神经保护
抗氧化剂
化学
活性氧
特罗洛克
脂质过氧化
生物化学
谷胱甘肽
碘化丙啶
药理学
氧化应激
生物
程序性细胞死亡
细胞凋亡
酶
DPPH
作者
Marta Šoltésová Prnová,Omar Noel Medina-Campos,José Pedraza-Chaverrı́,Ana Laura Colín-González,Francisco Piedra-García,Edgar Rangel-López,Lucia Kováčiková,Aslı F. Ceylan,Çi̇men Karasu,Abel Santamarı́a,Milan Štefek
出处
期刊:Neuroscience
[Elsevier]
日期:2020-09-01
卷期号:443: 206-217
被引量:9
标识
DOI:10.1016/j.neuroscience.2020.07.014
摘要
Neuroprotective action of the novel aldose reductase (AR) inhibitor cemtirestat (CMT), 2-(3-thioxo-2H-[1,2,4]triazino[5,6-b]indol-5(3H)-yl)acetic acid, was recently proved in experimental rat models of diabetes. The in vivo results indicated that the antioxidant activity of this compound might have participated on its effects. The aim of this study was to explore in a greater detail the putative antioxidant mechanisms potentially involved in CMT mediated neuroprotection. Antioxidant efficacy per se of CMT was proved by a ferric reducing antioxidant power (FRAP) test and CMT was found to scavenge reactive oxygen species (ROS) generated in water phase chemically with decreasing efficacy as follows ROO > H2O2 > O2−. Studies in liposomes revealed the ability of CMT to inhibit lipid peroxidation more efficiently than melatonin, yet less effectively than Trolox. In the rat brain cortical slices, CMT reduced the loss of cell viability/mitochondrial function induced by quinolinic acid (QUIN), and inhibited lipid peroxidation. In addition, CMT normalized the GSH/GSSG ratio which could be explained, at least partially, by the ability of this compound to release free GSH from the pool of endogenously bound disulfides. Neuronal cell damage induced by QUIN or H2O2 was reduced by CMT as proved by significant drop in propidium iodide incorporation into cells. On balance then, our results corroborated the notion of a multifunctional action of CMT as a drug combining AR inhibition with direct antioxidant and ROS scavenging activity. Moreover, the ability of CMT to restore thiol-disulfide homeostasis was proved.
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