• Marta Soltesova Prnova, Omar Noel Medina-Campos, José Pedraza-Chaverri, Ana Laura Colín-González, Francisco Piedra-García, Edgar Rangel-López, Lucia Kovacikova, Asli Ceylan, Cimen Karasu, Abel Santamaria, and Milan Stefek.
• Department of Biochemical Pharmacology, Institute of Experimental Pharmacology and Toxicology, CEM, Slovak Academy of Sciences, Bratislava, Slovakia.
• Neuroscience. 2020 Sep 1; 443: 206-217.

AbstractNeuroprotective 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.Copyright © 2020 IBRO. Published by Elsevier Ltd. All rights reserved.

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