Analysis of Cytoprotective Properties of Afobazole in Streptozotocin Model of Diabetes
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Bulletin of Experimental Biology and Medicine, Vol. 169, No. 6, October, 2020 PHARMACOLOGY AND TOXICOLOGY
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Analysis of Cytoprotective Properties of Afobazole in Streptozotocin Model of Diabetes
S. V. Ivanov, R. U. Ostrovskaya, A. V. Sorokina, and S. B. Seredenin Translated from Byulleten’ Eksperimental’noi Biologii i Meditsiny, Vol. 169, No. 6, pp. 727-731, June, 2020 Original article submitted February 28, 2020 Previous in vitro and in vivo studies revealed the neuroprotective effect of anxiolytic Afobazole. Based on similarities in the regulation of functions of neurons and β cells, we studied the effect of Afobazole on streptozotocin (STZ) model of type 2 diabetes in Wistar rats. Immunohistochemical analysis showed that the decrease in the number of β cells and a violation of their morphological structure caused by STZ were significantly alleviated by Afobazole administration (10 mg/kg orally for 28 days) to diabetic animals. A correlation between morphometric data and blood glucose level was revealed. A possible role of σ₁-receptors in the cytoprotective effects of Afobazole in respect to pancreatic β cells is discussed. Key Words: type 2 diabetes mellitus; Afobazole; σ₁-receptor; cytoprotection; β cells Published data demonstrate the physiological role of chaperone σ₁-receptors in cytoprotection mechanisms [2]. σ₁-Receptors bind various ligands, which contributes to their translocation to the membrane surface, where the chaperone function to the activity of important proteins is performed [8]. It was shown that σ₁receptor deficiency is a pathogenetic link in a number of neurodegenerative diseases, while their activation is associated with the neuroprotective effect. Anxiolytic Afobazole developed at the V. V. Zakusov Research Institute of Pharmacology binds among other targets to σ₁-receptors [2]. Afobazole induces translocation of σ₁-receptors to the membrane surface [13]. It was found in the in vitro model of Alzheimer’s disease that incubation of rat cortical neurons with Ab25-35 promotes an increase in the intracellular calcium concentration and accumulation of ROS, while addition of Afobazole to the incubation medium suppressed the development of these changes and reduces neuronal death [4]. Afobazole increases survival of glial cells, blocks ischemia-induced activation of astrocytes, and reduces manifestations of nitrosative stress on the model of ischemic stroke [5]. V. V. Zakusov Research Institute of Pharmacology, Moscow, Russia. Address for correspondence: [email protected]. R. U. Ostrovskaya
Experiments on isolated microglia cells showed that long-term ischemic exposure leads to cell death associated with increased expression of proapoptotic Bax and caspase-3 proteins and reduced expression of antiapoptotic Bcl-2 protein. Cells incubation with Afobazole reduced the expression of Bax and caspase-3 and increased the number of cells expressing Bcl-2 [4]. The dependence of the protective effects of Afobazole on σ₁-receptors was proved in experiments with their selective antagonists. The
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