Antioxidant Mechanisms in the Neuroprotective Action of Cemtirestat: Studies in Chemical Models, Liposomes and Rat Brain Cortical Slices

Neuroscience
Marta Soltesova PrnovaMilan Stefek

Abstract

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...Continue Reading

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