Update on Antioxidant Therapy with Edaravone: Expanding Applications in Neurodegenerative Diseases

Abstract

The brain is susceptible to oxidative stress, which is associated with various neurological diseases. Edaravone (MCI-186, 3-methyl-1 pheny-2-pyrazolin-5-one), a free radical scavenger, has promising effects by quenching hydroxyl radicals (∙OH) and inhibiting both ∙OH-dependent and ∙OH-independent lipid peroxidation. Edaravone was initially developed in Japan as a neuroprotective agent for acute cerebral infarction and was later applied clinically to treat amyotrophic lateral sclerosis (ALS), a neurodegenerative disease. There is accumulating evidence for the therapeutic effects of edaravone in a wide range of diseases related to oxidative stress, including ischemic stroke, ALS, Alzheimer's disease, and placental ischemia. These neuroprotective effects have expanded the potential applications of edaravone. Data from experimental animal models support its safety for long-term use, implying broader applications in various neurodegenerative diseases. In this review, we explain the unique characteristics of edaravone, summarize recent findings for specific diseases, and discuss its prospects for future therapeutic applications.

Keywords: Alzheimer’s disease; amyotrophic lateral sclerosis; edaravone; free radical scavenger; placental ischemia; stroke.

Figure 1

Reaction mechanism of edaravone with free radicals (revised from Nakagawa et al. 2006 [10]). The enolate form of edaravone interacts with both peroxyl radicals (LOO·) and hydroxy radicals (·OH) to form stable oxidation products (2-oxo-3-(phenylhydrazono)-butanoic acid; OPB).

Figure 2

In vivo oxidative stress imaging of Nrf2/ALS mice (revised from Ohta et al., 2019 [16]). (a–f) Note strong Nrf2 signals in the spine (e, arrowhead) and lower limbs (e, arrows) of vehicle at the early symptomatic stage (14 weeks of age) with a further emphasis at the late stage (18 weeks of age, f, arrowheads and arrows). Edaravone treatment markedly suppressed Nrf2 expression (g–i).

Figure 3

Representative photomicrographs of Aβ oligomer (A) and all forms of Aβ burden (B) in the CTX, CA1, CA3, DG, and TH at 12 M (revised from Feng et al. [18]). Edaravone treatment reduces the expression of Aβ oligomer and Aβ burden in APP23 + CCH mice. Scale bar = 50 µm. Abbreviation: Aβ, amyloid β; CCH, chronic cerebral hypoperfusion; CTX, cerebral cortex; DG, dentate gyrus; EDA, edaravone; HI, hippocampus; M, months; TH, thalamus.

Figure 4

Representative photographs of the double-stained endoskeleton of fetuses and their body parts from different groups (revised by Atallah et al., 2021 [19]). (A–E) Analyses of the whole fetus and each body part showed severe loss of ossification in the RUPP-vehicle group. Notably, the lumbar and sacral vertebrae showed highly ossified central bones in the SV and SE groups (E1 and E2) and complete loss of ossification in the RV group (E3) except for a small portion of the iliac bone (asterisk). On the other hand, there was moderate improvement after edaravone injection (E4). Abbreviations: Fe, femur; Fi, fibula; H, humerus; Il, ilium; Is, ischium; Mc, metacarpus; Mt, metatarsus; Ph, phalanges; Pu, pubis; R, radius; Sc, scapula; Ta, tarsus; T, tibia; U, ulna.