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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 -
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 -
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 -
Mediators of Inflammation 2022Our previous work has shown that inflammatory processes play a detrimental role in the pathophysiology of acute ischemic stroke (AIS). Neutrophil extracellular traps...
BACKGROUND
Our previous work has shown that inflammatory processes play a detrimental role in the pathophysiology of acute ischemic stroke (AIS). Neutrophil extracellular traps (NETs) have been recognized as a key contributor to the proinflammatory response in AIS and could aggravate blood-brain barrier (BBB) damage. Recently, experimental and clinical researches showed that Edaravone Dexborneol (Eda.B), which is comprised of two active ingredients, Edaravone and (+)-Borneol, was effective in treatment of AIS. However, it is not clear whether the effects of Eda.B against AIS are related to NETs and BBB permeability.
METHODS
Experiment 1 was to detect the effects of Eda.B in AIS patients. Serum samples of volunteers and AIS patients were collected before and 3 days after Edaravone Dexborneol treatment. Markers of NETs and occludin were detected by ELISA kit. Experiment 2 was to explore the effects of Eda.B on experimental stroke mice. Male C57BL/6 mice were subjected to distal middle cerebral artery occlusion (MCAO) and treated with vehicle, Eda.B, or DeoxyribonueleaseI (DNase I). After stroke, the neurobehavioral tests, infarct volume, and cerebral blood flow evaluation were determined. Leakage of Evans blue was to assess the integrity of BBB. Western blot, real-time quantitative polymerase chain reaction (RT-qPCR), and immunofluorescence were used to examine the expression of NETs and tight junction- (TJ-) associated proteins.
RESULTS
Eda.B significantly improved neurological function and cerebral blood flow but reduced infarct volume after experimental stroke. Eda.B downregulated level of NETs in serum samples of AIS patients and tissue samples of MCAO mouse cortex. Eda.B and DNase I alleviated BBB permeability by upregulating TJ-associated proteins.
CONCLUSION
NETs are related to the early stage of AIS. Eda.B exerted neuroprotective effects and ameliorated BBB permeability after AIS.
Topics: Animals; Blood-Brain Barrier; Brain Ischemia; Deoxyribonuclease I; Edaravone; Extracellular Traps; Humans; Infarction, Middle Cerebral Artery; Ischemic Stroke; Male; Mice; Mice, Inbred C57BL; Permeability; Stroke
PubMed: 36032782
DOI: 10.1155/2022/3855698 -
Amyotrophic Lateral Sclerosis &... Dec 2014Our objective was to confirm the efficacy and safety of edaravone in amyotrophic lateral sclerosis (ALS) patients. We conducted a 36-week confirmatory study, consisting... (Randomized Controlled Trial)
Randomized Controlled Trial
Our objective was to confirm the efficacy and safety of edaravone in amyotrophic lateral sclerosis (ALS) patients. We conducted a 36-week confirmatory study, consisting of 12-week pre-observation period followed by 24-week treatment period. Patients received placebo or edaravone i.v. infusion over 60 min for the first 14 days in cycle 1, and for 10 of the first 14 days during cycles 2 to 6. The efficacy primary endpoint was changed in the revised ALS functional rating scale (ALSFRS-R) scores during the 24-week treatment. Patients were treated with placebo (n = 104) and edaravone (n = 102). Changes in ALSFRS-R during the 24-week treatment were -6.35 ± 0.84 in the placebo group (n = 99) and -5.70 ± 0.85 in the edaravone group (n = 100), with a difference of 0.65 ± 0.78 (p = 0.411). Adverse events amounted to 88.5% (92/104) in the placebo group and 89.2% (91/102) in the edaravone group. In conclusion, the reduction of ALSFRS-R was smaller in the edaravone group than in the placebo group, but efficacy of edaravone for treatment of ALS was not demonstrated. Levels and frequencies of reported adverse events were similar in the two groups.
Topics: Adult; Aged; Amyotrophic Lateral Sclerosis; Analysis of Variance; Antipyrine; Double-Blind Method; Edaravone; Female; Follow-Up Studies; Free Radical Scavengers; Humans; Male; Middle Aged; Retrospective Studies; Severity of Illness Index; Time Factors; Young Adult
PubMed: 25286015
DOI: 10.3109/21678421.2014.959024 -
Brazilian Journal of Medical and... Jan 2019Dipyrone (metamizole), acting through its main metabolites 4-methyl-amino-antipyrine and 4-amino-antipyrine, has established analgesic, antipyretic, and spasmolytic... (Review)
Review
Dipyrone (metamizole), acting through its main metabolites 4-methyl-amino-antipyrine and 4-amino-antipyrine, has established analgesic, antipyretic, and spasmolytic pharmacological effects, which are mediated by poorly known mechanisms. In rats, intravenously administered dipyrone delays gastric emptying (GE) of liquids with the participation of capsaicin-sensitive afferent fibers. This effect seems to be mediated by norepinephrine originating from the sympathetic nervous system but not from the superior celiac-mesenteric ganglion complex, which activates β2-adrenoceptors. In rats, in contrast to nonselective non-hormonal anti-inflammatory drugs, dipyrone protects the gastric mucosa attenuating the development of gastric ulcers induced by a number of agents. Clinically, it has been demonstrated that dipyrone is effective in the control of colic-like abdominal pain originating from the biliary and intestinal tracts. Since studies in humans and animals have demonstrated the presence of β2-adrenoceptors in biliary tract smooth muscle and β2-adrenoceptor activation has been shown to occur in dipyrone-induced delayed GE, it is likely that this kind of receptors may participate in the reduction of smooth muscle spasm of the sphincter of Oddi induced by dipyrone. There is no evidence that dipyrone may interfere with small bowel and colon motility, and the clinical results of its therapeutic use in intestinal colic appear to be due to its analgesic effect.
Topics: Ampyrone; Animals; Anti-Inflammatory Agents, Non-Steroidal; Antipyrine; Autonomic Nerve Block; Dipyrone; Gastric Emptying; Rats; Rats, Wistar
PubMed: 30652827
DOI: 10.1590/1414-431X20188103