Free Radical Scavenger Edaravone Research Articles

Decreased proteasome function increases oxidative stress in the early stage of pressure ulcer development

The aging process in the elderly results in heightened skin fragility associated with various disorders, including pressure ulcers (PUs). Despite the high incidence of PUs in the elderly population, there is a limited body of research specifically examining the impact of aging on the development of pressure ulcers. Therefore, investigating age-related physiological abnormalities is essential to elucidate the pathogenesis of PUs. Ischemia-reperfusion (I/R) injury and the subsequent oxidative stress caused by reactive oxygen species (ROS) play essential roles in the early stage of PUs. In this study, we used a mouse model of proteasomal dysfunction with an age-related phenotype to examine the role of proteasome activity in cutaneous I/R injury in vivo. Decreased proteasome function did not affect the expression of inflammatory cytokines and adhesion molecules in the I/R area in transgenic mice; however, proteasome inhibition increased oxidative stress that was not attenuated by activation of the oxidative stress response mediated by NF-E2-related factor 2 (Nrf2). In dermal fibroblasts (FCs) subjected to hypoxia-reoxygenation (H/R), proteasome inhibition induced oxidative stress and ROS production, and Nrf2 activation did not adequately upregulate antioxidant enzyme expression, possibly leading to antioxidant/oxidant imbalance. The free radical scavenger edaravone had protective effects against I/R injury in vivo and decreased oxidative stress in FCs treated with a proteasome inhibitor and subjected to H/R in vitro. The results suggest that the age-related decline in proteasome activity promotes cutaneous I/R injury-induced oxidative stress, and free radical scavengers may exert protective effects by preventing oxidative stress in the early stage of PUs in elderly patients with impaired proteasome function.

Preventive effect of free radical scavenger edaravone lotion on cyclophosphamide chemotherapy-induced alopecia.

We investigated the inhibitory effect of edaravone (EDR) lotion on chemotherapy-induced alopecia (CIA) to improve the quality of life for patients with cancer. Wistar rats were intraperitoneally injected with cyclophosphamide (CPA, 75mg/kg) to induce CIA and divided into six groups: (1) Control; (2) EDR 0%; (3) EDR 0.3%; (4) EDR 3%. The TUNEL-positive area was examined histologically, and mRNA expression levels of the apoptosis-related factors, such as B-cell/CLL lymphoma 2 (Bcl-2), and Bcl-2-associated X protein (Bax), were determined. In the three CPA-treated groups, a decrease in the coverage score (percentage of hairs covered) was observed from days 16 to 18. In addition, coverage scores on day 21, the last day of observation, showed a tendency for the suppression of hair loss to increase, though hair loss was observed in all groups. The coverage scores of the EDR 0.3% and 3% groups after day 17 were significantly higher than those of the EDR 0% group. The TUNEL-positive area of skin tissue on day 16 was extensive in the EDR 0% group and decreased in the EDR 0.3% and 3% groups. The mRNA expression ratio of Bcl-2/Bax on day 21 was maintained at the same level as that of the control group only in the EDR 3% group. This study confirmed the use of EDR lotion to inhibit hair loss, indicating that the clinical application of EDR lotion may improve the quality of life for patients with cancer and their willingness to undergo treatment.

Postoperative Intimal Hyperplasia: Review from My Research

AbstractPostoperative intimal hyperplasia is the major cause of the vein graft occlusion. It is very important to establish an animal model for the start of research. After my vascular surgery residency in Japan, I started my research work on postoperative intimal hyperplasia at the University of Wisconsin-Madison. My research showed that endothelial injury and monocyte infiltration is the key for postoperative intimal hyperplasia, which is very similar to Ross' pathogenesis of atherosclerosis as an inflammatory disease. Focusing on postoperative intimal hyperplasia as an inflammatory disease, especially on tumor necrosis factor-α, FR-167653 (tumor necrosis factor-α suppressive agent, inhibitor of p38 mitogen-activated protein kinase; Fujisawa Pharmaceutical Co., Ltd., Japan) is found to suppress postoperative intimal hyperplasia in a rat model by reducing serum monocyte chemoattractant protein-1 levels. However, FR-167653 is not commercially available today. Because endothelial injury is the first step of postoperative intimal hyperplasia, I investigated whether the free radical scavenger, edaravone (Radicut, Mitsubishi Tanabe Pharma Co., Japan), which alleviates the endothelial injury in vitro, can also suppress postoperative intimal hyperplasia. Moreover, the free radical scavenger edaravone (Radicut®, Mitsubishi Tanabe Pharma Co.) is also found to suppress postoperative intimal hyperplasia, by alleviating endothelial injury. In clinical settings, it is very important to detect postoperative intimal hyperplasia before its establishment. Hepatocyte growth factor is not only a hepatic growth factor but also a vascular endothelial growth factor. Recently, serum hepatocyte growth factor level was found to be a candidate biomarker for postoperative intimal hyperplasia in our rat model.

Hybrids of selective COX-2 inhibitors and active derivatives of edaravone as COX-2 selective NSAIDs with free radical scavenging activity: Design, synthesis and biological activities

Novel hybrids of selective COX-2 inhibitors (coxibs) and active derivatives of free radical scavenger edaravone were designed to overcome the risk of cardiovascular events and stroke increased by NSAIDs (nonsteroidal anti-inflammatory drugs) in this study. All the hybrids were assayed for the COX-2 inhibitory and DPPH (2, 2-diphenyl-1-picrylhydrazyl) free radical scavenging activities in vitro. Finally, we found a series of hybrids with good inhibitory activity and selectivity of COX-2 and excellent free radical scavenging activity in vitro. The most promising compound 6a (WYZ90) exhibited very potent COX-2 inhibitory activity (COX-2, IC50 = 75 nM), weak COX-1 inhibitory activity (COX-1, IC50 = 5734 nM), better free radical scavenging activity (DPPH, IC50 = 19.9 μM) than edaravone, moderate drug-likeness and ADME properties in silico, acceptable pharmacokinetic properties (T1/2 = 4.16 h, 10 mg/kg, o.p.) and oral bioavailability (F% = 36.03 %) in mice. In addition, compound WYZ90 showed similar analgesic activity to the selective COX-2 inhibitor celecoxib in acetic acid-induced mice and better antioxidant activity in Fe2+-induced lipid peroxidation in mouse liver tissue homogenate than edaravone. In conclusion, this study provided a novel class of coxibs containing edaravone moiety as COX-2 selective NSAIDs with free radical scavenging activity and the candidate compound WYZ90 showed not only similar selective COX-2 inhibitory and analgesic activity to celecoxib but also better free radical scavenging and antioxidant activity than edaravone.

Targeting Ferroptosis Attenuates Inflammation, Fibrosis, and Mast Cell Activation in Chronic Prostatitis.

Purpose Chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS) is a common urological disorder. Although ferroptosis is closely associated with inflammation, oxidative stress, and neuropathic pain, its role in CP/CPPS has not yet been elucidated. Therefore, we sought to explore the role and mechanism of ferroptosis in the prostatitis development. Methods The experimental autoimmune prostatitis (EAP) was established through intradermal immunization of prostate extract. Iron chelator deferoxamine (DFO) and free radical scavenger edaravone (EDA) were applied to evaluate the effects of ferroptosis inhibition on oxidative stress, ferroptosis, inflammation, fibrosis, and mast cell activation in the context of CP/CPPS. Results Increased generation of lipid peroxidation products (ROS and MDA) and decreased activities of antioxidant enzymes (SOD and CAT) suggested an aberrant oxidative stress status in EAP model. Elevated iron concentration was observed in the EAP model. Meanwhile, we discovered significant biological performances associated with ferroptosis in CP/CPPS, including the downregulation of the system Xc−/GPX4 axis and the upregulation of the ACSL4/LPCAT3 axis. EAP rats performed serious leukocyte infiltration, advanced inflammatory grade, and abnormal expression of inflammatory mediators. Abundant collagen deposition, enhanced RhoA, ROCK1, and α-SMA protein levels indicated that EAP rats were prone to suffer from stromal fibrosis compared with control group. An elevated number of degranulated mast cells and corresponding marker TPSB2 represented that mast cell-sensitized pain was amplified in the EAP model. Furthermore, reduction of NRF2/HO-1 indicated a vulnerability of EAP towards ferroptosis response. However, application of DFO and EDA had partially reversed the adverse influences mentioned above. Conclusion We first demonstrated that ferroptosis might be a crucial factor of chronic prostatitis progression. Inhibition of ferroptosis using DFO and EDA represented a promising approach for treating prostatitis by ameliorating inflammation, fibrosis, and mast cell activation.

Застосування поглинача вільних кисневих радикалів едаравону у хворих на субарахноїдальний крововилив (аналітичний огляд)

Актуальність. Поглинач вільних кисневих радикалів ксаврон (едаравон) сприяє зменшенню зони ішемічного ушкодження й істотному поліпшенню віддалених наслідків інсульту, а тому широко використовується в лікуванні ішемічного інсульту. Проте роль едаравону в лікуванні хворих на субарахноїдальний крововилив досі не з’ясована. Мета: дослідити можливість та ефективність застосування поглинача вільних кисневих радикалів ксаврону (едаравону) в комплексі терапії у хворих на субарахноїдальний крововилив. Матеріали та методи. Було проведено пошук досліджень та систематичних оглядів за ключовими словами: «гострий інсульт»; «субарахноїдальний крововилив», «геморагічна трансформація», «едаравон» у базі даних Google Scholar, опублікованих за період з 2003 по 2021 рік. Результати. Застосування едаравону у хворих на субарахноїдальний крововилив супроводжувалося активацією протизапальних і зниженням прозапальних пептидів, активацією антиапоптозних механізмів, зниженням перекисного окислення ліпідів і зменшенням окислювальної травми, зменшенням проникності гематоенцефалічного бар’єра та вираженості набряку головного мозку. Висновки. Основні ефекти едаравону (ксаврону) сприяли зменшенню неврологічного дефіциту, прискоренню швидкості відновлення неврологічних порушень та покращенню функціональних результатів лікування. Таким чином, введення едаравону у хворих на субарахноїдальний крововилив є вірогідно ефективним та безпечним.

Application of a free radical scavenger edaravone in patients with hemorrhagic stroke

BACKGROUND. The free radical scavenger edaravone helps to reduce the area of ischemic injury and improve the longterm effects of stroke, and is therefore widely used in the treatment of ischemic stroke. However, the role of edaravone in the treatment of hemorrhagic stroke patients has not yet been clarified.
 OBJECTIVE. To investigate the feasibility and effectiveness of the use of the free radical scavenger edaravone in the treatment of patients with acute hemorrhagic stroke.
 MATERIALS AND METHODS. A search was conducted for studies and systematic reviews for the keywords “acute stroke”, “intracerebral hemorrhage”, “subarachnoid hemorrhage”, “hemorrhagic transformation”, “edaravone” in the Google Scholar database published between 2003 and 2020.
 RESULTS. The use of edaravone in patients with intracerebral hemorrhage was accompanied by activation of anti-inflammatory and reduction of pro-inflammatory peptides, activation of anti-apoptotic mechanisms, reduction of lipid peroxidation and oxidative trauma, reduction of permeability of the hematocenosis.
 CONCLUSIONS. The main effects of edaravone have been to reduce neurological deficits, accelerate the rate of recovery of neurological disorders, and improve functional outcomes. Thus, the introduction of edaravone in patients with hemorrhagic stroke has proven to be reliably effective and safe.

Real‐world safety of the novel, free radical scavenger edaravone for amyotrophic lateral sclerosis patients: Data from the post‐marketing surveillance SUNRISE Japan

AbstractBackgroundTreatment options for amyotrophic lateral sclerosis (ALS) are limited. SUNRISE Japan is an ongoing post‐marketing surveillance evaluating the long‐term efficacy and safety of edaravone, a novel neuroprotectant agent, and free radical scavenger, in patients with ALS.AimThis study aims to describe the real‐word safety results of ALS patients enrolled in SUNRISE Japan.MethodsPatients diagnosed with ALS and prescribed edaravone for the first time during the surveillance period were included. Patients were prescribed edaravone according to the prescribing information. The incidence of adverse drug reactions (ADRs) reported up to 1 year of follow‐up was evaluated.ResultsOf 805 patients enrolled up to April 2020, 800 were included in the safety analysis set. Patients had a mean age of 66.3 years, 55.1% were male, and they had a mean disease duration of 1.8 years. In total, 97 patients (12.1%) reported at least one ADR, with a total of 148 ADR events reported. Thirty patients (3.8%) reported at least one serious ADR with a total of 42 serious ADR events reported. Hepatic function abnormal was the most frequently reported ADR, with an incidence of 4.4% (35/800). A higher incidence of ADRs was observed in patients with percent forced vital capacity ≥80%, and those with previous/concomitant treatment with riluzole.ConclusionIn this surveillance study, hepatic ADRs were the most frequently reported events. These ADRs have also been reported previously in patients receiving standard therapy. No new safety concerns were raised with real‐world use of edaravone.

ACUTE ISCHEMIC STROKE IN WOMEN: EFFICACY OF THE FREE RADICAL SCAVENGER EDARAVONE

The aim: To investigate the effectiveness of usage of the free radical scavenger Edaravone in the therapy of women with AIS. Materials and methods: A prospective study was conducted of 48 women with AIS, divided into two groups. Patients in the first group (n = 36) were treated with edaravone 30 mg twice a day intravenously. Neuroprotectors were not used in the control group (n = 12). Clinical-instrumental and neurological examination (Glasgow scale (SCG), FOUR, NIHSS, and neuronspecific enolase (NSE) levels) were performed on all patients. Results: The mean FOUR score in the 1th group increased from 11.04±0.85 to 15.47±0.63 points against 11.39±0.56 to 13.46±1.49 in the control group (pp<0.05). The level of NSE in control group patients increased 10-fold (from 9.2 to 96.4 ng/ml, p<0.01). Subsequently, there was a rapid decrease in NSE level in 1th group, and in the control group until 10 days of treatment, the level of NSE did not reach the reference values (p p<0.05). Conclusions: The introduction of edaravone in women with AIS results in positive results already in the acute period of the disease. The use of edaravon was significantly effective on the FOUR scale and the dynamics of NSE levels.

Intravenous Edaravone plus Therapeutic Hypothermia Offers Limited Neuroprotection in the Hypoxic-Ischaemic Newborn Piglet

Background: Therapeutic hypothermia (TH) is a standard therapy for neonatal hypoxic-ischaemic encephalopathy. One potential additional therapy is the free radical scavenger edaravone (EV; 3-methyl-1-phenyl-2-pyrazolin-5-one). Objectives and Methods: This study aimed to compare the neuroprotective effects of edaravone plus therapeutic hypothermia (TH + EV) with those of TH alone after a hypoxic-ischaemic insult in the newborn piglet. Anaesthetized piglets were subjected to 40 min of hypoxia (3–5% inspired oxygen), and cerebral ischaemia was assessed using cerebral blood volume. Body temperature was maintained at 39.0 ± 0.5°C in the normothermia group (NT, n = 8) and at 33.5 ± 0.5°C (24 h after the insult) in the TH (n = 7) and TH + EV (3 mg/kg intravenous every 12 h for 3 days after the insult; n = 6) groups under mechanical ventilation. Results: Five days after the insult, the mean (standard deviation) neurological scores were 10.9 (5.7) in the NT group, 17.0 (0.4) in the TH group (p = 0.025 vs. NT), and 15.0 (3.9) in the TH + EV group. The histopathological score of the TH + EV group showed no significant improvement compared with that of the other groups. Conclusion: TH + EV had no additive neuroprotective effects after hypoxia-ischaemia in neurological and histopathological assessments.

Protective effects of edaravone on white matter pathology in a novel mouse model of Alzheimer’s disease with chronic cerebral hypoperfusion

White matter lesions (WMLs) caused by cerebral chronic hypoperfusion (CCH) may contribute to the pathophysiology of Alzheimer’s disease (AD). However, the underlying mechanisms and therapeutic approaches have yet to be totally identified. In the present study, we investigated a potential therapeutic effect of the free radical scavenger edaravone (EDA) on WMLs in our previously reported novel mouse model of AD (APP23) plus CCH with motor and cognitive deficits. Relative to AD with CCH mice at 12 months (M) of age, EDA strongly improved CCH-induced WMLs in the corpus callosum of APP23 mice at 12 M by improving the disruption of white matter integrity, enhancing the proliferation of oligodendrocyte progenitor cells, attenuating endothelium/astrocyte unit dysfunction, and reducing neuroinflammation and oxidative stress. The present study demonstrates that the long-term administration of EDA may provide a promising therapeutic approach for WMLs in AD plus CCH disease with cognitive deficits.

Improvement of a decreased anti-oxidative activity by edaravone in amyotrophic lateral sclerosis patients

BackgroundThe free radical scavenger edaravone is a proven neuroprotective drug for patients with amyotrophic lateral sclerosis (ALS). Our objective was to evaluate the therapeutic effects of edaravone for oxidative stress and anti-oxidative activity in ALS patients. MethodsTwenty-two ALS patients with a disease duration of 2 years, treated by edaravone, and 25 control participants were evaluated according to their clinical scores, including ALS functional rating scale-revised (ALSFRS-R), and serum and cerebrospinal fluid (CSF) markers of oxidative stress dROM and anti-oxidative activity OXY. ResultsSerum and CSF markers of anti-oxidative activity OXY were significantly decreased in ALS patients at pre-treatment compared with controls (##p < .01), which was improved in the course of edaravone treatment. Both serum and CSF OXY were significantly correlated with ALS clinical scores including ALSFRS-R (*p < .05, **p < .01, ***p < .001). Furthermore, serum OXY at pre-treatment was significantly correlated with a change in the ALSFRS-R score in the sixth cycle of edaravone treatment (*p < .05). ConclusionsThe present study suggests significant correlations between anti-oxidative activity and ALS clinical severity, and the therapeutic efficacy of edaravone for decreased anti-oxidative activity in ALS.

Edaravone attenuates myocyte apoptosis through the JAK2/STAT3 pathway in acute myocardial infarction

Basic and clinical studies have demonstrated that the free radical scavenger edaravone has cytoprotective effects on acute myocardial infarction (AMI) but the underlying mechanism is not fully understood. The aim of this research is to explore the effect of edaravone on the apoptotic process involving the JAK2/STAT3 signaling pathway. AMI in rats was established by left anterior descending coronary artery ligation. Two hours after AMI model established rats were treated with edaravone, edaravone plus AG490, physiological saline, respectively. We detected antioxidant effects by reduced glutathione (GSH), glutathione S-transferase (GST), and Glutathione Peroxidase (GSHPx) Activity. The expressions of t-JAK2, p-JAK2, t-STAT3, p-STAT3 and cleaved caspase-3 were examined by western blot. The mRNA levels for Bcl-2, Bax, Fas, and FasL were measured by RT-PCR and apoptosis was assessed by TUNEL. Edaravone significantly improved hemodynamics after AMI (p < 0.05) and reduced the total infarct volumes (p < 0.05). Compared with Sham rats, the mRNA of Bax, Fas, and FasL increased in different degrees in the AMI group, however, the mRNA of Bcl-2 and the ratio of Bcl-2/Bax decreased, especially the myocardial apoptosis index significantly increased in AMI hearts (all p < 0.05). After treatment with edaravone, the mRNA levels of Bcl-2 and the ratio of Bcl-2/Bax significantly upregulated whereas Bax, Fas, FasL apparently decreased, and the protein expressions of p-JAK2 and p-STAT3 dramatically increased (p < 0.05). In addition, cotreatment with JAK2 inhibitor AG490 abolished the effects of edaravone. We conclude that edaravone attenuated myocardial apoptosis induced by AMI via JAK2/STAT3 signaling pathway.

Edaravone inhibits procaspase-3 denitrosylation and activation through FasL-Trx2 pathway in KA-induced seizure.

Previous studies have demonstrated that excessive free radicals play an essential role in the initiation and progression of epilepsy and that a novel exogenous free radical scavenger edaravone (Ed) exerts some neuroprotective effects on seizure-induced neuronal damage. The purpose of this study was to elucidate the possible molecular mechanisms of Ed associated with procaspase-3 denitrosylation and activation through the FasL-Trx2 pathway in seizures rats. In this study, we investigated the effects of Ed on the regulation of the combination of Fas ligand/Fas receptor and the major components of the death-inducing signaling complex (DISC) in the hippocampus of kainic acid (KA)-treated Sprague Dawley (SD) rats. Treatment with Ed can attenuate the increased expression of FasL induced by KA and prevent procaspase-3 denitrosylation and activation via suppression of the FasL-Trx2 signaling pathway, which alleviates the neuronal damage in seizures. These results provide experimental evidence that Ed functions by preventing the denitrosylation and activation of procaspase-3 and that Ed acts as a therapeutic option for epilepsy.

Edaravone reduces oxidative stress and intestinal cell apoptosis after burn through up-regulating miR-320 expression

BackgroundIntestinal mucosa barrier dysfunction after burn injury is an important factor for causing mortality of burn patients. The current study established a burn model in rats and used a free radical scavenger edaravone (ED) to treat the rats, so as to investigate the effect of edaravone on intestinal mucosa barrier after burn injury.MethodsAnesthetized rats were subjected to 40% total body surface area water burn immediately, followed by treatment with ED, scrambled antagomir, or antagomiR-320. Intestinal mucosa damage was observed by hematoxylin-eosin staining and graded by colon mucosal damage index (CMDI) score. The contents of total sulfhydryl (TSH), superoxide dismutase (SOD), catalase (CAT) and malondialdehyde (MDA) were determined by spectrophotometry. Cell apoptosis, protein relative expression,and the in situ expressions of p-Akt and p-Bad were detected by flow cytometry, Western blotting and immunohistochemistry, respectively. The miR-320 expression was determined by quantitative real-time polymerase chain reaction.ResultsED alleviated intestinal mucosal damage caused by burn injury, down-regulated the levels of MDA, cytochrome C, cleaved caspase-9 and cleaved caspase-3, but up-regulated the levels of TSH, SOD, CAT and Bcl-2. We also found that ED could reduce oxidative stress, inhibit cell apoptosis, increase the expressions of p-Akt, p-Bad and miR-320, and decrease PTEN expression. PTEN was predicted to be the target gene for miR-320, and cell apoptosis could be promoted by inhibiting miR-320 expression.ConclusionED regulates Akt/Bad/Caspase signaling cascade to reduce apoptosis and oxidative stress through up-regulating miR-320 expression and down-regulating PTEN expression, thus protecting the intestinal mucosal barrier of rats from burn injury.

Neuroprotective therapy both for als and acute ischemic stroke

Although the underlying mechanism of amyotrophic lateral sclerosis (ALS) has not yet been fully clarified, several reports have implicated the involvement of oxidative stress under selective death of motor neurons in both ALS patients and animal models. Edaravone is a free radical scavenger, which is the first clinical drug for neuroprotection in the world which has been approved from 2001 in most ischemic stroke patients in Japan, and some of China and India. A recent multicenter prospective double-blind placebo-control clinical trial with edaravone for ALS patients conducted in Japan showed a positive effect for delaying the clinical score (ALS FRS-R) during the 24 weeks of examination. This clinical benefit of edaravone was shown as an add-on therapy after anti-glutamatergic riluzole. These data strongly suggest a potential underlying mechanism of oxidative stress in ALS and a clinical delay by a free radical scavenger. These translational studies on a free radical scavenger Edaravone allowed governmental permissions both for acute ischemic stroke after 2001 and for ALS after 2015. Edaravone was approved for ALS at 2015 in Japan, 2016 in Korea, and 2017 in USA. Use of Edaravone greatly reduced hemorrhagic transformation accompanied by tissue plasminogen activator (tPA) treatment, and may also extend therapeutic time window with tPA therapy for more than 4.5 h in human stroke patients for preserving neurovascular unit (NVU). An intensive Edaravine therapy for 3 days now showed a favorite recovery in 3 European countries.

Chronic cerebral hypoperfusion alters amyloid-β transport related proteins in the cortical blood vessels of Alzheimer’s disease model mouse

Abnormal accumulation of amyloid-β (Aβ) peptide defines progression of Alzheimer’s disease (AD) pathology in brain. Here, we investigated expressive changes of two main Aβ transport receptors low-density lipoprotein receptor related protein-1 (LRP1) and receptor for advanced glycation end products (RAGE) in a novel AD mice (APP23) with chronic cerebral hypoperfusion (CCH) model, moreover, examined a protective effect of a free radical scavenger edaravone (Eda). In contrast to wild type (WT) and APP23 mice, CCH strongly accelerated abnormal Aβ40 depositions and cerebral amyloid angiopathy (CAA) pathology, increased both LRP1 and RAGE expressions in brain parenchyma, while a decrease of LRP1 and an increase of RAGE were observed in vascular endothelial cells at age 12 months (M) of AD mice. Furthermore, CCH strongly increased expressions of two hypoxia-related proteins hypoxia inducible factor-1α (HIF-1α) and heme oxygenase-1 (HO-1), two oxidative-related proteins 4-hydroxy-2-nonenal (4-HNE) and 8-hydroxy-2′-deoxyguanosine (8-OHdG), and decreased both two vital nutrient transporter proteins major facilitator super family domain containing 2a (Mfsd2a) and glucose transporter 1 (Glut1) expressions. Such the above abnormal pathological changes were significantly ameliorated by edaravone treatment. The present study demonstrated that CCH strongly enhanced primary AD pathology causing double imbalances of Aβ efflux and influx transport related proteins in the cortical blood vessels in AD mice, and that such a neuropathologic abnormality was greatly ameliorated by Eda.

Edaravone for the treatment of amyotrophic lateral sclerosis

ABSTRACTIntroduction: Amyotrophic lateral sclerosis (ALS) is a progressive fatal disorder that affects all skeletal muscles, leading to death, mostly within 2–4 years from onset. To date, the anti-glutamatergic drug riluzole is the only drug that has been approved for the treatment of this disease; however, its efficacy is modest. Oxidative stress is considered to be involved in the pathology of ALS, and in this regard, the free radical scavenger edaravone, which was originally developed for the treatment of acute ischemic stroke, has also been developed for the treatment of ALS.Areas covered: This review describes the pharmacological properties of edaravone and the progress of clinical trials conducted to evaluate the efficacy of this drug in the treatment of ALS.Expert commentary: Edaravone is the first drug to show effective inhibition of the motor function deterioration experienced by ALS patients with early-stage probable and definite types. In order to effectively prolong the quality of motor function, edaravone treatment should be initiated as soon as the diagnosis has been confirmed; however, the respiratory function should be carefully monitored when a deterioration in breathing capacity is detected.

Enhanced oxidative stress and the treatment by edaravone in mice model of amyotrophic lateral sclerosis.

Oxidative stress is associated with the degeneration of both motor neurons and skeletal muscles in amyotrophic lateral sclerosis (ALS). A free radical scavenger edaravone has been proven as a therapeutic drug for ALS patients, but the neuroprotective mechanism for the oxidative stress of ALS has not been fully investigated. In this study, we investigated oxidative stress in ALS model mice bearing both oxidative stress sensor nuclear erythroid 2-related factor 2 (Nrf2) and G93A-human Cu/Zn superoxide dismutase (Nrf2/G93A) treated by edaravone. In vivo Nrf2 imaging analysis showed the accelerated oxidative stress both in spinal motor neurons and lower limb muscles of Nrf2/G93A mice according to disease progression in addition to the enhancement of serum oxidative stress marker dROMS. These were significantly alleviated by edaravone treatment accompanied by clinical improvements (rotarod test). The present study suggests that in vivo optical imaging of Nrf2 is useful for detecting oxidative stress in ALS, and edaravone alleviates the degeneration of both motor neurons and muscles related to oxidative stress in ALS patients.

Quinolinic Acid-Induced Huntington Disease-Like Symptoms Mitigated by Potent Free Radical Scavenger Edaravone—a Pilot Study on Neurobehavioral, Biochemical, and Histological Approach in Male Wistar Rats

In this study, we demonstrated for the first time the neuroprotective role of edaravone (Eda) (5 and 10mg/kg b.w.), a potent free radical scavenger against the unilateral stereotaxic induction of quinolinic acid (QA) (300nm/4μl saline)-induced Huntington disease (HD)-like symptoms in behavioral, biochemical, and histological features in male Wistar rats striatum. QA induction, which mimics the early stage of HD, commonly causes oxidative stress to the cell and decreases the antioxidant defense mechanism by altering the level of lipid peroxidation (LPO), protein carbonyls, and nitrate concentration (NO) and the activities of glutathione family enzymes (GPx, GST, GR) and acetyl choline esterase concentration (AChE) which was found to be ameliorated by Eda treatment in both the tested doses 5 and 10mg/kg b.w. in the significance of P <0.05 and P <0.01, respectively. Finally histopathological analysis by hematoxylin and eosin stain concluded the promising neurodefensive role of Eda in rat striatum at the dosage of 10mg/kg b.w., with the decreased tissue damage and the number of damaged granular cells when compared to QA-induced groups.