Contribution of Sigma‐1 receptor to cytoprotective effect of afobazole

Abstract

Anxiolytic afobazole (5‐Ethoxy‐2‐[2‐(morpholino)‐ethylthio]benzimidazole dihidrochloride) has pronounced ligand properties toward Sigma‐1 receptor (σ1 receptor,SigmaR1) and MT 3 receptors. Our previous work demonstrated that afobazole possess cytoprotective effect in the in vitro model of menadione genotoxicity (Woods et al. 1997) through interaction with MT 3 receptor (Kadnikov et al. 2014). Present study utilized previously described models to address the contribution of SigmaR1 to cytoprotective action of afobazole. The reduction in afobazole cytoprotective effect observed after preincubation of cell suspension with selective SigmaR1 antagonist BD‐1047 revealed an important contribution of SigmaR1 in afobazole‐mediated effect. We confirmed our observation using selective SigmaR1 agonist PRE‐084. We conclude that pronounced cytoprotective effect of afobazole over PRE‐084 is likely achieved by additive SigmaR1 and MT 3‐mediated effects.

Chaperone Sigma1R mediates the neuroprotective action of afobazole in the 6-OHDA model of Parkinson’s disease

“…The development of Parkinson’s disease is accompanied by the increased production of quinone compounds, such as dopamine quinone 69,70 , as well as by oxidative stress 71,72 . The contribution of Sigma1Rs to the protective effect of afobazole in the model of menadione cytotoxicity was also previously reported by our group 39 .…”

“…The drug has affinity to Sigma1Rs (Ki = 5.9E-6 M) and regulatory sites of NQO2 (Ki = 9.7E-7 M) and MAO A (Ki = 3.6E-06 M) 38 . In vitro and in vivo experiments with afobazole revealed cytoprotective and neuroprotective properties of the drug 39–42 . Our recent results showed the ability of afobazole to prevent decreases in striatal dopamine in the model of 6-OHDA-induced parkinsonism 43 ; however, the role of the above mentioned molecular targets of afobazole has not been defined.…”

Asciminib Mitigates DNA Damage Stress Signaling Induced by Cyclophosphamide in the Ovary

“…Breast cancer cells (MCF7) cultured in 60 mm dishes were incubated for 60 min with the allosteric inhibitors Asciminib (0.5 μM) or GNF-2 (10 μM), and treated with 4-hydroperoxycyclophosphamide (OH-Cy) for 4 h. To prevent the occurrence of additional DNA damage, all subsequent procedures were conducted under dim light, as previously described [ 42 ]. The cells were washed with PBS twice, and 20 μL of each cellular lysate was mixed with 730 μL of 0.5% low-melting agarose solution.…”

“…Cover-slipped slides were placed on ice for 5 min, and the coverslips were then gently eliminated. We followed all of the steps as previously described in [ 42 ]. After washing with deionized water, the slides were transferred into an electrophoresis chamber filled with alkaline electrophoretic solution [ 42 ].…”

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

“…Afobazole has an affinity to chaperone Sigma1R (Ki = 5.9 µM) and regulatory sites of ribosyldihydronicotinamide dehydrogenase [quinone] (NQO2, Ki = 0.97 µM) and monoamine oxidase A (MAO-A, Ki = 3.6 µM) [ 74 , 75 ]. In vitro and in vivo experiments suggest a role of Sigma1R in the mechanisms of previously described cytoprotective [ 76 ] and neuroprotective [ 77 , 78 , 79 , 80 , 81 , 82 ] properties of afobazole. Afobazole restored DA content in the striatum of mice with unilateral intrastriatal 6-OHDA lesions [ 83 ].…”