Selank Administration Affects the Expression of Some Genes Involved in GABAergic Neurotransmission. (2016)

Full Study: http://journal.frontiersin.org/article/10.3389/fphar.2016.00031/full

Our results suggest that Selank is able to directly influence the expression of genes involved in neurotransmission in nerve cells, and similar changes in the expression of these genes are also observed when GABA is administered. This is supported by the strong positive correlation between the changes in the expression of 45 genes 1 h after the Selank or GABA administration. However, the match between the expression profiles of these genes is not perfect. Thus, in addition to the 25 genes affected by either of the test compounds, GABA but not Selank affected the mRNA level of another 16 genes 1 h after administration. This difference in the number of genes whose expression changed suggests that Selank acts not directly through the center of the specific binding of GABA, but rather allosterically by altering the affinity of the GABA receptor for GABA. Previously, it was shown that Selank is able to affect the specific binding of GABA to its own receptors, which may be caused by modulating properties of regulatory peptide, which apparently change the affinity of endogenous ligands under the influence of Selank on the receptor (V'Yunova et al., 2014). We can assume that the observed similarity of expression profiles of our study genes after administration of Selank and GABA partly confirms the hypothesis about the possible effect of the peptide through the regulation of the activity of GABAA receptors.

Interestingly, the mRNA levels of four genes (Drd1a, Drd2, Ptgs2, and Slc6a13) altered only under the influence of Selank at the 1-h time point. Intriguing results were obtained in relation to Slc6a13, which encodes the low-affinity transporter of the GABA GAT-2. GAT-2 plays a key role in peripheral mechanisms involved in the work of GABAergic system and is also responsible for the redistribution and metabolism of drugs, which can affect the operation of the GABAergic system (Schlessinger et al., 2012). Thus, activation of the carrier only after exposure to Selank suggests the presence of an alternative path of action of the peptide on the distribution of peripheral GABA. Drd2 and Drd1a encode dopamine receptors, which are associated with G-protein and are involved in the regulation of adenylate cyclase activity, thereby mediating intracellular signal transduction (Beaulieu and Gainetdinov, 2011). The activation of Drd5 expression at the 3-h time point was observed only for Selank. Drd5 encodes the dopamine receptor, which plays a key role in the formation of memory and learning processes by ensuring long-term potentiation (Beaulieu and Gainetdinov, 2011). Activation of this gene by Selank at early and later times suggests an ability of the peptide to influence processes involved in synaptic plasticity and thereby render nootropic action. It has been shown previously that Selank modulates dopamine and serotonin receptors, which play a role in the stimulation of mental activity and in the pathogenesis of anxiety (Meshavkin et al., 2006).

Of particular interest is the significant change in the mRNA level of Hcrt 3 h after Selank administration. This gene encodes a precursor of orexins and is involved in the regulation of the balance between sleep and wakefulness (Ohno and Sakurai, 2008). Kolomin et al. have shown that the mRNA level of the Hcrt increases after a single administration of Selank (Kolomin et al., 2013). The presence of this significant effect of Selank suggests that the peptide has an active effect on the balance between sleep and wakefulness, and that the change in the expression of Hcrt may be in the foundation of the normalizing effect Selank has on the balance of sleep patterns in patients with general anxiety disorders. The observed changes may also explain the lack of hypnosedative action of Selank, which is common for classical benzodiazepines, because of the shift in the balance toward wakefulness.

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