Dual Antioxidant DH-217 Mitigated Cerebral Ischemia–Reperfusion Injury by Targeting IKKβ/Nrf2/HO-1 Signal Axis,Neurochemical Research

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Dual Antioxidant DH-217 Mitigated Cerebral Ischemia–Reperfusion Injury by Targeting IKKβ/Nrf2/HO-1 Signal Axis
Neurochemical Research ( IF 3.7 ) Pub Date : 2022-10-15 , DOI: 10.1007/s11064-022-03783-x
Mengya Shen _{1,

2} , Yuantie Zheng _{2,

3} , Ge Li ₂ , Yinqi Chen _{1,

2} , Lili Huang _{2,

4} , Jianzhang Wu _{1,

2} , Chenglv Hong ₅

Affiliation

Abstract

Antioxidants represent a potential therapy for cerebral ischemia–reperfusion injury (CIRI). Compounds which exhibit both direct and indirect antioxidative activity may potentially exert improved effects. Hence, we aimed to assess whether the dual antioxidant DH-217, a derivative of DHAP clinically used to treat coronary heart disease, can reduce oxidative stress damage and elucidate the underlying mechanism. Hydrogen peroxide (H₂O₂)-induced and Middle Cerebral Artery Occlusion (MCAO)-induced damages were used to imitate oxidative stress. The antioxidation of DH-217 was determined by MTT, ROS, colony and DPPH assay. Besides, immunofluorescence, Real-Time PCR Analyses, western blotting and si-RNA/Plasmid-induced protein expression were used for mechanism validation. DPPH scavenging assay evidenced DH-217 was a well free radical scavenger. Cell survival assay also showed that DH-217 had a significant cytoprotection through direct and indirect clearance mechanisms. Further, it clearly inhibited oxidative stress-induced IkappaB kinase beta (IKKβ) phosphorylation and increased heme oxygenase-1 (HO-1) expression. Significantly, these antioxidant beneficial effects were reversed by HO-1 inhibitor, si-nuclear erythroid 2-related factor 2 (Nrf2) and IKKβ plasmid. Meanwhile, DH-217 had a good neuroprotective effect on CIRI rats. The dual antioxidant DH-217 has potential reference value for drug development of CIRI. Furthermore, inhibition of IKKβ phosphorylation and activation of Nrf2/HO-1 could be a promising antioxidant pathway.

Graphical Abstract

Dual antioxidant DH-217 not only has the ability of directly scavenging ROS, but also can clear it by targeting IKKβ/Nrf2/HO-1 signal axis. Inhibition of IKKβ phosphorylation and activation of Nrf2/HO-1 may be a promising antioxidant pathway for CIRI.

中文翻译：

双抗氧化剂 DH-217 通过靶向 IKKβ/Nrf2/HO-1 信号轴减轻脑缺血再灌注损伤

摘要

抗氧化剂代表了脑缺血再灌注损伤 (CIRI) 的潜在疗法。表现出直接和间接抗氧化活性的化合物可能会发挥改善的作用。因此，我们旨在评估双重抗氧化剂 DH-217（临床上用于治疗冠心病的 DHAP 的衍生物）是否可以减少氧化应激损伤并阐明其潜在机制。过氧化氢 (H ₂ O ₂）诱导的和大脑中动脉闭塞（MCAO）诱导的损伤被用来模拟氧化应激。通过MTT、ROS、菌落和DPPH测定法测定DH-217的抗氧化作用。此外，免疫荧光、实时 PCR 分析、蛋白质印迹和 si-RNA/质粒诱导的蛋白质表达被用于机制验证。DPPH 清除试验证明 DH-217 是一种很好的自由基清除剂。细胞存活测定还表明，DH-217 通过直接和间接清除机制具有显着的细胞保护作用。此外，它明显抑制了氧化应激诱导的 IkappaB 激酶 β (IKKβ) 磷酸化并增加了血红素加氧酶 1 (HO-1) 的表达。值得注意的是，这些抗氧化有益作用被 HO-1 抑制剂、si-核红细胞 2 相关因子 2 (Nrf2) 和 IKKβ 质粒逆转。同时，DH-217对CIRI大鼠具有良好的神经保护作用。双抗氧剂DH-217对CIRI的药物开发具有潜在的参考价值。此外，抑制 IKKβ 磷酸化和激活 Nrf2/HO-1 可能是一种很有前途的抗氧化途径。