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Journal of Neuroinflammation Feb 2022The inflammation and oxidative stress (OS) have been considered crucial components of the pathogenesis of depression. Edaravone (EDA), a free radical scavenger,...
BACKGROUND
The inflammation and oxidative stress (OS) have been considered crucial components of the pathogenesis of depression. Edaravone (EDA), a free radical scavenger, processes strong biological activities including antioxidant, anti-inflammatory and neuroprotective properties. However, its role and potential molecular mechanisms in depression remain unclear. The present study aimed to investigate the antidepressant activity of EDA and its underlying mechanisms.
METHODS
A chronic social defeat stress (CSDS) depression model was performed to explore whether EDA could produce antidepressant effects. Behaviors tests were carried out to examine depressive, anxiety-like and cognitive behaviors including social interaction (SI) test, sucrose preference test (SPT), open field test (OFT), elevated plus maze (EPM), novel object recognition (NOR), tail suspension test (TST) and forced swim test (FST). Hippocampal and medial prefrontal cortex (mPFC) tissues were collected for Nissl staining, immunofluorescence, targeted energy metabolomics analysis, enzyme-linked immunosorbent assay (ELISA), measurement of MDA, SOD, GSH, GSH-PX, T-AOC and transmission electron microscopy (TEM). Western blotting (WB) and quantitative real-time polymerase chain reaction (qRT-PCR) detected the Sirt1/Nrf2/HO-1/Gpx4 signaling pathway. EX527, a Sirt1 inhibitor and ML385, a Nrf2 inhibitor were injected intraperitoneally 30 min before EDA injection daily. Knockdown experiments were performed to determine the effects of Gpx4 on CSDS mice with EDA treatment by an adeno-associated virus (AAV) vector containing miRNAi (Gpx4)-EGFP infusion.
RESULTS
The administrated of EDA dramatically ameliorated CSDS-induced depressive and anxiety-like behaviors. In addition, EDA notably attenuated neuronal loss, microglial activation, astrocyte dysfunction, oxidative stress damage, energy metabolism and pro-inflammatory cytokines activation in the hippocampus (Hip) and mPFC of CSDS-induced mice. Further examination indicated that the application of EDA after the CSDS model significantly increased the protein expressions of Sirt1, Nrf2, HO-1 and Gpx4 in the Hip. EX527 abolished the antidepressant effect of EDA as well as the protein levels of Nrf2, HO-1 and Gpx4. Similarly, ML385 reversed the antidepressant and anxiolytic effects of EDA via decreased expressions of HO-1 and Gpx4. In addition, Gpx4 knockdown in CSDS mice abolished EDA-generated efficacy on depressive and anxiety-like behaviors.
CONCLUSION
These findings suggest that EDA possesses potent antidepressant and anxiolytic properties through Sirt1/Nrf2/HO-1/Gpx4 axis and Gpx4-mediated ferroptosis may play a key role in this effect.
Topics: Animals; Anxiety; Behavior, Animal; Depression; Edaravone; Hippocampus; Mice; NF-E2-Related Factor 2; Sirtuin 1; Stress, Psychological
PubMed: 35130906
DOI: 10.1186/s12974-022-02400-6 -
Drug discovery and amyotrophic lateral sclerosis: Emerging challenges and therapeutic opportunities.Ageing Research Reviews Jan 2023Amyotrophic lateral sclerosis (ALS) is characterized by the degeneration of upper and lower motor neurons (MNs) leading to paralysis and, ultimately, death by... (Review)
Review
Amyotrophic lateral sclerosis (ALS) is characterized by the degeneration of upper and lower motor neurons (MNs) leading to paralysis and, ultimately, death by respiratory failure 3-5 years after diagnosis. Edaravone and Riluzole, the only drugs currently approved for ALS treatment, only provide mild symptomatic relief to patients. Extraordinary progress in understanding the biology of ALS provided new grounds for drug discovery. Over the last two decades, mitochondria and oxidative stress (OS), iron metabolism and ferroptosis, and the major regulators of hypoxia and inflammation - HIF and NF-κB - emerged as promising targets for ALS therapeutic intervention. In this review, we focused our attention on these targets to outline and discuss current advances in ALS drug development. Based on the challenges and the roadblocks, we believe that the rational design of multi-target ligands able to modulate the complex network of events behind the disease can provide effective therapies in a foreseeable future.
Topics: Humans; Amyotrophic Lateral Sclerosis; Edaravone; Riluzole; Oxidative Stress; Drug Discovery
PubMed: 36402404
DOI: 10.1016/j.arr.2022.101790 -
JAMA Neurology Feb 2022Intravenous edaravone is approved as a disease-modifying drug for patients with amyotrophic lateral sclerosis (ALS), but evidence for efficacy is limited to short-term... (Randomized Controlled Trial)
Randomized Controlled Trial
IMPORTANCE
Intravenous edaravone is approved as a disease-modifying drug for patients with amyotrophic lateral sclerosis (ALS), but evidence for efficacy is limited to short-term beneficial effects shown in the MCI186-ALS19 study in a subpopulation in which efficacy was expected.
OBJECTIVE
To evaluate the long-term safety and effectiveness of intravenous edaravone therapy for patients with ALS in a real-world clinical setting.
DESIGN, SETTING, AND PARTICIPANTS
Multicenter, propensity score-matched cohort study conducted between June 2017 and March 2020 at 12 academic ALS referral centers associated with the German Motor Neuron Disease Network. Of 1440 patients screened, 738 were included in propensity score matching. Final analyses included 324 patients with ALS comprising 194 patients who started intravenous edaravone treatment (141 received ≥4 consecutive treatment cycles; 130 matched) and 130 propensity score-matched patients with ALS receiving standard therapy. All patients had probable or definite ALS according to the El Escorial criteria, with disease onset between December 2012 and April 2019. Subgroups were defined by applying the MCI186-ALS19 study inclusion criteria to evaluate whether patients would have been considered eligible (EFAS) or ineligible (non-EFAS).
EXPOSURES
Intravenous edaravone plus riluzole vs riluzole only.
MAIN OUTCOMES AND MEASURES
Patient characteristics and systematic safety assessment for patients who received at least 1 dose of intravenous edaravone. Effectiveness assessment of edaravone was conducted among patients who received at least 4 treatment cycles compared with propensity score-matched patients with ALS who received only standard therapy. Primary outcome was disease progression measured by decrease in the ALS Functional Rating Scale-Revised (ALSFRS-R) score. Secondary outcomes were survival probability, time to ventilation, and change in disease progression before vs during treatment. To account for the matched design, patients receiving edaravone and their corresponding matched controls were regarded as related samples in disease progression analyses; stratification for propensity score quintiles was used for survival probability and time to ventilation analyses.
RESULTS
A total of 194 patients started intravenous edaravone treatment; 125 (64%) were male, and the median age was 57.5 years (IQR, 50.7-63.8 years). Potential adverse effects were observed in 30 cases (16%), most notably infections at infusion sites and allergic reactions. Disease progression among 116 patients treated for a median of 13.9 months (IQR, 8.9-13.9 months) with edaravone did not differ from 116 patients treated for a median of 11.2 months (IQR, 6.4-20.0 months) with standard therapy (ALSFRS-R points/month, -0.91 [95% CI, -0.69 to -1.07] vs -0.85 [95% CI, -0.66 to -0.99]; P = .37). No significant differences were observed in the secondary end points of survival probability, time to ventilation, and change in disease progression. Similarly, outcomes between patients treated with edaravone and matched patients did not differ within the EFAS and non-EFAS subgroups.
CONCLUSIONS AND RELEVANCE
This cohort study using propensity score matching found that, although long-term intravenous edaravone therapy for patients with ALS was feasible and mainly well tolerated, it was not associated with any disease-modifying benefit. Intravenous edaravone may not provide a clinically relevant additional benefit compared with standard therapy alone.
Topics: Administration, Intravenous; Amyotrophic Lateral Sclerosis; Cohort Studies; Disease Progression; Double-Blind Method; Edaravone; Female; Humans; Male; Middle Aged; Patient Compliance; Patient Satisfaction; Propensity Score; Respiration, Artificial; Risk Assessment; Treatment Outcome
PubMed: 35006266
DOI: 10.1001/jamaneurol.2021.4893 -
Stroke Mar 2021Edaravone dexborneol, comprised of 2 active ingredients, edaravone and (+)-borneol, has been developed as a novel neuroprotective agent with synergistic effects of... (Comparative Study)
Comparative Study Randomized Controlled Trial
BACKGROUND AND PURPOSE
Edaravone dexborneol, comprised of 2 active ingredients, edaravone and (+)-borneol, has been developed as a novel neuroprotective agent with synergistic effects of antioxidant and anti-inflammatory in animal models. The present clinical trial aimed at testing the effects of edaravone dexborneol versus edaravone on 90-day functional outcome in patients with acute ischemic stroke (AIS).
METHODS
A multicenter, randomized, double-blind, comparative, phase III clinical trial was conducted at 48 hospitals in China between May 2015 and December 2016. Inclusion criteria included patients diagnosed as AIS, 35 to 80 years of age, National Institutes of Health Stroke Scale Score between 4 and 24, and within 48 hours of AIS onset. AIS patients were randomized in 1:1 ratio into 2 treatment arms: 14-day infusion of edaravone dexborneol or edaravone injection. The primary end point was the proportion of patients with modified Rankin Scale score ≤1 on day 90 after randomization.
RESULTS
One thousand one hundred sixty-five AIS patients were randomly allocated to the edaravone dexborneol group (n=585) or the edaravone group (n=580). The edaravone dexborneol group showed significantly higher proportion of patients experiencing good functional outcomes on day 90 after randomization, compared with the edaravone group (modified Rankin Scale score ≤1, 67.18% versus 58.97%; odds ratio, 1.42 [95% CI, 1.12-1.81]; =0.004). The prespecified subgroup analyses indicated that a greater benefit was observed in female patients than their male counterparts (2.26, 1.49-3.43 versus 1.14, 0.85-1.52).
CONCLUSIONS
When edaravone dexborneol versus edaravone was administered within 48 hours after AIS, 90-day good functional outcomes favored the edaravone dexborneol group, especially in female patients. Registration: URL: https://www.clinicaltrials.gov. Unique identifier: NCT02430350.
Topics: Adult; Aged; Aged, 80 and over; Animals; Anti-Inflammatory Agents; Antioxidants; Camphanes; Double-Blind Method; Edaravone; Female; Humans; Ischemic Stroke; Male; Middle Aged; Neuroprotective Agents; Treatment Outcome
PubMed: 33588596
DOI: 10.1161/STROKEAHA.120.031197 -
Drugs Sep 2022Amyotrophic lateral sclerosis (ALS) is a rapidly progressive neurodegenerative disorder involving loss of upper and lower motor neurons, with most cases ending in death... (Review)
Review
Amyotrophic lateral sclerosis (ALS) is a rapidly progressive neurodegenerative disorder involving loss of upper and lower motor neurons, with most cases ending in death within 3-5 years of onset. Several molecular and cellular pathways have been identified to cause ALS; however, treatments to stop or reverse disease progression are yet to be found. Riluzole, a neuroprotective agent offering only a modest survival benefit, has long been the sole disease-modifying therapy for ALS. Edaravone, which demonstrated statistically significant slowing of ALS disease progression, is gaining approval in an increasing number of countries since its first approval in 2015. Sodium phenylbutyrate and taurursodiol (PB-TURSO) was conditionally approved in Canada in 2022, having shown significant slowing of disease progression and prolonged survival. Most clinical trials have focused on testing small molecules affecting common cellular pathways in ALS: targeting glutamatergic, apoptotic, inflammatory, and oxidative stress mechanisms among others. More recently, clinical trials utilizing stem cell transplantation and other biologics have emerged. This rich and ever-growing pipeline of investigational products, along with innovative clinical trial designs, collaborative trial networks, and an engaged ALS community', provide renewed hope to finding a cure for ALS. This article reviews existing ALS therapies and the current clinical drug development pipeline.
Topics: Amyotrophic Lateral Sclerosis; Biological Products; Clinical Trials as Topic; Disease Progression; Edaravone; Humans; Neuroprotective Agents; Riluzole
PubMed: 36121612
DOI: 10.1007/s40265-022-01769-1 -
International Journal of Molecular... Feb 2022Amyotrophic lateral sclerosis (ALS) is a rapidly debilitating fatal neurodegenerative disorder, causing muscle atrophy and weakness, which leads to paralysis and... (Review)
Review
Amyotrophic lateral sclerosis (ALS) is a rapidly debilitating fatal neurodegenerative disorder, causing muscle atrophy and weakness, which leads to paralysis and eventual death. ALS has a multifaceted nature affected by many pathological mechanisms, including oxidative stress (also via protein aggregation), mitochondrial dysfunction, glutamate-induced excitotoxicity, apoptosis, neuroinflammation, axonal degeneration, skeletal muscle deterioration and viruses. This complexity is a major obstacle in defeating ALS. At present, riluzole and edaravone are the only drugs that have passed clinical trials for the treatment of ALS, notwithstanding that they showed modest benefits in a limited population of ALS. A dextromethorphan hydrobromide and quinidine sulfate combination was also approved to treat pseudobulbar affect (PBA) in the course of ALS. Globally, there is a struggle to prevent or alleviate the symptoms of this neurodegenerative disease, including implementation of antisense oligonucleotides (ASOs), induced pluripotent stem cells (iPSCs), CRISPR-9/Cas technique, non-invasive brain stimulation (NIBS) or ALS-on-a-chip technology. Additionally, researchers have synthesized and screened new compounds to be effective in ALS beyond the drug repurposing strategy. Despite all these efforts, ALS treatment is largely limited to palliative care, and there is a strong need for new therapeutics to be developed. This review focuses on and discusses which therapeutic strategies have been followed so far and what can be done in the future for the treatment of ALS.
Topics: Amyotrophic Lateral Sclerosis; Combined Modality Therapy; Deep Brain Stimulation; Drug Discovery; Edaravone; Humans; Induced Pluripotent Stem Cells; Riluzole
PubMed: 35269543
DOI: 10.3390/ijms23052400 -
Fundamental & Clinical Pharmacology Oct 2022Stroke is the leading cause of disability and death. When blood flow is restored after prolonged ischemia and hypoxia, it leads to excessive production of reactive...
Stroke is the leading cause of disability and death. When blood flow is restored after prolonged ischemia and hypoxia, it leads to excessive production of reactive oxygen species (ROS), increased local inflammation, and apoptosis, which are the cause of most cerebral ischemia reperfusion injury (CIRI), leading to secondary brain tissue damage. Edaravone dexborneol is a novel neuroprotective agent consisting of edaravone and borneol. Studies have shown that it has synergistic antioxidant and anti-inflammatory effects. However, whether Edaravone dexborneol stimulates the Nrf2/HO-1 pathway to regulate NADPH oxidase 2 (NOX2) remains unclear. In this study, wild-type (WT) mice and Nrf2 knockout (KO) mice were used to investigate the antioxidant, anti-inflammatory, and anti-apoptotic effects of Edaravone dexborneol on CIRI and its mechanism. The cognitive function of mice was evaluated with the Morris water maze (MWM), test and the cell structures of hippocampus were observed by hematoxylin and eosin (H&E) staining. Nrf2, HO-1, and NOX2 proteins and apoptosis-related proteins Bcl-2, Bax, and Caspase 3 were detected by western blotting. Nrf2, HO-1, NOX2, and inflammatory factors TNF-α, IL-1β, IL-4, and IL-10 were detected by real-time polymerase chain reaction. The results showed that Edaravone dexborneol treatment improved learning and memory performance, neuronal damage, and enhanced antioxidant, inflammation, and apoptosis in CIRI mice. In addition, Edaravone dexborneol induced the activation Nrf2/HO-1 signaling pathway activation while inhibiting NOX2 expression. Overall, these results indicate that Edaravone dexborneol ameliorates CIRI-induced memory impairments by activating Nrf2/HO-1 signaling pathway and inhibiting NOX2.
Topics: Animals; Antioxidants; Apoptosis; Brain Ischemia; Edaravone; Heme Oxygenase-1; Inflammation; Membrane Proteins; Mice; NF-E2-Related Factor 2; Oxidative Stress; Rats; Rats, Sprague-Dawley; Reperfusion Injury; Signal Transduction
PubMed: 35470467
DOI: 10.1111/fcp.12782 -
Expert Review of Neurotherapeutics Jan 2023Amyotrophic lateral sclerosis (ALS) is a rapidly progressive, fatal neurodegenerative motor neuron disease. Despite the overwhelming need for effective therapeutics for... (Review)
Review
INTRODUCTION
Amyotrophic lateral sclerosis (ALS) is a rapidly progressive, fatal neurodegenerative motor neuron disease. Despite the overwhelming need for effective therapeutics for ALS, riluzole and edaravone were the only two FDA-approved disease-modifying therapies prior to 2022. The randomized, double-blind, multicenter, placebo-controlled CENTAUR trial demonstrated the safety and efficacy of sodium phenylbutyrate-taurursodiol (PB-TURSO) in persons with ALS (PALS), leading to its conditional approval in Canada in June 2022 and full approval in the USA in September 2022.
AREAS COVERED
Herein, the authors provide a review of the pharmacology and clinical trials evaluating sodium phenylbutyrate and/or taurursodiol in PALS.
EXPERT OPINION
The safety and tolerability of both PB and TURSO were previously demonstrated in small PALS trials. The phase 2 CENTAUR study and its open-label extension demonstrated the safety and efficacy of AMX0035 (a sachet containing a fixed co-formulation of 3 g of PB and 1 g of TURSO given twice daily) in PALS. A phase 3 PHOENIX trial (NCT05021536) will offer more insight into safety and efficacy of AMX0035. AMX0035 currently costs $ 158,000 annually in the US, which may become a financial barrier for PALS to receive the medication.
Topics: Humans; Amyotrophic Lateral Sclerosis; Edaravone; Randomized Controlled Trials as Topic; Multicenter Studies as Topic
PubMed: 36705941
DOI: 10.1080/14737175.2023.2174018 -
International Immunopharmacology Dec 2022Edaravone dexborneol (EDB) is a traditional prescription that consists of two components, edaravone and (+)-borneol, which have synergistic antioxidant and...
Edaravone dexborneol (EDB) is a traditional prescription that consists of two components, edaravone and (+)-borneol, which have synergistic antioxidant and anti-inflammatory activities in animal models of ischemic stroke. Pyroptosis is a form of cell death that has only recently been discovered. In this study, we investigated the therapeutic effects and potential mechanisms of EDB in acute ischemic stroke. We used an in vivo mouse transient middle cerebral artery occlusion (tMCAO) model along with an in vitro BV2 cell oxygen-glucose deprivation (OGD) model to perform specific experiments. The executive protein of pyroptosis, gasdermin D (GSDMD), was increased after tMCAO. The administration of EDB dramatically reduced sensorimotor deficits and infarct sizes in mice with tMCAO. In addition, EDB inhibited the production of the NLRP3-inflammasome and the activation of the NF-κB signaling pathway. This effect inhibited both the in vitro and in vivo expression of inflammatory factors, including IL-1β and IL-18. Collectively, our data indicate that EDB exerted positive effects after ischemic stroke. EDB inhibited the activation of NLRP3 inflammasome-induced microglial pyroptosis in experimental ischemic stroke. The findings of this research indicate that the NF-κB/NLRP3/GSDMD signaling pathway may serve as a therapeutic target for EDB to promote functional recovery after stroke.
Topics: Mice; Animals; Inflammasomes; Pyroptosis; NLR Family, Pyrin Domain-Containing 3 Protein; Microglia; Ischemic Stroke; Edaravone; NF-kappa B; Infarction, Middle Cerebral Artery
PubMed: 36279668
DOI: 10.1016/j.intimp.2022.109315