4-Cl-edaravone and (E)-2-chloro-3-[(E)-phenyldiazenyl]-2-butenoic acid are the specific reaction products of edaravone with hypochlorite.

Abstract

3-Methyl-1-phenyl-2-pyrazolin-5-one (edaravone) is a synthetic one-electron antioxidant used as a drug for treatment against acute phase cerebral infarction in Japan. This drug also reacts with two-electron oxidants like peroxynitrite to give predominantly 4-nitrosoedaravone but no one-electron oxidation products. It is believed that this plays a significant role in amelioration of amyotrophic lateral sclerosis. The drug was approved for treatment of amyotrophic lateral sclerosis in Japan and USA in 2015 and 2017, respectively. In this study, we examined the reaction of edaravone with another two-electron oxidant, hypochlorite anion (ClO−). Edaravone reacted with ClO− in 50% methanolic phosphate buffer (pH 7.4) solution containing typical two-electron reductants, such as glutathione, cysteine, methionine, and uric acid, as internal references. The concentration of edaravone decreased at a similar rate as each co-existing reference, indicating that it showed comparable reactivity toward ClO− as those references. Furthermore, 4-Cl-edaravone and (E)-2-chloro-3-[(E)-phenyldiazenyl]-2-butenoic acid (CPB) were identified as primary and end products, respectively, and no one-electron oxidation products were detected. These results suggest that edaravone treatment can bring greater benefit against ClO−-related injury such as inflammation, and 4-Cl-edaravone and CPB can be good biomarkers for ClO−-induced oxidative stress.