Edaravone, a scavenger for multiple reactive oxygen species, reacts with singlet oxygen to yield 2-oxo-3-(phenylhydrazono)-butanoic acid

Abstract

Edaravone (3-methyl-1-phenyl-2-pyrazolin-5-one) is a synthetic antioxidant used as a drug to treat acute ischemic stroke in Japan and amyotrophic lateral sclerosis in Japan and USA. Its pharmacological mechanism is thought to be scavenging of reactive oxygen species, which are intimately related with these diseases. Recently, the singlet oxygen ( 1 O 2 ) has attracted attention among reactive oxygen species. In this study, we investigated the reactivity of edaravone toward 1 O 2 and identified its reaction products. Edaravone showed a reactivity toward 1 O 2 greater than those of uric acid, histidine, and tryptophan, which are believed to be 1 O 2 scavengers in vivo. And we confirmed that 2-oxo-3-(phenylhydrazono)-butanoic acid was formed as an oxidation product. We propose a plausible mechanism for 2oxo-3-(phenylhydrazono)-butanoic acid production by 1 O 2 -induced edaravone oxidation. Since 2-oxo-3-(phenylhydrazono)-butanoic acid has already been identified as a radical-initiated oxidation product, free radical-induced oxidation should be seriously reconsidered. We also found that edaravone can react with not only hypochlorous anions but also 1 O 2 that are formed from myeloperoxidase. This result suggests that edaravone treatment can be beneficial against myeloperoxidase-related injuries such as inflammation.

Edaravone Dexborneol Alleviates Cerebral Ischemic Injury via MKP-1-Mediated Inhibition of MAPKs and Activation of Nrf2

“…BioMed Research International Eda-Bor is a compound medicine containing edaravone and borneol in a mass ratio of 4 : 1. Edaravone exhibited high radical-scavenging activity against a broad spectrum of radical species, including the hydroxyl radical, superoxide anion, singlet oxygen, methyl radical, alkoxyl radical, and alkylperoxyl radical [20,21]. Since cerebral ischemic injury induces the generation of many different types of radical species, the broad scavenging activity of edaravone is important for its therapeutic effects on ischemic stroke.…”

Stem cell-based ischemic stroke therapy: Novel modifications and clinical challenges

“…Since excitotoxicity, oxidative stress and inflammatory mediators are essential for IS progression [33] , they provide a wide range of targets for neuroprotective therapy strategies. Neuroprotective agents, including human urokininogenase [46] , cattle encephalon glycoside and ignotin [47] , edaravone [48 , 49] , statins [50 , 51] and iron‐gallic acid coordination polymer nanodots [52] , exert diverse neuroprotective effects through various target mechanisms [45] .…”