Antistress Action of Melanocortin Derivatives Associated with Correction of Gene Expression Patterns in the Hippocampus of Male Rats Following Acute Stress.

Ivan B Filippenkov,Julia A Remizova,Natalia G Levitskaya,Svetlana A Limborska,Liya V Valieva,Elena A Sebentsova,Vasily V Stavchansky,Natalya Yu Glazova,Lyudmila V Dergunova,Nikolai F Myasoedov

doi:10.3390/ijms221810054

Abstract

Natural melanocortins (MCs) have been used in the successful development of drugs with neuroprotective properties. Here, we studied the behavioral effects and molecular genetic mechanisms of two synthetic MC derivatives-ACTH(4–7)PGP (Semax) and ACTH(6–9)PGP under normal and acute restraint stress (ARS) conditions. Administration of Semax or ACTH(6–9)PGP (100 μg/kg) to rats 30 min before ARS attenuated ARS-induced behavioral alterations. Using high-throughput RNA sequencing (RNA-Seq), we identified 1359 differentially expressed genes (DEGs) in the hippocampus of vehicle-treated rats subjected to ARS, using a cutoff of >1.5 fold change and adjusted p-value (Padj) < 0.05, in samples collected 4.5 h after the ARS. Semax administration produced > 1500 DEGs, whereas ACTH(6–9)PGP administration led to <400 DEGs at 4.5 h after ARS. Nevertheless, ~250 overlapping DEGs were identified, and expression of these DEGs was changed unidirectionally by both peptides under ARS conditions. Modulation of the expression of genes associated with biogenesis, translation of RNA, DNA replication, and immune and nervous system function was produced by both peptides. Furthermore, both peptides upregulated the expression levels of many genes that displayed decreased expression after ARS, and vice versa, the MC peptides downregulated the expression levels of genes that were upregulated by ARS. Consequently, the antistress action of MC peptides may be associated with a correction of gene expression patterns that are disrupted during ARS.

Highlights

Growing evidence suggests that acute/chronic stress leads to altered body homeostasis, resulting in physiological changes linked to serious health risks [1]
Vehicle-treated rats exposed to acute restraint stress (ARS) demonstrated a significantly increased time spent in enclosed sector-2 (p = 0.048; d = 0.96; Figure 1c), and the percentage of entries into enclosed sector-2 (p = 0.022; d = 1.47; Figure 1d), and marginally decreased time spent in enclosed sector-1 (p = 0.061; d = 0.81; Figure 1b) compared with non-stressed controls
Pretreatment with adrenocorticotropic hormone (ACTH)(6–9)PGP prevented ARS-induced behavioral alterations: time spent in enclosed sector-1 was significantly higher (p = 0.044; d = 1.05; Figure 1b), while time spent in enclosed sector-2 (p = 0.037; d = 1.12; Figure 1c) and the percentage of entries into enclosed sector-2 (p = 0.048; d = 1.45; Figure 1d) were significantly lower in the Stress + ACTH(6–9)PGP (STR-A)

Summary

Introduction

Growing evidence suggests that acute/chronic stress leads to altered body homeostasis, resulting in physiological changes linked to serious health risks [1]. Learning and memory, in animals and humans [2]. Acute stressful events can provoke cognitive dysfunction, and mood and anxiety disorders [3]. The search for ways to provide pharmacological correction of negative stress consequences is an important problem for modern neurobiology research. When developing anti-stress drugs, great importance is attached to the creation of medicines based on natural regulatory proteins and peptides [4,5,6]. Melanocortins (MCs) are a group of biologically active, endogenous peptides that are expressed within the central nervous system and in several peripheral tissues, including the skin, stomach, kidney, intestine, immunocompetent myeloid, and lymphoid cells [7,8]

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