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

Preclinical animal study investigating behavioral and transcriptomic effects of synthetic melanocortin derivatives in rats under normal and acute restraint stress conditions.

“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.”

Male Wistar rats.

“Male Wistar rats weighing 220–250 g were obtained from the Stolbovaya Breeding Center (Moscow region, Russia).”

A total of 58 rats were used, divided into six experimental groups of 9–10 rats each for behavioral tests, with n=3 animals per group for RNA-Seq analysis.

“A total of 58 rats were used in this study.”

Behavioral testing occurred 4 hours after acute restraint stress termination, and hippocampal samples were collected 4.5 hours after stress termination.

“Four hours after ARS termination, the animals were subjected to the behavioral test (elevated zero maze) and then were euthanized 30 min later to collect hippocampal samples.”

Administration of Semax or ACTH(6–9)PGP 30 minutes before acute restraint stress attenuated stress-induced behavioral alterations in the elevated zero maze test.

“Administration of Semax or ACTH(6–9)PGP (100 μg/kg) to rats 30 min before ARS attenuated ARS-induced behavioral alterations.”

RNA-Seq analysis identified 1359 differentially expressed genes in the hippocampus of vehicle-treated rats subjected to acute restraint stress.

“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.”

Both peptides modulated gene expression associated with biogenesis, translation of RNA, DNA replication, and immune and nervous system function, often counteracting the expression changes induced by stress.

“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.”

The study analyzed only mRNA expression and did not include genome-wide analysis of noncoding RNAs.

“A limitation of our study is the analysis of the expression of only mRNAs; the genome-wide noncoding RNAs expression analysis may reveal some additional regulatory axes involved in the response after MC peptide administration under normal and ARS conditions.”