How is edaravone effective against acute ischemic stroke and amyotrophic lateral sclerosis?

Abstract

Edaravone is a low-molecular-weight antioxidant drug targeting peroxyl radicals among many types of reactive oxygen species. Because of its amphiphilicity, it scavenges both lipid- and water-soluble peroxyl radicals by donating an electron to the radical. Thus, it inhibits the oxidation of lipids by scavenging chain-initiating water-soluble peroxyl radicals and chain-carrying lipid peroxyl radicals. In 2001, it was approved in Japan as a drug to treat acute-phase cerebral infarction, and then in 2015 it was approved for amyotrophic lateral sclerosis (ALS). In 2017, the U.S. Food and Drug Administration also approved edaravone for treatment of patients with ALS. Its mechanism of action was inferred to be scavenging of peroxynitrite. In this review, we focus on the radical-scavenging characteristics of edaravone in comparison with some other antioxidants that have been studied in clinical trials, and we summarize its pharmacological action and clinical efficacy in patients with acute cerebral infarction and ALS.

Keywords: acute ischemic stroke; amyotrophic lateral sclerosis; antioxidant; edaravone; radical scavenger.

Fig. 1

Design of a phenol-like compound.

Fig. 2

Optimization of 3-methyl-1-phenyl-2-pyrazolin-5-one.

Fig. 3

Chemical structure of edaravone.

Fig. 4

Edaravone tautomerism and acid dissociation equilibrium.

Fig. 5

Effects of edaravone on peroxidation of liposome membranes by water- and lipid-soluble free radicals. PC-OOH: phosphatidylcholine hydroperoxide; ▲: without antioxidant; □: ascorbic acid (100 µM); ■: edaravone (50 µM); ◯: edaravone (50 µM) + α-tocopherol (2 µM); △: α-tocopherol (2 µM); ●: edaravone (50 µM) + ascorbic acid (100 µM). (Reprinted from ref 31: ‘Antioxidant activity of 3-methyl-1-phenyl-2-pyrazolin-5-one’, Yamamoto Y, Kuwahara T, Watanabe K, Watanabe K., Redox Report, 1996, 2, pp. 333–338, Taylor & Francis Ltd., reprinted by permission of the publisher Taylor & Francis Ltd. http://www.tandfonline.com)

Fig. 6

A hypothetical mechanism for the production of edaravone radical by electron transfer from edaravone anion to peroxyl radical and the formation of oxidation products.

Fig. 7

Typical chromatogram of extracts from the rat cerebral cortex after perfusion of ¹⁴C-edaravone. (Reprinted from ref 39: ‘Effects of a novel free radical scavenger, MCI-186, on ischemic brain damage in the rat distal middle cerebral artery occlusion model’, J Pharmacol Exp Ther, Kawai H, Nakai H, Suga M, Yuki S, Watanabe T, Saito K, 1997, 281(2), pp. 921–927, reprinted by permission of The American Society for Pharmacology and Experimental Therapeutics, http://www.aspet.org)

Fig. 8

Representative chemical structures of free-radical-eliminating agents and antioxidants.

Fig. 9

Chemical structure of PBN.

Fig. 10

Effects of edaravone and various antioxidants, and mechanisms of action. Reactive oxygen species eliminated by various antioxidants in living organisms are indicated by arrows.

Fig. 11

Effects of edaravone (MCI-186) on infarct volume 1 day after distal middle cerebral arterial occlusion. Expressed as the mean ± SE in 10 animals Comparison with the vehicle group: *p<0.05 (Dunnett’s test). (Reprinted from ref 39: ‘Effects of a novel free radical scavenger, MCI-186, on ischemic brain damage in the rat distal middle cerebral artery occlusion model’, J Pharmacol Exp Ther, Kawai H, Nakai H, Suga M, Yuki S, Watanabe T, Saito K, 1997, 281(2), pp. 921–927, reprinted by permission of The American Society for Pharmacology and Experimental Therapeutics, http://www.aspet.org)

Fig. 12

Effects of edaravone (MCI-186) on neuropathy 1 day after distal middle cerebral arterial occlusion. Expressed as the mean ± SE in 10 animals Comparison with the vehicle group: *p<0.05 (nonparametric Dunnett’s test). (Reprinted from ref 39: ‘Effects of a novel free radical scavenger, MCI-186, on ischemic brain damage in the rat distal middle cerebral artery occlusion model’, J Pharmacol Exp Ther, Kawai H, Nakai H, Suga M, Yuki S, Watanabe T, Saito K, 1997, 281(2), pp. 921–927, reprinted by permission of The American Society for Pharmacology and Experimental Therapeutics, http://www.aspet.org)

Fig. 13

Sequential change of ¹H-MRS profile.

Scheme 1