Peptide Selank Enhances the Effect of Diazepam in Reducing Anxiety in Unpredictable Chronic Mild Stress

It was shown that the anxiolytic effect of Selank is comparable to that of classical benzodiazepine drugs and that the basis of their mechanism of action may be similar. These data suggest that the presence of Selank may change the action of classical benzodiazepine drugs. To test this hypothesis, we evaluated the anxiolytic activity of Selank and diazepam in rats both under conditions of unpredictable chronic mild stress and in its absence, after the individual and combined administration of these compounds using the elevated plus maze test. We found that, even in the absence of chronic stress, the administration of a course of test substances changed anxiety indicators toward their deterioration, but the changes after the administration of a course of Selank were less pronounced. In conditions of chronic stress, anxiety indicator values after the simultaneous use of diazepam and Selank did not differ from the respective values observed before chronic stress exposure. The data obtained indicate that the individual administration of Selank was the most effective in reducing elevated levels of anxiety, induced by the administration of a course of test substances, whereas the combination of diazepam with Selank was the most effective in reducing anxiety in unpredictable chronic mild stress conditions.

1. Introduction

A large number of stress factors of varying intensity influence people in modern society. Chronic stressful experiences lead to the development of neuropsychiatric disorders, especially anxiety disorders and depression [1].

Until recently, classical benzodiazepine drugs were widely used for the treatment of diseases such as neurosis, neurosis-like disorders (a group of neuropsychiatric disorders, which look like neurosis but are not caused by psychogenic effects, such as asthenic, phobic, monosymptomatic, motor, and somatic-vegetative syndromes), psychopathic conditions, and generalized anxiety disorders. Although these drugs have a strong protective effect under various stress loads, they have pronounced side effects. The basis of the mechanism of action of benzodiazepines (BZD), of which the reference representative drug is diazepam (DZ), is their ability to allosterically modulate GABAA receptors, thereby amplifying the effects of the inhibitory neurotransmitter gamma-aminobutyric acid (GABA) in the central nervous system (CNS) [2].

Currently, anxiolytic drugs are used increasingly often in clinical practice, including those based on endogenous regulatory peptides that possess a wide spectrum of activity and minimal side effects and do not cause addiction and withdrawal syndrome [3]. One such drug is Selank, the structure of which includes a short fragment (Thr-Lys-Pro-Arg) of the human immunoglobulin G heavy chain, which was elongated at the C terminus via the addition of three natural L-amino acids (Pro-Gly-Pro) to enhance its metabolic stability and the length of action of the drug [45]. Selank has a pronounced anxiolytic activity and sustained neuropsychotropic, antidepressant, and antistress effects and removes the reaction of aggression and fear [68].

Clinical studies have shown that the anxiolytic effect of Selank is comparable to the effect of low doses of the benzodiazepine tranquillizers; however, the action of Selank is not accompanied by the characteristic side effects of those drugs [910]. Furthermore, Selank affects the specific binding of GABA to GABAA receptors, which may be caused by a change in the affinity of endogenous ligand receptors under the action of Selank [11]. This suggests that the presence of Selank may change the action of classical BZD.

To test this hypothesis, we evaluated the anxiolytic activity of Selank and DZ in rats subjected to unpredictable chronic mild stress (UCMS) after the single and combined administration of these compounds.

2. Methods and Materials

2.1. Chemicals

Dry preparations of Selank (Nα-Thr-Lys-Pro-Arg-Pro-Gly-Pro-diacetate salt) and DZ (Sigma-Aldrich, USA) were dissolved to a concentration of 12 mg/ml and 20 mg/ml, respectively, in saline.

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