drug injection. In the Vehicle-treated group the same volume of saline was given every 1.5 hours from just after MCAO to just before reperfusion. In the Vehicle + tPA-treated group saline injection was given as above and tPA (5 mg/kg, i.v.) was given once just after reperfusion. Edaravone+tPA-treated group: Edaravone (3 mg/kg, i.v.) was given every 1.5 hours instead of saline and tPA injection as above. Survival rate, infarct size and evidence of apoptosis and hemorrhage were examined in the animals. Combining administration of Edaravone+tPA significantly increased survival rate after 3 hours of transient MCAO, and reduced infarct volume after 1.5 hours of transient MCAO compared with the vehicle or vehicle+tPA groups. In Edaravone+tPA-treated group, the number of terminal deoxynucleotidyl transferase-mediated dUTP-biotin in situ nick end labeling (TUNEL) and 4-hydroxynonenal (4-HNE) positive cells were reduced at 16 hours after 3 hours of transient MCAO, but not in advanced glycation end products (AGEs) and 8-hydroxy-2'-deoxyguanosine (8-OHdG). Hemorrhage rate and the area decreased in the Edaravone+tPA-treated group. The combination therapy of Edaravone+tPA increased survival rate, and reduced the infarct volume and hemorrhage with reduction of lipid peroxidation. Therefore, Edaravone combination is expected to extend the therapeutic time window of tPA in the clinical situation.

Aldehydes↗

PubMed2004

The reaction rate of edaravone (3-methyl-1-phenyl-2-pyrazolin-5-one (MCI-186)) with hydroxyl radical.

The pyrazoline derivative edaravone is a potent hydroxyl radical scavenger that has been approved for attenuation of brain damage caused by ischemia-reperfusion. In the present work, we first determined the rate constant, k(r), at which edaravone scavenges radicals generated by a Fenton reaction in aqueous solution in the presence of the spin trap agent, 5,5-dimethyl-1-pyrroline-N-oxide (DMPO), which competed with edaravone. We detected the edaravone radicals in the process of hydroxyl radical scavenging and found that edaravone reacts with hydroxyl radical around the diffusion limit (k(r)=3.0 x 10(10) M(-1) s(-1)). The EPR (electron paramagnetic resonance) spectrum of the edaravone radical was observed by oxidation with a horseradish peroxidase-hydrogen peroxide system using the fast-flow method. This radical species is unstable and changed to another radical species with time. In addition, it was found that edaravone consumed molecular oxygen when it was oxidized by horseradish peroxidase (HRP)-H(2)O(2) system, and that edaravone was capable of providing two electrons to the electrophiles. The possible mechanisms for oxidation of edaravone were investigated from these findings.

Antipyrine↗

PubMed2004

In vivo radioprotection of mice by 3-methyl-1-phenyl-2-pyrazolin-5-one (edaravone; Radicut), a clinical drug.

Edaravone (3-methyl-1-phenyl-2-pyrazolin-5-one; Radicut) is a brain-protecting agent used clinically to treat acute ischemic stroke with a reaction mechanism of free radical scavenging. Since the initial stage of radiation damage involves the formation of free radicals, edaravone is expected to be effective in preventing lethal damage from ionizing radiation. In the present study, we used mice to examine in vivo the radioprotective effect of edaravone on whole body X-ray irradiation. A solution of edaravone was administered intraperitoneally to C3H mice (male, 10 weeks old), and they were irradiated with a total dose of 8.0 Gy. Edaravone exhibited dose-dependent and injection time-dependent radioprotection. When injected 30 min before the X-ray irradiation, it had the greatest radioprotective effect, whereas an injection after the irradiation showed no protective effect. The LD(50/30) was about 8.8 Gy for edaravone-injected mice and 6.6 Gy for control mice, yielding a DRF for edaravone (450 mg/kg bw) of 1.3. Edaravone decreased the body temperature transiently about 3-6C, but this did not seem to be responsible for the radioprotection. Since the radioprotection was observed only when the reagent was administered before the irradiation, the primary action of edaravone might be the quenching of free radicals with a short lifetime generated by the irradiation.

Animals↗

PubMed2004

Edaravone, a newly developed radical scavenger, protects against ischemia-reperfusion injury of the small intestine in rats.

Although edaravone (3-methyl-1-phenyl-pyrazolin-5-one), a newly developed radical scavenging agent, has been widely used for protection against ischemia-reperfusion (I-R) injury in patients with cerebral infarction, its effects on gastrointestinal I-R injury have not been evaluated. In the present study, we examined the effects of edaravone on experimental intestinal I-R damage in rats. In male Wistar rats with and without edaravone treatment, intestinal damage was induced by clamping the superior mesenteric artery for 30 min, followed by reperfusion. Edaravone was administered via intravenous infusion at 5 min before reperfusion was achieved by removal of the clamp. The rats were sacrificed after 60 min of reperfusion. Luminal protein and hemoglobin concentrations were measured as an index of mucosal injury and histological examination of hematoxylin and eosin-stained sections was performed. Thiobarbituric acid (TBA)-reactive substances and tissue-associated myeloperoxidase (MPO) activity were measured in the mucosa as indicators of lipid peroxidation and neutrophil infiltration, respectively. The mucosal concentration of cytokine-induced neutrophil chemoattractant (CINC)-1 (a member of the IL-8 family) was determined by enzyme-linked immunosorbent assay (ELISA). Additionally, CINC-1 messenger RNA (mRNA) was measured by the reverse-transcription polymerase chain reaction (RT-PCR). As a result, the levels of luminal protein and hemoglobin, TBA-reactive substances, and MPO activity were all increased significantly by I-R injury, and these increases were significantly inhibited by treatment with edaravone. Multiple erosions and bleeding were observed macroscopically after the small intestine was exposed to I-R injury, and these changes were inhibited by administration of edaravone. Microscopic I-R damage was also reduced by treatment with edaravone. CINC-1 protein and CINC-1 mRNA were both increased by I-R injury, while edaravone markedly reduced the levels of both protein and mRNA. In summary, these results suggest that edaravone can protect the small intestine against I-R injury by scavenging oxygen-derived free radicals.

Animals↗

PubMed2003

Effects of edaravone on experimental brain injury in view of free radical reaction.

The purpose of this study is to clarify the influence of a novel free radical scavenger edaravone on experimental brain injury. Male Wistar rats were anesthetized with 1-2% halothane. Brain injury was produced using a controlled cortical impact injury device. Experimental rats were divided into 2 groups. In the edaravone group, edaravone (3 mg/kg) was twice administered intravenously for 30 minutes. In the saline group, saline solution was administered in the same way. This administration of edaravone or saline solution made it possible to evaluate the relative effects of edaravone by assessment of free radical reaction and water content. As a result, the level of oxygen free radicals at 50 minutes after brain injury was significantly lower in the edaravone group than in the saline group. The water content in the injured brain at 180 minutes was significantly lower in the edaravone group than in the saline group. Therefore, we propose that edaravone may be effective for treatment in head injury.

Animals↗

PubMed2006

Potent free radical scavenger, edaravone, suppresses oxidative stress-induced endothelial damage and early atherosclerosis.

OBJECTIVE: Effects of potent free radical scavenger, edaravone, on oxidative stress-induced endothelial damage and early atherosclerosis were investigated using animal models and cultured cells. METHODS AND RESULTS: Endothelial apoptosis was induced by 5-min intra-arterial exposure of a rat carotid artery with 0.01 mmol/L H(2)O(2). Edaravone treatment (10mg/kg i.p.) for 3 days suppressed endothelial apoptosis, as evaluated by chromatin staining of en face specimens at 24h, by approximately 40%. Similarly, edaravone dose-dependently inhibited H(2)O(2)-induce apoptosis of cultured endothelial cells in parallel with the inhibition of 8-isoprostane formation, 4-hydroxy-2-nonenal (4-HNE) accumulation and VCAM-1 expression. Next, apolipoprotein-E knockout mice were fed a high-cholesterol diet for 4 weeks with edaravone (10mg/kg i.p.) or vehicle treatment. Edaravone treatment decreased atherosclerotic lesions in the aortic sinus (0.18+/-0.01 to 0.09+/-0.01 mm(2), P<0.001) and descending aorta (5.09+/-0.86 to 1.75+/-0.41 mm(2), P<0.05), as evaluated by oil red O staining without influence on plasma lipid concentrations or blood pressure. Dihydroethidium labeling and cytochrome c reduction assay showed that superoxide anions in the aorta were suppressed by edaravone. Also, plasma 8-isoprostane concentrations and aortic nitrotyrosine, 4-HNE and VCAM-1 contents were decreased by edaravone treatment. CONCLUSIONS: These results suggest that edaravone may be a useful therapeutic tool for early atherosclerosis, pending the clinical efficacy.

Aldehydes↗

PubMed2004

Neuroprotection of edaravone on hypoxic-ischemic brain injury in neonatal rats.

Edaravone has an inhibitory effect on lipid peroxidation by scavenging free radicals and prevents vascular endothelial cell injury. We examined whether edaravone was effective on hypoxic-ischemic (HI) brain injury in immature brain or not using the Rice-Vannucci model. The initial dose, 3 mg/kg (0.05 ml) of edaravone, was injected intraperitoneally just before hypoxic exposure. Subsequently, the same dose was injected every 12 h until the animals were killed. Controls received saline injection as the same protocol. Macroscopic evaluation of brain injury revealed that the neuroprotective effect of edaravone on HI brain after 48 h post HI. TUNEL showed that edaravone injection decreased neurodegeneration. Quantitative analysis of cell death using H&E-stained 2.5 microm sections showed that there was a trend for both necrotic and apoptotic cells to decrease in edaravone injection group. Edaravone injection inhibited the release of cytochrome c from mitochondria to cytosol and caspase-3 activation in cortex and hippocampus between 24 and 168 h post HI. Our results suggest that edaravone is protective after HI insult in the immature brain by decreasing both apoptosis and necrosis and also by inhibiting mitochondrial injury.

Animals↗

PubMed2005

Edaravone protects against lung injury induced by intestinal ischemia/reperfusion in rat.

Intestinal ischemia/reperfusion (I/R) is a critical and triggering event in the development of distal organ dysfunction, frequently involving the lungs. Respiratory failure is a common cause of death and complications after intestinal I/R. In this study we investigated the effects of edaravone (3-methyl-1-phenyl-2-pyrazoline-5-one) on the prevention of lung injury induced by intestinal I/R in rats. Edaravone has been used for protection against I/R injury in patients with cerebral infarction. When rats were subjected to 180 min of intestinal ischemia, a high incidence of mortality was observed within 24 h. In this situation, intravenous administration of edaravone just before the start of reperfusion reduced the mortality in a dose-dependent manner. To examine the efficacy of edaravone on the lung injury induced by intestinal I/R in more detail, we performed 120 min of intestinal ischemia followed by 120 min of reperfusion. Edaravone treatment decreased the neutrophil infiltration, the lipid membrane peroxidation, and the expression of proinflammatory cytokine interleukin-6 mRNA in the lungs after intestinal I/R compared to the I/R-treated rat lungs without edaravone treatment. Histopathological analysis also indicated the effectiveness of edaravone. In conclusion, edaravone ameliorated the lung injury induced by intestinal I/R, resulting in a reduction in mortality.

Animals↗