<br>N6022 通过促进 Nrf2 核转位和抑制 GSNOR/GSTP1 轴减轻脑缺血/再灌注损伤诱导的小胶质细胞铁死亡,European Journal of Pharmacology

当前位置： X-MOL 学术 › Eur. J. Pharmacol. › 论文详情

Our official English website, www.x-mol.net, welcomes your feedback! (Note: you will need to create a separate account there.)

N6022 通过促进 Nrf2 核转位和抑制 GSNOR/GSTP1 轴减轻脑缺血/再灌注损伤诱导的小胶质细胞铁死亡
European Journal of Pharmacology ( IF 4.2 ) Pub Date : 2024-04-02 , DOI: 10.1016/j.ejphar.2024.176553
Wan-Li Duan ₁ , Ya-Ping Ma ₁ , Xue-Jie Wang ₁ , Chang-Sheng Ma ₁ , Bo Han ₁ , Zhi-Mei Sheng ₁ , Hao Dong ₁ , Li-Ying Zhang ₁ , P Andy Li ₂ , Bao-Gang Zhang ₃ , Mao-Tao He ₄

Affiliation

中风造成重大死亡风险，尤其是老年人群。缺血性脑卒中的病理生理过程复杂，阐明其分子机制并探索潜在的保护药物至关重要。铁死亡是一种新认识的程序性细胞死亡形式，不同于坏死、细胞凋亡和自噬，与缺血性中风的病理生理学密切相关。 N6022 是一种 S-亚硝基谷胱甘肽还原酶 (GSNOR) 的选择性抑制剂，是一种具有潜在治疗应用的治疗哮喘的“一流”药物。然而，N6022是否对缺血性脑卒中发挥保护作用尚不清楚，其作用的确切机制尚不清楚。本研究旨在探讨 N6022 是否通过减少铁死亡来减轻脑缺血/再灌注 (I/R) 损伤并阐明其潜在机制。因此，我们建立了氧糖剥夺/再灌注（OGD/R）细胞模型和大脑中动脉闭塞/再灌注（MCAO/R）小鼠模型来模拟脑缺血再灌注损伤。我们的体外和体内数据表明，N6022 能有效防止 I/R 诱导的小鼠脑损伤和神经功能缺损，以及 OGD/R 诱导的 BV2 细胞损伤。从机制上讲，N6022促进Nrf2核转位，增强SLC7A11-GPX4系统的细胞内抗氧化能力。此外，N6022 干扰 GSNOR 与 GSTP1 的相互作用，从而增强 GSTP1 的抗氧化能力并减轻铁死亡。这些发现提供了新的见解，表明 N6022 通过促进 Nrf2 核易位和抑制 GSNOR/GSTP1 轴来减轻脑 I/R 损伤引起的小胶质细胞铁死亡。

"点击查看英文标题和摘要"

N6022 attenuates cerebral ischemia/reperfusion injury-induced microglia ferroptosis by promoting Nrf2 nuclear translocation and inhibiting the GSNOR/GSTP1 axis

Stroke poses a significant risk of mortality, particularly among the elderly population. The pathophysiological process of ischemic stroke is complex, and it is crucial to elucidate its molecular mechanisms and explore potential protective drugs. Ferroptosis, a newly recognized form of programmed cell death distinct from necrosis, apoptosis, and autophagy, is closely associated with the pathophysiology of ischemic stroke. N6022, a selective inhibitor of S-nitrosoglutathione reductase (GSNOR), is a “first-in-class” drug for asthma with potential therapeutic applications. However, it remains unclear whether N6022 exerts protective effects in ischemic stroke, and the precise mechanisms of its action are unknown. This study aimed to investigate whether N6022 mitigates cerebral ischemia/reperfusion (I/R) injury by reducing ferroptosis and to elucidate the underlying mechanisms. Accordingly, we established an oxygen-glucose deprivation/reperfusion (OGD/R) cell model and a middle cerebral artery occlusion/reperfusion (MCAO/R) mouse model to mimic cerebral I/R injury. Our data, both in vitro and in vivo, demonstrated that N6022 effectively protected against I/R-induced brain damage and neurological deficits in mice, as well as OGD/R-induced BV2 cell damage. Mechanistically, N6022 promoted Nrf2 nuclear translocation, enhancing intracellular antioxidant capacity of SLC7A11-GPX4 system. Furthermore, N6022 interfered with the interaction of GSNOR with GSTP1, thereby boosting the antioxidant capacity of GSTP1 and attenuating ferroptosis. These findings provide novel insights, showing that N6022 attenuates microglial ferroptosis induced by cerebral I/R injury through the promotion of Nrf2 nuclear translocation and inhibition of the GSNOR/GSTP1 axis.

更新日期：2024-04-02

点击分享查看原文

点击收藏

公开下载

阅读更多本刊新发论文本刊介绍/投稿指南