Neuroprotective properties of quinone reductase 2 inhibitor M-11, a 2-mercaptobenzimidazole derivative

Abstract

The ability of NQO2 to increase the production of free radicals under enhanced generation of quinone derivatives of catecholamines (doi:10.1124/molpharm.120.000105) is considered to be a component of neurodegenerative disease pathogenesis (doi:10.1016/j.freeradbiomed.2018.03.002). 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, apop-tosis and lesion of nuclear DNA were evaluated using flow cytometry and single-cell gel electro-phoresis 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 trig-gered 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 per-centage reduction. The obtained results provide a rationale for further development of the M-11 compound as a potential neuroprotective agent.