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

Abstract

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.

• Authors: Wenpeng Liu, Linlin Wang, Canwen Liu, Ziwei Dai, Tenglong Li, Biao Tang
• Journal: Biological & pharmaceutical bulletin (Biol Pharm Bull) Vol. 45 Issue 9 Pg. 1269-1275 ( 2022) ISSN: 1347-5215 [Electronic] Japan
• PMID: 36047195 (Publication Type: Journal Article)

Chemical References

• Cation Transport Proteins
• NF-E2-Related Factor 2
• metal transporting protein 1
• Glutathione
• Edaravone

Topics

• Animals
• Brain Ischemia (drug therapy, metabolism)
• Cation Transport Proteins
• Edaravone (pharmacology)
• Ferroptosis
• Glutathione
• Infarction, Middle Cerebral Artery (drug therapy, pathology)
• NF-E2-Related Factor 2 (metabolism)
• Rats
• Reperfusion Injury (metabolism)