Neuroprotective Properties of Quinone Reductase 2 Inhibitor M-11, a 2-Mercaptobenzimidazole Derivative

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.

Effect of fabomotizole on brain gene expression in MR rats upon open field test

Selective anxiolytic fabomotisol (Afobazol®) has affinity for the Sigma-1 chaperone receptor site, quinone reductase 2 (NQO2) and MAO-A regulatory sites, and melatonin receptor type 1 (MT1 receptor). The analysis of the effect of fabomotisol on the gene expression profile in the brain of MR (Maudsley Reactive) rats was carried out when modeling emotional stress in the open field test. A change in the expression of 14 genes was found, the results of the functional annotation of which show that the mechanisms of action of fabomotisol may be associated with the regulation of translation of proteins (Rpl5, Rpl15, Ncl, Ybx1), synaptic functions (Cplx2, Dlg4, Syngap1, Add1, Rab8b, Klc1, Chn1) and cellular metabolism (Akr1d1, Bcat1, Pkm).