Edaravone Ameliorates Cerebral Ischemia–Reperfusion Injury by Downregulating Ferroptosis via the Nrf2/FPN Pathway in Rats

• Published in: Biological & pharmaceutical bulletin Vol. 45; no. 9; pp. 1269 - 1275
• Main Authors: Liu, Wenpeng, Wang, Linlin, Liu, Canwen, Dai, Ziwei, Li, Tenglong, Tang, Biao
• Format: Journal Article
• Language: English
• Published: Tokyo The Pharmaceutical Society of Japan 01.09.2022; Japan Science and Technology Agency
• Subjects: Brain injury; Cerebral blood flow; Cerebral infarction; cerebral ischemia–reperfusion; edaravone; ferroportin; Ferroptosis; Glutathione peroxidase; IL-1β; Interleukin 6; Iron; Ischemia; Neurological complications; nuclear factor E2-related factor 2; Reperfusion; Sensorimotor system; Tumor necrosis factor-TNF; Tumor necrosis factor-α
• ISSN: 0918-6158; 1347-5215
• DOI: 10.1248/bpb.b22-00186

Edaravone, an antioxidant protective agent, has anti-cerebral ischemic reperfusion injury (CIRI) effects, but its anti-CIRI mechanism is unclear. The aim of this study is to investigate the anti-CIRI mechanism of edaravone based on the nuclear factor-E2-related factor 2 (Nrf2)/ferroportin (FPN) pathway that regulates ferroptosis-mediated cerebral ischemia–reperfusion injury. We evaluated the brain injury by constructing a middle cerebral artery occlusion and reperfusion (MCAO/R) model in rats. The results showed that cerebral infarct volume and neurological impairment scores were increased in cerebral ischemia–reperfusion rats, with impaired sensorimotor ability; furthermore, brain tissue glutathione (GSH) content was decreased, Fe2+, malondialdehyde (MDA) and lipide peroxide (LPO) content were increased, and the expression level of glutathione peroxidase 4 (GPX4), a key protein of ferroptosis, was also decreased. Meanwhile, the Nrf2 expression level was increased and the FPN expression level was decreased after cerebral ischemia–reperfusion, while the levels of interleukin (IL)-6, IL-1β, tumor necrosis factor (TNF)-α, and myeloperoxidase (MPO) were increased. However, edaravone exhibited a protective effect on cerebral infarct and neurological and sensorimotor function in relevant tests. In addition, we also found that edaravone decreased the contents of Fe2+, MDA, and LPO in the brain tissue of MCAO/R rats and increased GSH content to inhibit ferroptosis. Furthermore, Western blot showed that after treatment with edaravone, the expression of Nrf2, GPX4, and FPN was up-regulated, the nuclear location of Nrf2 was increased, and the levels of inflammation-related indicators IL-6, IL-1β, TNF-α, and MPO were lower than in the MCAO/R group. Our results demonstrated that edaravone inhibits ferroptosis to attenuate CIRI, probably through the activation of the Nrf2/FPN pathway.