Analysis of Quinone Reductase 2 Implication in Mechanism of Antiparkinsonian Action of Afobazole

Kadnikov, I. A.; Воронков, Д. Н.; Voronin, M. V.; Seredenin, S. B.

doi:10.1134/s1819712420010110

Cited by 4 publications

(4 citation statements)

References 47 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…In the model of Parkinson’s disease, we have shown neuroprotective effect of M-11 (7.5 mg/kg, i.p.) when the compound was administered over 14 days to ICR mice, starting on the day of 6-OHDA injection [ 74 ]. The neuroprotective effect of M-11 is consistent with the ability of the NQO2 inhibitor S29434 to prevent ROS production and cell death induced by paraquat in vitro and in vivo [ 100 , 105 ], as well as to exert a protective effect on dopaminergic neurons when incubated with the active metabolite of 1-methyl-4-phényl-1,2,3,6-tetrahydropyridine MPP+ [ 81 ].…”

Section: Discussionmentioning

confidence: 99%

“…Radioligand analysis (Eurofins Cerep) have indicated that compound M-11 interacts only with the NQO2 regulatory site (Ki = 0,39 μM) [ 68 ]. We have shown that M-11 inhibits NQO2 [ 71 ], and possesses cytoprotective [ 72 , 73 ] and neuroprotective [ 74 ] effects. Our experiments did not reveal any influence of M-11 on the effects related to the activity of homologous enzyme NQO1 ( Figure A1 ) [ 72 , 75 ].…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

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

Voronin

Kadnikov

Зайнуллина

et al. 2021

IJMS

View full text Add to dashboard Cite

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.

show abstract

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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

Voronin

Kadnikov

Зайнуллина

et al. 2021

IJMS

View full text Add to dashboard Cite

show abstract

“…Motor behavior was studied in male ICR mice utilizing a Rota-rod/RS LE 8500 apparatus (Panlab/Harvard apparatus, Barcelona, Spain). The rotarod test was performed as described previously [ 22 , 87 ]. Two training sessions spaced 24 h apart were performed to acclimate the experimental animals to the apparatus and to exclude hypodynamic animals from the study.…”

Section: Methodsmentioning

confidence: 99%

Deferred Administration of Afobazole Induces Sigma1R-Dependent Restoration of Striatal Dopamine Content in a Mouse Model of Parkinson’s Disease

Kadnikov

Verbovaya

Воронков

et al. 2020

IJMS

View full text Add to dashboard Cite

Previously, we demonstrated that the immediate administration of multitarget anxiolytic afobazole slows down the progression of neuronal damage in a 6-hydroxidodamine (6-OHDA) model of Parkinson’s disease due to the activation of chaperone Sigma1R. The aim of the present study is to evaluate the therapeutic potential of deferred afobazole administration in this model. Male ICR mice received a unilateral 6-OHDA lesion of the striatum. Fourteen days after the surgery, mice were treated with afobazole, selective Sigma1R agonist PRE-084, selective Sigma1R antagonist BD-1047, and a combination of BD-1047 with afobazole or PRE-084 for another 14 days. The deferred administration of afobazole restored the intrastriatal dopamine content in the 6-OHDA-lesioned striatum and facilitated motor behavior in rotarod tests. The action of afobazole accorded with the effect of Sigma1R selective agonist PRE-084 and was blocked by Sigma1R selective antagonist BD-1047. The present study illustrates the Sigma1R-dependent effects of afobazole in a 6-OHDA model of Parkinson’s disease and reveals the therapeutic potential of Sigma1R agonists in treatment of the condition.

show abstract

“…NQO2 was linked to the development of various diseases such as neurodegenerative disorders [ 3 , 6 , 7 , 8 , 9 ], malaria [ 10 ], glaucoma [ 11 ], COVID-19 [ 12 ] and various cancers. It is important to note that the role of NQO2 in cancer pathogenesis is still being discussed.…”

Section: Introductionmentioning

confidence: 99%

3-Arylidene-2-oxindoles as Potent NRH:Quinone Oxidoreductase 2 Inhibitors

et al. 2023

View full text Add to dashboard Cite

The enzyme NRH:quinone oxidoreductase 2 (NQO2) plays an important role in the pathogenesis of various diseases such as neurodegenerative disorders, malaria, glaucoma, COVID-19 and cancer. NQO2 expression is known to be increased in some cancer cell lines. Since 3-arylidene-2-oxindoles are widely used in the design of new anticancer drugs, such as kinase inhibitors, it was interesting to study whether such structures have additional activity towards NQO2. Herein, we report the synthesis and study of 3-arylidene-2-oxindoles as novel NRH:quinone oxidoreductase inhibitors. It was demonstrated that oxindoles with 6-membered aryls in the arylidene moiety were obtained predominantly as E-isomers while for some 5-membered aryls, the Z-isomers prevailed. The most active compounds inhibited NQO2 with an IC50 of 0.368 µM. The presence of a double bond in the oxindoles was crucial for NQO2 inhibition activity. There was no correlation between NQO2 inhibition activity of the synthesized compounds and their cytotoxic effect on the A549 cell line.

show abstract

Analysis of Quinone Reductase 2 Implication in Mechanism of Antiparkinsonian Action of Afobazole

Cited by 4 publications

References 47 publications

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

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

Deferred Administration of Afobazole Induces Sigma1R-Dependent Restoration of Striatal Dopamine Content in a Mouse Model of Parkinson’s Disease

3-Arylidene-2-oxindoles as Potent NRH:Quinone Oxidoreductase 2 Inhibitors

Contact Info

Product

Resources

About