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.
Highlights
Epidemiological data indicate an increasing prevalence of neurodegenerative diseases, especially in countries with high life expectancy [1]
We used HT-22 cells treated with NQO2 endogenous substrate adrenochrome and co-substrate BNAH as an in vitro model for NQO2-mediated reactive oxygen species (ROS) production, since HT-22 cells express NQO2 [82] (Figure S1) and NQO2 has been shown to be capable of producing ROS in reaction with the aforementioned substrate and co-substrate [43]
Pre-incubation of cells for 30 min with M-11 or S29434 prevented the oxidative stress caused by 15 min incubation with adrenochrome (125 μM) and BNAH (100 μM) in a concentration-dependent manner (Figure 3)
Summary
Epidemiological data indicate an increasing prevalence of neurodegenerative diseases, especially in countries with high life expectancy [1]. Pathogenesis of Alzheimer’s, Parkinson’s and Huntington’s diseases include imbalance of cellular bioenergetics, increased ROS production, protein misfolding resulting in neuron and glial cells loss, synaptic deterioration and decreased neuroplasticity [2,3,4], which determine physiological function impairment and clinical symptoms [5]. Extensive information on natural and synthesized antioxidant use for central nervous system disease treatment has been accumulated [13,14]. Their pharmacotherapeutic use requires further elaboration based on the study of pathogenetic mechanisms [15,16]
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