GABA, Selank, and Olanzapine Affect the Expression of Genes Involved in GABAergic Neurotransmission in IMR-32 Cells.

Svetlana Limborska,Nikolay Myasoedov,Elena Filatova,Lyudmila Andreeva,Anelya Alieva,Anastasiya Kasian,Galina Pavlova,Ekaterina Rybalkina,Petr Slominsky,Timur Kolomin,Maria Shadrina

doi:10.3389/fphar.2017.00089

Abstract

Clinical studies have shown that Selank had an anxiolytic effect comparable to that of classical benzodiazepine drugs, which can enhance the inhibitory effect of GABA by allosteric modulation of GABAA receptors. These data suggest that the molecular mechanism of the effect of Selank may also be related to its ability to affect the performance of the GABAergic system. To test this hypothesis, we studied the changes in expression of 84 genes involved in the functioning of the GABAergic system and in the processes of neurotransmission in the culture of neuroblastoma IMR-32 cells using qPCR method. As test substances, in addition to Selank, we selected the major GABAA receptor ligand, GABA, the atypical antipsychotic, olanzapine, and combinations of these compounds (Selank and GABA; Selank and olanzapine). We found no changes in the mRNA levels of the genes studied under the effect of Selank. The combined effect of GABA and Selank led to nearly complete suppression of changes in expression of genes in which mRNA levels changed under the effect of GABA. When Selank was used in conjunction with olanzapine, the expression alterations of more genes were observed compared with olanzapine alone. The data obtained indicate that Selank has no direct effect on the mRNA levels of the GABAergic system genes in neuroblastoma IMR-32 cells. At the same time, our results partially confirm the hypothesis that the peptide may affect the interaction of GABA with GABAA receptors. Our data also suggest that Selank may enhance the effect of olanzapine on the expression of the genes studied.

Highlights

Drugs that are based on natural regulatory peptides are currently becoming more widely used
We studied the effects of Selank, Gamma-aminobutyric acid (GABA), olanzapine, as well as combinations of these compounds (Selank and GABA; Selank and olanzapine) on the changes of mRNA levels of the 84 genes involved in neurotransmission processes in nerve cells in the human neuroblastoma cell line IMR-32
This effect of the peptide is similar to that of classical benzodiazepine drugs (Seredenin et al, 1990, 1998), which can enhance the inhibitory effect of GABA by allosteric modulation of GABAA receptors

Summary

Introduction

Drugs that are based on natural regulatory peptides are currently becoming more widely used. Selank is a synthetic analog of the natural immunopeptide taftsin, belonging to a group of drugs of peptidic nature, and was developed at the Institute of Molecular Genetics of the Russian Academy of Sciences, in cooperation with the Zakusov Scientific Research Institute of Pharmacology. This peptide consists of the short fragment Thr-Lys-Pro-Arg of the heavy chain of the human immunoglobulin G and the tripeptide Pro-Gly-Pro at the end of the molecule, which provides metabolic stability and duration of action of the drug (Ashmarin et al, 2005; Ashmarin, 2007). The Selank action mechanism may be related to its ability to affect the performance of the GABAergic system

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Conclusion