Phytomedicine : international journal of phytotherapy and phytopharmacology · 2025
Moracin N alleviates ischaemic brain injury in mice by suppressing neuronal ferroptosis via the activation of the Keap1/Nrf2 signalling pathway.
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Zhang Jianbin, Xia Qian, Zhan Gaofeng, Zhang Xue, Gao Shuai, Han Tangrui, Zhao Yilin, Li Xing, Wang Yonghong
Аннотация
BACKGROUND: Emerging evidence suggests that oxidative stress-induced lipid peroxidation ultimately results in ferroptosis, which contributes to the progression of ischaemic brain injury. Moracin N is a leading chemical purified from mulberry leaves. Previous studies have reported that moracin N has good antioxidant activity. However, the specific impact of moracin N on ischaemic stroke have not been determined.
PURPOSE: The present research sought to investigate the neuroprotective effects and mechanisms by which moracin N protects against ferroptosis after ischaemic stroke.
METHODS: An animal model of ischaemic stroke was established via middle cerebral artery occlusion (MCAO) in mice. Mice received moracin N (20 mg·kg-1·d-1) via intracerebroventricular injection for three days before the start of reperfusion.
RESULTS: Moracin N treatment reduced the brain infarct volume and water content, attenuated neurological deficit scores, and improved long-term neurological function recovery in a mouse model of ischaemic stroke (p < 0.05). Moreover, moracin N treatment prevented ferroptosis in the brains of MCAO mice and in primary neurons challenged with oxygen-glucose deprivation in vitro by downregulating FTH1 and ACSL4 and increasing glutathione synthesis (p < 0.05). Mechanistic studies revealed that moracin N increased the activation of the Keap1/Nrf2 signalling pathway. Finally, the neuroprotective effects of moracin N were blocked by the use of ML385, an Nrf2 inhibitor, as evidenced by the excessive iron accumulation and deactivation of the ferroptosis defence system (p < 0.05).
CONCLUSIONS: Moracin N suppresses oxidative stress-induced neuronal cell death after ischaemic stroke by inhibiting ferroptosis via the Keap1/Nrf2 signalling pathway, indicating that it could serve as a potential therapeutic candidate for cerebral ischaemia.
PURPOSE: The present research sought to investigate the neuroprotective effects and mechanisms by which moracin N protects against ferroptosis after ischaemic stroke.
METHODS: An animal model of ischaemic stroke was established via middle cerebral artery occlusion (MCAO) in mice. Mice received moracin N (20 mg·kg-1·d-1) via intracerebroventricular injection for three days before the start of reperfusion.
RESULTS: Moracin N treatment reduced the brain infarct volume and water content, attenuated neurological deficit scores, and improved long-term neurological function recovery in a mouse model of ischaemic stroke (p < 0.05). Moreover, moracin N treatment prevented ferroptosis in the brains of MCAO mice and in primary neurons challenged with oxygen-glucose deprivation in vitro by downregulating FTH1 and ACSL4 and increasing glutathione synthesis (p < 0.05). Mechanistic studies revealed that moracin N increased the activation of the Keap1/Nrf2 signalling pathway. Finally, the neuroprotective effects of moracin N were blocked by the use of ML385, an Nrf2 inhibitor, as evidenced by the excessive iron accumulation and deactivation of the ferroptosis defence system (p < 0.05).
CONCLUSIONS: Moracin N suppresses oxidative stress-induced neuronal cell death after ischaemic stroke by inhibiting ferroptosis via the Keap1/Nrf2 signalling pathway, indicating that it could serve as a potential therapeutic candidate for cerebral ischaemia.