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PubMed2003

A theoretical investigation on DPPH radical-scavenging mechanism of edaravone.

The mechanism of edaravone (3-methyl-1-phenyl-2-pyrazolin-5-one) to scavenge DPPH radical is clarified by density functional theory (DFT) calculations. It is revealed that H-atom-abstraction rather than electron-transfer reaction is involved in the radical-scavenging process of edaravone, and H-atom at position 4 is readily to be abstracted. The C-H bond dissociation enthalpy (BDE) of edaravone is higher than the O-H BDE of alpha-tocopherol, accounting for the activity difference between the two antioxidants. As substituents have little influence on the C-H BDE, 2-pyrazolin-5-one is recognized as the active center for edaravone.

Antipyrine↗

PubMed2005

Temporal effects of edaravone, a free radical scavenger, on transient ischemia-induced neuronal dysfunction in the rat hippocampus.

We examined the effect of a free radical scavenger edaravone on ischemia/reperfusion-induced impairment of long-term potentiation in the perforant path-dentate gyrus synapses of the rat hippocampus, as a measure of functional outcome 4 days after transient global ischemia (2-vessel occlusion, 10 min). Edaravone (3 and 10 mg/kg, i.v.) immediately after reperfusion (Day 0) alleviated ischemia-induced impairment of long-term potentiation in a dose-related manner, whereas treatment on Day 1 or 4 after reperfusion failed to rescue the impaired long-term potentiation. Edaravone administration on Day 0 also prevented the post-ischemic increase in hydroxyl radical formation and the expression of vascular endothelial growth factor, basic fibroblast growth factor and neuronal and inducible nitric oxide synthases of the hippocampus. Thus, edaravone protected the rat hippocampus from ischemia-induced long-term potentiation impairment with a therapeutic time window, suggesting that free radical formation after ischemia/reperfusion is a pivotal trigger of neurofunctional complications after global ischemic stroke.

Animals↗

PubMed2005

Post-exposure administration of edaravone attenuates noise-induced hearing loss.

We investigated the effects of the antioxidant edaravone against acoustic trauma in guinea pigs. Edaravone (1.722 x 10(-2) M) was infused into the right ear by an osmotic pump, and the left ear was untreated for control. Animals received edaravone 9 h before (-9 h group, n = 7) and 9 h (+9 h group, n = 8), 21 h (+21 h group, n = 7) and 33 h (+33 h group, n = 4) after 3-h exposure to 130-dB noise. Seven days after noise exposure, we examined the shift in auditory brainstem response thresholds and histopathologic characteristics of the sensory epithelia. The smallest shift in auditory brainstem response threshold and smallest proportion of missing outer hair cells were observed in the +9 h group. This result was supported by immunohistochemical analysis of 4-hydroxy-2-nonenal. Our data suggest that edaravone may be clinically effective in the treatment of acoustic trauma, especially if given within 21 h of noise exposure.

Aldehydes↗

PubMed2006

Treatment with edaravone improves the survival rate in renal warm ischemia-reperfusion injury using rat model.

Renal ischemia-reperfusion (I/R) injury during renal transplantation is a significant cause of renal dysfunction. The pathological role of free radicals in this process is a major concern. We investigated the effect of a free radical scavenger, edaravone (MCI-186), in renal I/R injury. Male Lewis rats (270 to 320 g) were used for the model. The right kidney was harvested and left renal artery and vein were clamped as laparotomy. The kidney was reperfused after 90 minutes of ischemia. Edaravone (10 mg/kg) was delivered intravenously before ischemia and after reperfusion to prevent the neutrophil activation. In the nontreatment I/R group, no rat survived beyond 4 days. However, in the edaravone I/R treatment group, one among five rats survived more than 7 days. These results suggested that treatment with edaravone ameliorated renal I/R injury, and that the agent has the potential to ameliorate preservation injury in renal transplantation.

Animals↗

PubMed2006

Investigation of the therapeutic effects of edaravone, a free radical scavenger, on amyotrophic lateral sclerosis (Phase II study).

Amyotrophic lateral sclerosis (ALS) is a rare disease involving selective and progressive degeneration and disappearance of motor neurons. Oxidative stress is believed to contribute to its pathogenesis. We have investigated the efficacy and safety of edaravone, a free radical scavenger previously approved for treatment of acute cerebral infarction, in ALS patients. Within an open trial design, 20 subjects with ALS received either 30 mg (5 subjects) or 60 mg (15 subjects) of edaravone via intravenous drip once per day. Two weeks of administration was followed by a two-week observation period. This four-week cycle was repeated six times. The primary endpoint was the change in the revised ALS functional rating scale (ALSFRS-R) score, while the secondary endpoint was 3-nitrotyrosine (3NT) level in cerebrospinal fluid (CSF). Efficacy was evaluated in the 60 mg group. During the six-month treatment period, the decline in the ALSFRS-R score (2.3+/-3.6 points) was significantly less than that in the six months prior to edaravone administration (4.7+/-2.1 points); the difference between the two was 2.4+/-3.5 points (Wilcoxon signed rank test, p = 0.039). In almost all patients, CSF 3NT, a marker for oxidative stress, was markedly reduced to almost undetectable levels at the end of the six-month treatment period. Data from the present study suggest that edaravone is safe and may delay the progression of functional motor disturbances by reducing oxidative stress in ALS patients.

Amyotrophic Lateral Sclerosis↗

PubMed2007

Does edaravone (MCI- 186) act as an antioxidant and a neuroprotector in experimental traumatic brain injury?

Edaravone (MCI-186) is a novel synthetic free radical scavenger intended to have neuroprotective effect against ischemic insult. It is currently used on patients with cerebral infarction. Here, we note beneficial pharmaceutical effects of edaravone in rat experimental traumatic brain injury. Under specific experimental conditions, edaravone minimized traumatic brain injury by functioning as a synthetic antioxidant. Clinical trials testing the efficacy of edaravone are warranted.

Animals↗

PubMed2004

Effect of edaravone on streptomycin-induced vestibulotoxicity in the Guinea pig.

OBJECTIVES/HYPOTHESIS: The effect of topical administration of edaravone to the inner ear was investigated in guinea pigs with streptomycin-induced vestibulotoxicity. METHODS: Vestibulotoxicity was induced in 20 animals by delivery of streptomycin into the inner ear through osmotic pump for 24 hours. Edaravone (n = 8, systemic administration group) or saline (n = 6, control group) was injected intraperitoneally once a day for 7 days or edaravone-soaked Gelfoam was placed on the round window before wound closure (n = 6, topical administration group). RESULTS: Yaw head tilt and spontaneous nystagmus were observed in all animals after the operation. The number of spontaneous nystagmus beats in the topical administration group was statistically less than that in other two groups at 12, 18, and 24 hours after the operation. CONCLUSION: The study results suggest that topical administration of edaravone better suppresses streptomycin-induced vestibulotoxicity than systemic administration.

Administration, Topical↗

PubMed2006

Edaravone inhibits JNK-c-Jun pathway and restores anti-oxidative defense after ischemia-reperfusion injury in aged rats.

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.

Aging↗

PubMed2006

[Homeostatic conditions affect the protective effect of edaravone on ischemic injury in neurons].

OBJECTIVE: To determine whether homeostatic conditions (pH, glycine or ion concentration) affect the protective effects of edaravone on ischemic injury in rat cortical neurons. METHODS: In cultured rat cortical neurons, the compositions in the experimental solutions were changed to mimic the disturbance of homeostasis after cerebral ischemia. In vitro ischemic injury was induced by oxygen-glucose deprivation (OGD) for 3 h and reperfusion for 12 h, and the neuron injury was evaluated by 3-(4, 5-dimethylthiazol-2yl)-2, 5-diphenyl tetrazolium bromide (MTT) reduction assay and lactate dehydrogenase (LDH) release. Effect of edaravone on OGD injury was observed in different experimental solutions. RESULT: In weak alkalified solution (pH 7.8) or the solution containing glycine (10 micromol/L), OGD injury became more serious; but in weak acidic (pH 6.5) or higher Mg(2+) (1.8 mmol/L) solutions, OGD injury was attenuated. Edaravone (1 micromol/L) reversed the injury in the solutions with pH 6.1,7.4 and 7.8 or the solution containing glycine, but did not show protective effect in the solution with pH 6.5 and the higher Mg(2+) or lower Ca(2+) solution. CONCLUSION: The changes of homeostatic conditions affect the severity of ischemic injury of neurons and the protective effect of edaravone.

Animals↗

PubMed2003

[The clinical effect of combination therapy with edaravone and sodium ozagrel for acute cerebral infarction].

Sodium ozagrel (ozagrel), a selective thromboxane A2 synthetase inhibitor, has been used for the treatment of various types of acute ischemic stroke, except cardioembolic stroke. Recently, edaravone, a novel free radical scavenger, has been approved for the treatment of acute ischemic stroke within 24 hours after onset. Since these two drugs differ in mode of action, we hypothesized that combination of both drugs would yield further improvement of the outcome of patients with acute ischemic stroke. The clinical efficacy of combination therapy with edaravone and ozagrel for acute ischemic stroke was studied retrospectively, and compared with that of ozagrel alone. A total of 62 patients who suffered acute ischemic stroke within 24 hours after onset during the 10-month period from June 2001 to March 2002, were treated with both edaravone and ozagrel (E-O group), while 76 patients during August 2000 to May 2001, were treated with ozagrel alone (O group). The rate of modified Rankin Scale (MRS) 0 and 1 at discharge in the total ischemic stroke and atherothrombotic stroke, was significantly higher in the E-O group than in the O group. The improvement in MRS also differed between E-O group and O group in total. The difference was significant in patients with atherothrombotic stroke but not in those with lacunar stroke. These results indicate that combination therapy with edaravone and ozagrel is more effective than mono-therapy with ozagrel for the treatment of acute ischemic, especially of atherothrombotic stroke.

Aged↗

PubMed2004

The clinical free radical scavenger, edaravone, protects cochlear hair cells from acoustic trauma.

It is known that reactive oxygen species have toxicity to the cochlea. We investigated the effect of edaravone, a free radical scavenger for clinical use, on the cochleae of guinea pigs subjected to acoustic trauma. We assessed auditory brainstem response (ABR) thresholds to evaluate cochlear function and observed the sensory epithelium. After noise exposure (130 dB SPL, 3 h), we observed that the auditory brainstem response threshold shift in edaravone-treated ears was significantly less than that in untreated ears. This result suggests that edaravone protected the cochleae from acoustic trauma.

Animals↗

PubMed2006

Protective effect of edaravone in inner-ear barotrauma in guinea pigs.

OBJECTIVE: The purpose of this study was to determine the protective effect of edaravone, a free radical scavenger, on inner-ear barotrauma (IEB) in guinea pigs, based on a hypothesis implicating free radicals in the development of IEB. MATERIALS AND METHODS: One hundred and twenty-five guinea pigs were divided into a control group and a pretreatment group. After auditory brainstem response (ABR) testing, the pretreatment group received 9.0 mg/kg intraperitoneal edaravone. Animals were exposed to pressure loading and then to further ABR testing. RESULTS: The incidence of IEB was 62.7 per cent in the control group and 42.9 per cent in the pretreatment group (p<0.01). The distributions of threshold elevation in the control group were 37.3 per cent (for 10 dB or less), 21.3 per cent (for 20-30 dB), 18.0 per cent (for 40-60 dB) and 23.4 per cent (for 70 dB or more), and those in the pretreatment group were 57.1 per cent, 19.1 per cent, 14.3 per cent and 9.5 per cent, for the same respective decibel levels (p<0.01). CONCLUSIONS: These results suggest that protective treatment with edaravone can significantly reduce both the incidence of IEB and the severity of the resultant ABR threshold elevation.

Animals↗

PubMed2005

A radical scavenger, edaravone, protects canine kidneys from ischemia-reperfusion injury after 72 hours of cold preservation and autotransplantation.

BACKGROUND: Cold ischemia-reperfusion (I/R) injury is a prominent cause of delayed graft function after kidney transplantation. Reactive oxygen species play a crucial role in I/R injury. Edaravone is a synthetic radical scavenger that has been used in acute stroke. Some animal experiments have revealed its beneficial effects against I/R injury, but its effects after cold preservation and transplantation of canine kidneys are unknown. METHODS: Female hybrid dogs weighing 11 to 13 kg were used. Under anesthesia, the left kidney was harvested. After 72 hr of preservation in cold histidine-tryptophan-ketoglutarate solution, autotransplantation was performed in the right iliac fossa, with contralateral nephrectomy. Animals were divided into control and treatment groups (n=6 per group). In the treatment group, edaravone was administered intravenously at harvest and at reperfusion (3 mg/kg) and in addition was added to the preservation solution (50 microM). RESULTS: Animal survival at 2 weeks was four of six in the control group and six of six in the treatment group. Compared with controls, treated animals had higher mean urine output, higher mean glomerular filtration rate, improved tubular cell function, lower mean serum creatinine, and lower renal vascular resistance. Biopsy specimens from treated animals showed less tubular cell damage and decreased P-selectin expression in endothelial cells. Lipid peroxidation of renal tissue and urinary excretion of 8-hydroxy-2'-deoxyguanosine were suppressed by the treatment. CONCLUSIONS: Edaravone reduced cold I/R injury in canine renal transplantation. The agent has the potential to ameliorate preservation injury in clinical transplantation.

Animals↗

PubMed2006

Edaravone inhibits the disease activity in rheumatoid arthritis.

A male patient with rheumatoid arthritis (RA) developed acute stroke and was treated with the free radical scavenger, edaravone. Polyarthralgia improved with a reduction in serum C-reactive protein concentration soon after the start of edaravone administration. The disease activity score 28 (DAS28) also decreased. Edaravone appears to be effective for the control of RA. The usefulness of this potentially novel therapeutic agent should be tested in a well designed randomized controlled trial.

Antipyrine↗

PubMed2005

Intrathecal edaravone, a free radical scavenger, is effective on inflammatory-induced pain in rats.

BACKGROUND: Free radicals have some roles in inflammation and systemic and local tissue injuries. (Free radical scavengers are neuroprotective against excitotoxic insults.) Therefore, we hypothesized that free radical scavenger would be analgesic on pain induced by excitotoxicity or inflammation. The purpose of this study was to investigate analgesic effects of intrathecally administered edaravone, a free radical scavenger, on thermal and inflammatory pain. METHODS: Sprague-Dawley rats were implanted with lumbar intrathecal catheters. Edaravone 0.05, 0.1, 0.5, and 1 mg per 20 microl or saline 20 microl (control) were administered intrathecally, and the withdrawal response to thermal stimulation to the tail (tail-flick test) or flinch responses to subcutaneous formalin injection into the hind paw (formalin test) were tested. General behaviour and motor function were also examined. In each dose group, eight rats were used. RESULTS: No dose-dependent analgesic effects were observed in the tail-flick test. However, dose-dependent analgesia was obtained in both phase 1 and 2 of the formalin test. The 50% effective dose values were 0.25 mg (95% confidence interval, 0.11-0.56 mg) in phase 1 and 0.25 mg (95% confidence interval, 0.061-1.05 mg) in phase 2. No behavioural side-effects nor motor dysfunction was observed, even with the maximum soluble dose (1 mg/20 microl). CONCLUSION: Intrathecally administered edaravone, a free radical scavenger, had analgesic effects on inflammatory-induced acute and facilitated pain but not on acute thermal pain, without any behavioural side-effects.

Animals↗

PubMed2005

Attenuation of extravasation of tissue plasminogen activator by the free radical scavenger, edaravone: evaluation in a rat thromboembolic stroke model.

OBJECTIVES AND METHODS: Deleterious effects of tissue plasminogen activator (tPA) have been described recently in experimental studies. For example, tPA can aggravate ischemic neuronal damage through its proteolytic activity. The present study was undertaken to examine whether or not the free radical scavenger, edaravone, could prevent the extravasation of tPA administered for the purpose of fibrinolysis in a rat model of thromboembolic stroke. RESULTS: Significant amounts of tPA were extravasated through the cerebral vessels even when early recanalization was induced by administering tPA at 30 minutes after the onset of schema. Edaravone significantly attenuated such extravasation of tPA. CONCLUSION: In acute ischemic stroke patients, combination therapy using tPA with edaravone appears to be a reasonable strategy for diminishing the negative effects of tPA.

Analysis of Variance↗

PubMed2003

Structure-activity relationship of 3-methyl-1-phenyl-2-pyrazolin-5-one (edaravone).

This paper describes the discovery of a novel free radical scavenger, 3-methyl-1-phenyl-2-pyrazolin-5-one (edaravone, 1), as a potent antioxidant agent against lipid peroxidation. The structure-activity relationship of edaravone indicated that lipophilic substituents were essential to show its lipid peroxidation-inhibitory activity. In vivo studies revealed that edaravone showed brain-protective activity in a transient ischemia model.

Animals↗

PubMed2007

Effects of edaravone on singlet oxygen released from activated human neutrophils.

The effects of edaravone, a curative agent for acute brain infarction, on singlet oxygen ((1)O2) released from activated human neutrophils were examined, and the effects were compared to those of histidine, a (1)O2 singlet oxygen scavenger. The neutrophils, stimulated with opsonized zymosan, released (1)O2 that was detected by chemiluminescence using a (1)O2 specific probe, trans-1-(2'-methoxyvinyl)pyrene. Edaravone dose-dependently suppressed the (1)O2 release with an IC(50) of approximately 0.3 microM, while the IC(50) of histidine was approximately 1 mM. This (1)O2 scavenging activity of edaravone might be involved in its curative effects on acute brain infarction.

Adult↗