Neuroprotective Properties of Quinone Reductase 2 Inhibitor M-11, a 2-Mercaptobenzimidazole Derivative |
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Authors: | Mikhail V. Voronin Ilya A. Kadnikov Liana F. Zainullina Ilya O. Logvinov Ekaterina R. Verbovaya Tatyana A. Antipova Yulia V. Vakhitova Sergei B. Seredenin |
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Affiliation: | Department of Pharmacogenetics, Federal State Budgetary Institution “Research Zakusov Institute of Pharmacology”, Baltiyskaya Street 8, 125315 Moscow, Russia; (L.F.Z.); (I.O.L.); (E.R.V.); (T.A.A.) |
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Abstract: | The ability of NQO2 to increase the production of free radicals under enhanced generation of quinone derivatives of catecholamines is considered to be a component of neurodegenerative disease pathogenesis. The present study aimed to investigate the neuroprotective mechanisms of original NQO2 inhibitor M-11 (2-[2-(3-oxomorpholin-4-il)-ethylthio]-5-ethoxybenzimidazole hydrochloride) in a cellular damage model using NQO2 endogenous substrate adrenochrome (125 µM) and co-substrate BNAH (100 µM). The effects of M-11 (10–100 µM) on the reactive oxygen species (ROS) generation, apoptosis and lesion of nuclear DNA were evaluated using flow cytometry and single-cell gel electrophoresis assay (comet assay). Results were compared with S29434, the reference inhibitor of NQO2. It was found that treatment of HT-22 cells with M-11 results in a decline of ROS production triggered by incubation of cells with NQO2 substrate and co-substrate. Pre-incubation of HT-22 cells with compounds M-11 or S29434 results in a decrease of DNA damage and late apoptotic cell percentage reduction. The obtained results provide a rationale for further development of the M-11 compound as a potential neuroprotective agent. |
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Keywords: | NQO2 adrenochrome BNAH ROS comet assay apoptosis HT-22 cells NQO2 inhibitors 2-mercaptobenzimidazole derivative S29434 |
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