Effects of the Edaravone, a Drug Approved for the Treatment of Amyotrophic Lateral Sclerosis, on Mitochondrial Function and Neuroprotection

Joo, Sun Hyung; Kim, Kiyoung

doi:10.3390/antiox11020195

Cited by 36 publications

(19 citation statements)

References 82 publications

(87 reference statements)

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Section: Resultsmentioning

confidence: 99%

“…Besides the H2O2 endogenously produced by the pneumococcus, the bactericidal activities of fluroquinolones may be impacted by the free radicals induced by the antibiotic. To test this, we utilized a clinically approved drug (edaravone) that scavenges free radicals to determine the effect of diminished free radicals in the antibiotic kill kinetic experiments 66,67 . Supplementation of the media with edaravone dramatically reduced the bactericidal activities of both levofloxacin and ciprofloxacin, resulting in over two orders of magnitude reduction in killing following four hours of antibiotic exposure (Figure 7A and B).…”

Section: Redox Stress Plays a Critical Role In Tolerance To Fluroquin...mentioning

confidence: 99%

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Pneumococcal Evasion of Antibiotics via Metabolic Adaptation During Infection

Dao

Echlin

McKnight

et al. 2022

Preprint

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Streptococcus pneumoniae is a major human pathogen of global health concern, causing a range of mild to severe infections, including acute otitis media, pneumonia, sepsis, and meningitis. The rapid emergence of antibiotic resistance among S. pneumoniae isolates poses a serious public health problem worldwide. Resistant pneumococcal strains have rendered the mainstay treatment with beta-lactams, fluoroquinolones, and macrolides, ineffective. Antibiotic resistance in S. pneumoniae has spread globally via the emergence of de novo mutations and horizontal transfer of resistance. Fluoroquinolone resistance in S. pneumoniae is an intriguing case because the prevalence of fluoroquinolone resistance does not correlate with increasing usage, as is often the case with other classes of antibiotics. In this study, we demonstrated that deleterious fitness costs constrain the emergence of individual fluoroquinolone resistance mutations in either topoisomerase IV or gyrase A in S. pneumoniae. Generation of double point mutations in the target enzymes in topoisomerase IV and gyrase A conferred high-level fluoroquinolone resistance while restoring fitness comparable to the sensitive wild-type. During an in vivo model of antibiotic resistance evolution,S. pneumoniae was able to circumvent deleterious fitness costs imposed by resistance determinants through development of antibiotic tolerance through metabolic adaptation that reduced the production of reactive oxygen species, an effect that could be recapitulated pharmacologically. The metabolic mutants conferring tolerance resulted in a fitness benefit during infection following antibiotic treatment with fluroquinolones. These data suggest that emergence of fluoroquinolone resistance is tightly constrained in S. pneumoniae by host fitness tradeoffs and that mutational pathways involving metabolic networks to enable tolerance phenotypes may be an important contributor to the evasion of antibiotic mediated killing.

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Section: Resultsmentioning

confidence: 99%

Section: Redox Stress Plays a Critical Role In Tolerance To Fluroquin...mentioning

confidence: 99%

Pneumococcal Evasion of Antibiotics via Metabolic Adaptation During Infection

Dao

Echlin

McKnight

et al. 2022

Preprint

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“…Other proteins involved in the Nrf2 ubiquitination and subsequent proteasomal degradation, such as HRD1, βTrCP, CRIF1 and WDR23, are currently under investigation for their potential to interfere with ALS progression [ 82 , 86 ]. It is worth mentioning here that the FDA-approved compound edaravone has been shown to increase expression of Nrf2 although the mechanism has not been defined yet [ 84 , 87 , 109 ]. Although the efficacy of this drug is very limited, its mechanism of action could be exploited to design more effective molecules.…”

Section: Other Ways For Nrf2 Activationmentioning

confidence: 99%

“…They include inhibitors of BACH1, an Nrf2-competitor for the ARE elements, inhibitors of GSK3β, a kinase involved in Nrf2 degradation, and inhibitors of other proteins involved in Nrf2 ubiquitination [ 1 , 86 ]. Edaravone, a FDA-approved ALS compound, was also shown to activate Nrf2 [ 87 ], but the mechanism is still elusive. Nrf2, nuclear factor erythroid 2–related factor 2; Keap1, Kelch-like ECH-associated protein 1; ARE, antioxidant responsive element; GSK3β, glycogen synthase kinase 3 beta; BACH1, BTB Domain And CNC Homolog 1 (created with BioRender.com, accessed on 27 January 2022).…”

Section: Figurementioning

confidence: 99%

Activation of the Nrf2 Pathway as a Therapeutic Strategy for ALS Treatment

Arslanbaeva

Bisaglia

2022

Molecules

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Amyotrophic lateral sclerosis is a progressive and fatal disease that causes motoneurons degeneration and functional impairment of voluntary muscles, with limited and poorly efficient therapies. Alterations in the Nrf2-ARE pathway are associated with ALS pathology and result in aberrant oxidative stress, making the stimulation of the Nrf2-mediated antioxidant response a promising therapeutic strategy in ALS to reduce oxidative stress. In this review, we first introduce the involvement of the Nrf2 pathway in the pathogenesis of ALS and the role played by astrocytes in modulating such a protective pathway. We then describe the currently developed activators of Nrf2, used in both preclinical animal models and clinical studies, taking into consideration their potentialities as well as the possible limitations associated with their use.

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“…Edaravone (Radicut ® , here designated EDA) is a cell protective agent, capable of reducing oxidative damages in various diseases, especially neurodegenerative diseases [ 20 , 21 ]. It is a potent antioxidant compound, acting as a scavenger for a large variety of oxygen free radicals [ 22 , 23 ].…”

Section: Introductionmentioning

confidence: 99%

Antioxidant Properties and Aldehyde Reactivity of PD-L1 Targeted Aryl-Pyrazolone Anticancer Agents

et al. 2022

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Small molecules targeting the PD-1/PD-L1 checkpoint are actively searched to complement the anticancer arsenal. Different molecular scaffolds have been reported, including phenyl-pyrazolone derivatives which potently inhibit binding of PD-L1 to PD-1. These molecules are structurally close to antioxidant drug edaravone (EDA) used to treat amyotrophic lateral sclerosis. For this reason, we investigated the capacity of five PD-L1-binding phenyl-pyrazolone compounds (1–5) to scavenge the formation of oxygen free radicals using electron spin resonance spectroscopy with DPPH/DMPO probes. In addition, the reactivity of the compounds toward the oxidized base 5-formyluracil (5fU) was assessed using chromatography coupled to mass spectrometry and photodiode array detectors. The data revealed that the phenyl-pyrazolone derivatives display antioxidant properties and exhibit a variable reactivity toward 5fU. Compound 2 with a N-dichlorophenyl-pyrazolone moiety cumulates the three properties, being a potent PD-L1 binder, a robust antioxidant and an aldehyde-reactive compound. On the opposite, the adamantane derivative 5 is a potent PD-L1 binding with a reduced antioxidant potential and no aldehyde reactivity. The nature of the substituent on the phenyl-pyrazolone core modulates the antioxidant capacity and reactivity toward aromatic aldehydes. The molecular signature of the compound can be adapted at will, to confer additional properties to these PD-L1 binders.

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Effects of the Edaravone, a Drug Approved for the Treatment of Amyotrophic Lateral Sclerosis, on Mitochondrial Function and Neuroprotection

Cited by 36 publications

References 82 publications

Pneumococcal Evasion of Antibiotics via Metabolic Adaptation During Infection

Pneumococcal Evasion of Antibiotics via Metabolic Adaptation During Infection

Activation of the Nrf2 Pathway as a Therapeutic Strategy for ALS Treatment

Antioxidant Properties and Aldehyde Reactivity of PD-L1 Targeted Aryl-Pyrazolone Anticancer Agents

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